Early age onset_colorectal_cancer_2015

Increase in incidence of colorectal cancer
among young adults in the US
Rebecca Siegel, MPH
Surveillance & Health Services Research Program
March 21, 2015

Among <50 years: 13,000 cases and 3,000 deaths
Estimated numbers of new cases & deaths in 2015

Top 5 cancers, ages 20-49 years
Lung (18%)
Colorectum (12%)
Brain (8%)
Leukemia (7%)
Pancreas (5%)
Breast (26%)
Lung (15%)
Colorectum (8%)
Cervix uteri (7%)
Ovary (5%)
Colorectum (10%)
Testis (9%)
Prostate (9%)
Melanoma (8%)
NHL (7%)
Incidence Mortality
Breast (36%)
Thyroid (12%)
Melanoma (7%)
Colorectum (5%)
Cervix uteri (5%)
Men Women Men Women

Anatomy of the colorectum
(right-sided colon)
(left-sided colon)

Subsite distribution by age at diagnosis
0-49 years 50+ years
Proximal 25% 43%
Distal 27% 23%
Rectum 41% 28%
Other 8% 6%
Right side
Left side

0
50
100
150
200
250
300
350
400
Age-specificincidencerateper100,000
Age at diagnosis
Men
Women
Source: SEER 18 registries, 2007-2011.
Age-specific incidence rates by sex
90% of cases
20-49 years: 11 per 100,000
vs.
50+ years: 140 per 100,000

0
10
20
30
40
50
60
70
1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Rateper100,000
Year of diagnosis
Colorectum, 3% per year
Colon, 3% per year
Rectum, 2% per year
Incidence trends overall, 1975-2011
Declines during 2002-2011:

The American Surgeon, Oct
2003
SEER 9, 5,383 patients 20-39 yrs
1973-1999
Cancer Epidemiol, Biomarkers, &
Prevention, June 2009
SEER 13, 20,646 patients 20-49 yrs
1992-2005
The American Surgeon, Sept
1998
LSU Medical Ctr, 37 patients < 40
1976-1997
Awareness of the increase in early-onset disease

Incidence trends by age: 50+ versus 20-49
Source: SEER 9 registries, 1975-2011; 2-yr moving average.
0
2
4
6
8
10
12
14
1975-
76
1980-
81
1985-
86
1990-
91
1995-
96
2000-
01
2005-
06
2010-
11
Rateper100,000
Men
Women
45%
2% per year
Since 1993-1994
0
50
100
150
200
250
300
1975-
76
1980-
81
1985-
86
1990-
91
1995-
96
2000-
01
2005-
06
2010-
11
Rateper100,000
Men
Women
Ages 50+ Ages 20-49

Trends by anatomic subsite in ages 20-49
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Rateper100,000
2.6 in 1991
4.9 in 2011
Proximal colon
Rectum
Distal colon

Incidence trends by stage at diagnosis, ages 20-49 years
Source: SEER 9 registries, 1975-2011; 2-year moving average.
0
0.5
1
1.5
2
2.5
3
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Colon
Localized
Regional
Distant
0
0.5
1
1.5
2
2.5
3
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Rectum
Localized
Regional
Distant
Rateper100,000
3.6% per year from
2002-2011
2.9% per year
from 2002-2011

Trends by histologic subtype, 20-49 years
Mucinous
Signet-ring cell
Adenocarcinoma, NOS
Source: SEER 9 registries and Joinpoint Regression Program.

Incidence trends by 10-year age group
40-49
2% per year
30-39
2% per year
20-29
3% per year
0
5
10
15
20
25
30
1975-
76
1980-
81
1985-
86
1990-
91
1995-
96
2000-
01
2005-
06
2010-
11
Rateper100,000people
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
20-29 years
20-29 years
5%
30-39 years
20%
40-49 years
75%
Increase during 2002-2011:

Incidence trends in ages 50-59 years
0
5
10
15
20
25
30
35
40
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Rectum
55-59
50-54
0
10
20
30
40
50
60
70
80
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11
Rateper100,000
Colon
50-54
55-59
2.4% per year
since 1996

Incidence trends by race/ethnicity, ages 20-49 years
0
2
4
6
8
10
12
14
Non-Hispanic white
Colon and
Rectum
Colon
Rectum
0
2
4
6
8
10
12
14
1992-93
1994-95
1996-97
1998-99
2000-01
2002-03
2004-05
2006-07
2008-09
2010-11
Non-Hispanic
black
0
2
4
6
8
10
12
14
1992-93
1994-95
1996-97
1998-99
2000-01
2002-03
2004-05
2006-07
2008-09
2010-11
Asian/Pacific
Islanders
0
2
4
6
8
10
12
14
1992-93
1994-95
1996-97
1998-99
2000-01
2002-03
2004-05
2006-07
2008-09
2010-11
Hispanic
Colorectal Colon Rectum
Non-Hispanic white 2.3 1.6 3.4
Hispanic 2.1 2.0 2.2
Asian/Pac Islander 0.7 0.8 stable
Non-Hispanic black stable stable 1.9
Average annual % increase from 2002-2011:
Source: SEER 13 registries, 1992-2011; 2-year moving average. AAPCs based on Joinpoint Regression Program.

Stage distribution: early vs. later onset
33%
38%
25%
3%
41%
34%
19%
6%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Localized Regional Distant Unknown
20-49 years 50+ years

Five-year relative survival
Data Source: Trends, SEER 9 registries; Stage-specific, SEER 18 registries, 2007-2011.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
55%
68%
Trend
94
76
19
90
70
12
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Localized Regional Distant
20-49 years
50+ years
By stage

Mortality trends in ages 20-49 years
0
0.5
1
1.5
2
2.5
3
3.5
4
Deathsper100,000
20-49 years
Source: National Center for Health Statistics, National Vital Statistics System.
0
20
40
60
80
100
120
50+ years

Factors that influence population cancer trends
Detection/imaging
practices
Risk factors
Screening behaviors MortalityIncidence
Treatment
Increase in: Incidence Mortality
Risk factor ↑ ↑
Screening ↑ ↓
Detection/imaging practice ↑ Possible artifactual ↑
Effective treatment No effect ↓

Colorectal cancer risk factors: medical and family history
Relative risk
Family history
1 first-degree relative 2.2
More than 1 relative 4.0
Relative with diagnosis
before age 45
3.9
Medical history
Inflammatory bowel disease
Crohn disease 2.6
Ulcerative colitis
Colon 2.8
Rectum 1.9
Diabetes 1.2

Increase risk: Relative risk Trend
Alcohol consumption (heavy vs.
nondrinkers)
1.6
Obesity 1.2
Red meat consumption 1.2
Processed meat consumption 1.2 ?
Smoking (current vs. never) 1.2
Colorectal cancer risk factors: behavioral
Decrease risk: Relative risk Trend
Physical activity (colon) 0.7
Milk/total dairy consumption 0.8
Fruit consumption 0.9 ?
Vegetable consumption 0.9 ?
Total dietary fiber (10 g/day) 0.9 ?

Trends in obesity and diabetes
0
5
10
15
20
25
1971-74 1976-80 1988-94 1999-02 2003-06 2007-08 2009-10 2011-12
Percent
Ages 6-11
Ages 12-19
6%
Obesity prevalence
6
16
0
2
4
6
8
10
12
14
16
18
20
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
Rateper1,000
167%
Diabetes, ages 0-44 years
21%
Source: National Health and Nutrition Examination Survey. Source: National Health Interview Survey.

Obesity and colorectal cancer: pooled relative risk
Ning et al. A quantitative analysis of body mass index and colorectal cancer: findings from 56 observational studies. Obesity
Reviews 2010.
Relative risk (95% CI)
BMI
<23.0
BMI > 30
Subsite Colon 1.0 1.49 (1.35,
1.63)
Rectum 1.0 1.26 (1.17,
1.37)
Sex Men 1.0 1.53 (1.44,
1.62)
Women 1.0 1.25 (1.14,

Trends in beverage consumption
Nielsen et al. Changes in beverage intake between 1977 and 2001. Am J Prev Med 2004.
0
2
4
6
8
10
12
14
2-18 yrs 19-39 yrs 2-18 yrs 19-39 yrs
Sweetened beverages Milk
Percentoftotaldailycalorieintake
1977-78
1989-91
1994-96
1999-01

State patterns in obesity and CRC incidence rates
Obesity prevalence, ages 18-49, 2001 CRC incidence rates, ages 20-49, 2007-2011
Pearson’s r = 0.57
Source: Behavioral and Risk Factors Surveillance System Source: US Cancer Statistics, WONDER Online Database

Most colorectal cancers are due to unknown risk factors
Source: The Cancer Atlas, 2nd Edition
Up to 87% of colorectal cancers worldwide are
due to unknown risk factors.

Strategies for reducing colorectal cancer risk
 Maintain a healthy weight
 Be physically active
 Consume a healthy diet
 Limit alcohol consumption
 Consume recommended levels of calcium
 Avoid tobacco products
 Screening at 50, OR earlier with a family history of
adenomas or CRC

Who should begin screening before 50?
High risk Age to begin
Familial adenomatous polyposis (FAP) 10-12 years
Lynch syndrome 20-25 years*
Inflammatory bowel disease
(ulcerative colitis or Crohn disease)
Varies depending on
age at onset
*Or 10 years before youngest case in immediate family

Who else should begin screening before 50?
Increased risk Age to begin
Cancer/adenomas in a first-degree
relative
40 years OR
10 years before
youngest case
Cancer in > 2 second-degree relatives 40 years

Conclusions
• CRC incidence rates continue to increase in young adults
• Know when to begin screening based on your family history
• Increase awareness to hasten follow-up of symptomatic young adults
1. Rectal bleeding
2. Abdominal pain
3. Change in bowel habits
• Critical need for further research to elucidate the cause of this trend

Acknowledgements
• Kim Miller, MPH
• Ann Goding-Sauer, MPH
• Stacey Fedewa, MPH

American Cancer Society CRC screening guidelines
• Increase unestablished during previous evidence review
• In beginning stages of guideline review; independent, systematic review of
the literature, including harms & benefits of screening
• Current evidence may justify earlier screening
• Benefits must outweigh harms at the population level
 rare before 50 (0.3%)
 3 serious adverse events (perforation, adverse reaction to sedation) per 1,000
colonoscopies
 cost

Percentage of individuals who develop CRC by specific age
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
3.00%
3.50%
4.00%
4.50%
5.00%
15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 95+
Age (years)

Harms & limitations of colonoscopy screening
• 33% of patients report at least 1 GI symptom following the
procedure
• Serious adverse event rate: 2.8 per 1,000
• Adverse reaction to the sedative
• Bleeding if a polyp or tissue sample is taken
• Perforation of the colon wall
• Screening won’t detect all cancers

0
2
4
6
8
10
12
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
20-49
Canada_20_49
UK_20_49
0
20
40
60
80
100
120
140
160
180
200
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
50-85+
Canada_50plus UK_50plus
Incidence trends in Canada and the UK by age,
through 2007

Screening test use in ages 40-49 years
0
2
4
6
8
10
12
14
2000 2003 2005 2008 2010 2013
Ever routine endoscopy
0
2
4
6
8
10
12
14
2000 2003 2005 2008 2010 2013
Ever diagnostic endoscopy
Source: NHIS

US meat consumption per person, 1909-2012

Defining Body Mass Index (BMI)
Weight
(kg)
Height
(m)2
BMI =
For children & adolescents, obesity is
defined as a BMI > the 95th percentile
based on age/sex-specific growth
charts developed by CDC

40-49
30-39
20-29
Incidence trends by age group and subsite
0
2
4
6
8
10
12
14
16
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Colon
0
2
4
6
8
10
12
14
16
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Rectum
Rateper100,000
40-49
3%
per
year
2%
per
year
20-29
30-39

State variation in incidence rates by age
50+ years20-49 years

What is a colon adenomatous polyp?
Polyps begin in the cells of glandular
structures lining the colon. Most polyps are
benign, but one kind is the cause of greater
concern–the colon adenomatous polyp
(adenoma). This growth is associated with
DNA changes in the lining of the colon. Polyps
can become cancerous if undetected or
ignored.

ACS screening guidelines – average risk
Men and women, ages 50+ Frequency
Fecal occult blood test (FOBT)
with at least 50% test
sensitivity for cancer, or fecal
immunochemical test (FIT) with
at least 50% test sensitivity for
cancer
Annual
Stool DNA test Every 3 years
Flexible sigmoidoscopy Every 5 years
Double contrast barium enema Every 5 years
Colonoscopy Every 10 years
CT colonography Every 5 years

Trends in the use of screening tests (ages 50-75)
0
10
20
30
40
50
60
70
80
2000 2003 2005 2008 2010 2013
Percentage
Any exam
Colonoscopy (10 yrs)
FOBT (past year)
Sigmoidoscopy (5 yrs)

Changes in dietary patterns
Then…

THE CLINICAL CHALLENGES OF EAO-
CRC :
REDUCING LATE STAGE DIAGNOSIS;
IMPROVING SURVIVAL
Y. Nancy You, MD, MHsc
Assistant Professor
Department Of Surgical Oncology
Medical Director
Familial High-risk Gastrointestinal Cancer Clinic
University Of Texas MD Anderson Cancer Center
March 21, 2015

• Persistently increasing incidence
• Majority between ages of 40-49
• Predominately located in distal colon and rectum
• Advanced-stage disease at presentation
CLINICAL CHALLENGES OF EAO-CRC
UNIQUE FEATURES OF EAO-CRC: SUMMARY

39 year-old dental hygienist
Single mother; estranged family
Grandmother, colon cancer in
60’s
Intermittent rectal bleeding > 1
year
ER visit x 3, no work-up
AN ILLUSTRATION

COLORECTAL CANCER TRENDS
39 YEAR-OLD, STAGE IV RECTAL CANCER
5/year 0
Chemo
10-12/year0
Liver
surgery
#1
Liver
surgery
#2
Chemo +
Radiation
5/year 1 11/year 1
Rectal
surgery
#1
Chemo
Rectal
surgery #2;
Liver
surgery #3
8/year 3 –
3/year 4
Chemo Chemo
Hospice
2/year 2

OUTLINE
• What are the clinical challenges ?
• How can we improve ?

WHAT ARE THE CHALLENGES
 Interrupts adulthood
 Stresses support network
 Hereditary? Genetic?
 Delay in self referral
 Variable access to care
 Late-stage at diagnosis
39 year-old dental hygienist
Single mother; estranged
family
Grandmother, colon cancer in
60’s
Intermittent rectal bleeding >
1 year
ER visit x 3, no work-up

WHAT ARE THE CHALLENGES
 Multiple treatments
 Many modalities
 Long time
 Treatment-related
toxicities/adverse effects
 Variable survival outcome
 Quality of survival
5/year 0
Chemo
10-12/year0
Liver
surgery
#1
Liver
surgery
#2
Chemo +
Radiation
5/year 1 11/year 1
Rectal
surgery
#1
Chemo
Rectal
surgery #2;
Liver
surgery #3
8/year 3 –
3/year 4
Chemo Chemo
Hospice
2/year 2

OUTLINE
• Focusing on Survival
• How can we improve ?

Bleyer et al. Nature Reviews Oncology. 2007.
SURVIVAL : SEER 1993-1998

OUTLINE
Focusing on Survival
• What influences survival and how can we improve ?
 Stage of disease
 Treatment
 Quality of life

You et al. Arch Int Med.
NCDB, 1998-2007
Age 18-49 Years (N=64,068) vs. Age 50+ Years (N=524,801)

Age-adjusted CRC death
rate has declined between
1975-2005
Factors thought to contribute to the
decline in death rate:
AGE-ADJUSTED DEATH RATE: DECLINED 1975-2005

All CRC
~ 5%
“Hereditary”
Burt et al. Gastroenterology 2000.
SUBGROUPS OF CRC & SCREENING GUIDELINES
3-5%

All CRC
~ 5%
“Hereditary”
Start Frequency
High Risk
(“Heredita
ry”)
Hereditary
syndromes;
Inflammatory
bowel
syndrome etc
Teen-25;
8 years of
disease
Every 1-2
years
Increased
Risk
(“Familial
”)
Family history;
Prior polyp or
cancer
Age 40, or 10
years before the
youngest case in
the immediate
family,
Every 3-5
years
Average
Risk
(“Sporadi
Age 50 Every 7-10
years
American Cancer Society

You et al. ASCRS Annual Meeting 2013.
• 223 CRC patients aged 18-50
• Stratify by Tumor mismatch repair (MMR) status & Family history
APPLYING TO EAO-CRC SUBGROUPS

All CRC
~ 5%
“Hereditary”
Goal
High Risk
(“Hereditary”)
Defined and effective
prevention, surveillance
strategies exist
Make the diagnosis
• Clinical suspicion
• Proband and family
diagnosis /Registry

Ampullary,
Pancreas,
Hepatoblastoma
Colon and
Rectum
Familial Adenomatous Polyposis Surveillance
Thyroid
Brain
Desmoid
/
Why Hereditary Syndrome Should Not Be Missed

Biliary,
Pancreas
Colon and
Rectum
Lynch Syndrome Surveillance
UrinaryTract
Brain
Skin
Uterine &
Ovary
Why Hereditary Syndrome Should Not Be Missed

All CRC
~ 5%
“Hereditary”
Goal
High Risk
(“Hereditary”)
Defined and effective
prevention, surveillance
strategies exist
Make the diagnosis
• Clinical suspicion
• Proband and family
diagnosis /Registry
Increased
Risk
(“Familial”)
Guidelines for
screening younger
than age 50 exist
Know family history
Engage in screening
Average Risk
(“Sporadic”)
Symptom to diagnosis
time

OUTLINE
• What influences survival and how can we improve ?
 Stage of disease
 Treatment
 Quality of life

THE IMPACT OF YOUNG AGE ON SURVIVAL IN
PATIENTS WITH METASTATIC COLORECTAL
CANCER: ANALYSIS FROM THE ARCAD
CLINICAL TRIALS PROGRAM
CHRISTOPHER H. LIEU, LINDSAY RENFRO, AIMERY DE
GRAMONT, TIMOTHY S. MAUGHAN, MATTHEW T.
SEYMOUR, LEONARD SALTZ, RICHARD M. GOLDBERG,
DAN SARGENT, S. GAIL ECKHARDT, CATHY ENG
75
Courtesy of Dr Cathy Eng
SAME TREATMENT, WORSE OUTCOME ?
Lieu et al. JCO 2014

Overall Survival
Age in Years
RelativeHazard
1.0
1.2
1.4
1.6
1.8
20 40 60 80
p < 0.0001
Progression-Free Survival
Age in Years
RelativeHazard
1.0
1.1
1.2
1.3
1.4
20 40 60 80
20,000 patients enrolled to 22 first-line phase III trials
ARCAD Foundation Colorectal Database
OS 1-year: 28% increased risk
of death (REF: age 57)
p < 0.0001
PFS 1-year: 28% increased risk
of progression (REF: age 61)
Lieu et al. JCO 2014

You et al. In Press JAMA Surgery
NCDB,
2003 to 2005
OR for
Chemo
(95% CI)
OR for Multi-
agent
regimen
(95% CI)
5-year
Adjusted
Relative
Survival (No
chemo)
5-year
Adjusted
Relative
Survival
(Chemo)
Stage I
Aged 65-75
(n=8,991)
1 1 96.8 --
Aged18-49
(n=1,926)
2.88
(2.21-3.77)
1.38
(0.71-2.68)
98.4 --
Stage II low risk
Aged 65-75
(n=4822)
1 1 89.2 95.4
Aged18-49
(n=1636)
4.22
(3.70-4.81)
1.67
(1.34-2.09)
93.3 95.2
OVER-TREATMENT, NO BETTER OUTCOME ?

NCDB,
2003 to
2005
OR for
Chemo
(95% CI)
OR for Multi-
agent
regimen
(95% CI)
5-year Adjusted
Relative
Survival (No
chemo)
5-year
Adjusted
Relative
Survival
(Chemo)
Stage II high risk
Aged 65-75
(n=6189)
1 1 74.6 85.8
Aged18-49
(n=1447)
3.69
(3.23-4.20)
1.77
(1.46-2.14)
78.9 87.7
Stage III
Aged 65-75
(n=11202)
1 1 39.1 71.0
Aged18-49
(n=4780)
2.42
(2.18-2.68)
1.75
(1.58-1.93)
54.7
0.64(0.57-0.71)
73.7
0.84(0.79-0.9)
OVER-TREATMENT, NO BETTER OUTCOME ?
You et al. In Press JAMA Surgery

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0%
Benefits
Positive feelings
Family distress
Recurrence distress
Appearance concerns
Financial problems
Sexual dysfunction
Sexual disinterest
Social avoidance
Fatigue
Physical pain
Cognitive problems
Negative feelings
QUALITY OF LIFE IN ADULT CANCER SURVIVORS (QLACS)
% of Scores ≥ 4 per Domain
YS LS
• 830 (68%) survivors responded
• 282 Young-onset (43.4 ± 6.1 years)
• 548 Later-onset (62.6 ± 7.5 years)
• Mean years from diagnosis: 10.8 years*
*
*
*
*
*
*
*

EORTC CR-29 (SCORE > 3)
*P<0.05
34.2
19.5
57.3
23.0
20.5
13.4
40.2
16.4
0 10 20 30 40 50 60 70
* Anxiety
* Body image
* Male sexual function
* Female sexual function
Percent of Respondents Reporting Score > 3
Young-Onset Survivors Late-Onset Survivors
FUNCTIONAL OUTCOMES & CANCER SURVIVORSHIP

SUMMARY
• Key challenge : improve survival
• Factors that influence survival
Stage of disease :
 Reduce late-stage diagnosis
Treatment :
 Optimize benefit (response) vs. risk
(toxicity)
Quality of life :
 Maximize quality

THANK YOU
ynyou@mdanderson.org
THE CLINICAL CHALLENGES OF EAO-CRC :
REDUCING LATE STAGE DIAGNOSIS;
IMPROVING SURVIVAL

Hereditary Colorectal Cancer
Syndromes and the Contribution
to Early Age Onset Colorectal
Cancer
Fay Kastrinos MD, MPH
Columbia University Medical Center
Herbert Irving Comprehensive Cancer Center
Hereditary GI Cancer Risk and Prevention Program, Director

Sporadic
(~75%)
Familial
colorectal cancer
(~20%)
Inherited colorectal cancer
syndromes (~5%)
Epidemiology of
Colorectal Cancer

Hereditary Colorectal Cancer
Syndromes
• Lynch Syndrome/ Hereditary
Nonpolyposis Colorectal Cancer (HNPCC)
• Familial Adenomatous Polyposis (FAP)
• MYH Associated Polyposis (MAP)
• Hamartomatous Polyposis Syndromes

Genes Associated with a
High Risk of Colorectal Cancer
Gene Syndrome Hereditary Pattern Predominant Cancer
Tumor suppressor genes
APC FAP/ Attenuated
polyposis
Dominant Colon, intestine, etc.
STK11 Peutz-Jeghers Dominant Multiple (including intestine)
PTEN Cowden Dominant Multiple (including intestine)
BMPR1A Juvenile polyposis Dominant Gastrointestinal
SMAD4 (DPC4) Juvenile polyposis Dominant Gastrointestinal
Repair/Stability genes
hMLH1, hMSH2, hMSH6,
PMS2
Lynch Dominant Multiple (including colon, uterus, and
others)
MYH (MutYH) Attenuated polyposis Recessive Colon

How common is CRC in adults
younger than 50?
• ~10% of CRCs arise in men and women <50
yrs
140,000 new cases, 2014
• Incidence in US is 7 per 100,000 people/year
(<50) vs 130 per 100,000 people/year (≥50)
14,000
10% <50 years

How common are inherited CRC
syndromes in EAO-CRC?
• ~10% of EAO-CRC is attributed to known
inherited CRC syndromes
– 14,000 ~1,400 total cases
• Likely underestimated
– This has not been comprehensively studied
• What about the pool of “at-risk” individuals?
10%

Lynch Syndrome
 Most prevalent hereditary CRC syndrome
 5% of all CRC
 Defective DNA Mismatch Repair
 Mutations in MLH1, MSH2, MSH6, PMS2
 Lifetime risk of CRC ~60%; endometrial cancer ~40-
60%
 Risk is markedly lower if colonoscopies begin early

Lynch Syndrome Results
From Failure of Mismatch
Repair (MMR) Genes
Base pair
mismatch
Normal
DNA repair
Defective DNA
repair (MMR+)
T CTA C
A G C T G
T C G A C
A G C T G
T CTA C
A G C T G A G A T G
T C T A C

Mismatch Repair Failure Leads
to Microsatellite Instability (MSI)
Normal
Microsatellite
instability Addition of
nucleotide repeats

Lynch Syndrome Clinical
Features
 Striking family history affecting
multiple generations
 Early (but variable) age at CRC
diagnosis (mean 45 years)
 Multiple primary cancers
 Extracolonic cancers:
 Endometrium
 Ovary
 Urinary tract
 Stomach
 small bowel
 sebaceous carcinomas of skin

Lynch Syndrome
• Sine qua non is identification of a germline mutation
• Families originally identified based
on Amsterdam Criteria (AC-I)
• ≥ 3 cases of CRC
• ≥ 2 generations affected
• at least one CRC< 50 years
• no evidence of FAP
• 50% of AC-I families do not have a MMR mutation
• Testing only those who meet AC fails to detect 50%

Clinical Criteria for the Identification of
Lynch Syndrome
• Revised Bethesda Guidelines
– Incorporates MSI testing, extracolonic cancers
– Cumbersome criteria to apply regularly which makes
uptake low
– Testing those who meet any of the Bethesda criteria would
fail to detect 30% of gene mutations carriers

Lynch syndrome and EAO-CRC
• Lynch syndrome accounts for 3-4% of ALL
CRCs, regardless of ages
• What % of EAO-CRC is due to Lynch
syndrome?
• Few studies have examined random samples
of the prevalence among CRC patients <50
years

• US study examining the prevalence of Lynch
syndrome
– Unselected, population-based sample
– Young-onset CRC cases diagnosed <50 years
– Identified through the CCFR
• Results: 195 eligible subjects
– Mean age of diagnosis: 43 years
– 5.6% (11/195) had MMR gene associated with
Lynch syndrome
Limburg PJ et al. Clin Gastroenterol Hepatol. 2011;9(6):497-502

• Spanish study examining the prevalence of
Lynch syndrome
– Unselected, population-based sample
– Young-onset CRC cases diagnosed <50 years
– Identified through 2 surgical centers in Spain
• Results: 140 eligible subjects
– Mean age of diagnosis: 44.1 years
– 7.8 (11/140) had MMR gene associated with
Lynch syndrome
Giraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.

Summary of Lynch syndrome and
contribution on EAO-CRC
• 3-4 % of all CRCs, regardless of age, are due
to Lynch syndrome
• 6-8% of EAO-CRC are due to Lynch syndrome
• Largest impact for at-risk individuals
– Early identification of mutation carriers prevents
cancer

Hereditary GI Cancer Syndromes:
How good are we at identifying
families with germline mutations?
Proband
HEREDITARY GI CANCER SYNDROME
Germline Testing
Pedigree
Clinical Criteria
+/- tumor testing
+
?

Hereditary GI cancer syndromes:
What have we learned from
clinical genetic testing?
• Ability to define new conditions from
existing ones
• Familial Colorectal Cancer Type X
• Identification of new gene mutations
• MYH associated polyposis

Original Contribution. JAMA. 2005;293(16):1979-1985.
Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch
Repair Deficiency: Familial Colorectal Cancer Type X
Noralane M. Lindor, MD; Kari Rabe, MS; Gloria M. Petersen, PhD; Robert Haile, PhD; Graham Casey,
PhD; John Baron, MD; Steve Gallinger, MD; Bharati Bapat, PhD; Melyssa Aronson, MSc, CGC; John
Hopper, PhD; Jeremy Jass, MD; Loic LeMarchand, MD, PhD; John Grove, PhD; John Potter, MD, PhD;
Polly Newcomb, PhD; Jonathan P. Terdiman, MD; Peggy Conrad, MS; Gabriella Moslein, MD; Richard
Goldberg, MD; Argyrios Ziogas, PhD; Hoda Anton-Culver, PhD; Mariza de Andrade, PhD; Kim Siegmund,
PhD; Stephen N. Thibodeau, PhD; Lisa A. Boardman, MD; Daniela Seminara, PhD, MPH
Ability to define new conditions from
existing ones

• Families fulfill AC-I criteria
– Suspected Lynch syndrome but no mutation
• Lower CRC incidence than Lynch syndrome
– SIR 2.3 (1.7-3.0) vs SIR 6.1 (5.2-7.2)
• Incidence may be lower for other cancers
• Families should not be described or counseled
as having Lynch syndrome
• Lynch Syndrome ≠ Familial CRC Type X
Familial Colorectal Cancer Type X

• Genetic etiology is largely unknown
– Has a monogenic component
• likely caused by high-penetrance mutations
– ?Polygenic component: Is there an interaction of
multiple low-penetrance genetic variants
• Clinical characteristics such as lower risk of CRC and
fewer associated extracolonic cancers suggest this
• More similar to sporadic CRC?
• Represents a novel form of familial CRC and
families are resource for research
Familial Colorectal Cancer Type X

HOWEVER….
• Phenotype varies from “classic” to “attenuated”
• 30% are de novo cases: no family history
• Classic FAP easy to recognize
• Penetrance for adenomas and
cancer near 100% in APC+
gene mutation carriers
Familial Adenomatous Polyposis

Variations of classic phenotypes are
common: Attenuated FAP
• Attenuated polyposis is a phenotypically distinct variant of FAP
• Arises from mutations in proximal or distal portions of APC gene
Characteristics
• Mean age at CRC diagnosis: 54 years
• Cumulative risk of CRC by the age of 80 yr is ~69%
• Proximal>>distal colon polyps and 75% of tumors occur in the
proximal colon
*The prevalence of APC mutations is likely similar in
EAO-CRC*

• Polyp phenotype more so “attenuated”
• Autosomal recessive pattern of inheritance
• Biallelic mutation carriers: 53 fold excess risk of CRC
• Up to 80% increased risk of CRC in lifetime
• Monoallelic mutation carriers: OR 1.15
• Mutational hotspots:
–White, Northern Europeans : Y165C
G382D
–Indian/Pakistani: E466X
MYH associated polyposis (MAP):
A newer entity in inherited CRC risk
account for 80%
of all mutations
Jenkins MA, et al. Cancer Epidemiol Biomarkers Prev 2006; 15:312-4
Win AK, et al. Fam Cancer 2011; 10:1-9

MYH associated polyposis
• ~3% of EAO-CRC is due to MYH mutations
– Compared to <1% of all CRC cases, regardless of
age
• ~30% of biallelic MYH carriers develop CRC
without polyps
– According to population-based studies
• Recommendation that all early-onset CRC
should be tested for MUTYH mutations
Riegert-Johnson DL et al. Genet Test. 2007;11:361–365.
Giraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.

Germline Testing
Proband
HEREDITARY GI CANCER SYNDROME
Pedigree
Clinical Criteria
+/- tumor testing
+
Stepwise Approach for Inherited CRC Syndromes
• Requires recognition of cancer syndromes by providers
–Diagnosis may be missed
–Additional genes with other cancer syndromes increase
CRC risk
• Time consuming process, multiple decisions
–Test and re-test
–Complex decision-making for patients

Germline p53 Mutations and
Early Age Onset Cancers
• Li-Fraumeni syndrome
– caused by p53 mutations
• Lifetime risk of cancer is ~70-100%
• Carriers develop early onset cancers
– Leukemias, brain tumors, sarcomas, breast cancer,
adenocortical cancers
– Reports of gastric and CRC

• 457 patients with CRC ≤40 years old
• 1.3% carried a p53 gene mutation
– Comparable to the prevalence of APC gene
mutations associated with FAP
• None of the patients met clinical criteria for
Li-Fraumeni Syndrome

Advances in Genetic Testing for
Inherited CRC
• Next Generation Sequencing (NGS) allows for simultaneous
assessment of many cancer susceptibility genes with multi-
gene panel testing:
– Breast, colon, ovarian, pancreas….
• The role of NGS panel testing and its yield over traditional
genetic testing strategies are unclear
• Will change the conventional approach to genetic evaluation

Expanded Commercial Cancer
Genetic Testing

47%
Uptake of NGS Panel Testing in EAO-CRC
LaDuca H et al. Genet Med. 2014 Nov;16(11):830-7

Additional Results from NGS Panel
Testing in EAO-CRC

Pilot study
• To determine the frequency and clinical phenotype
of patients undergoing genetic testing for Lynch
syndrome using a 25- gene hereditary cancer panel
• 343 non-consecutive subjects with banked blood
samples
• Validation study ongoing
MLH1 APC BRCA1 PTEN RAD51C
MSH2 MYH BRCA2 TP53 RAD51D
MSH6 BMPR1A PALB2 CDH1 BRIP1
PMS2 SMAD4 CHEK2 CDKN2A BARD1
EPCAM STK11 ATM CDK4 NBN
Yurgelun M et al. J Clin Oncol 32, 2014 (suppl 15s; abstr 1509)

Overall Panel Testing Results
Total cohort 343 patients
No mutation found 277 (81%)
All mutation carriers 66 (19%)
Lynch mutation 48 (14%)
Any non-Lynch mutation 19 (6%)
Non-Lynch CRC* mutation 3
BRCA1/2 mutation 10
Other† mutation 9
Rows not mutually exclusive due to 4 subjects having ≥1 pathogenic mutation
* APC, biallelic MYH, BMPR1A
† ATM, BARD1, BRIP1, CHEK2, NBN

Summary & Future Directions
• 85 % of EAO-CRC are not explained by known inherited CRC
syndromes
• NGS Panel testing will redefine the contribution of known cancer-
related genes in EAO-CRC
• Continued research efforts are necessary in affected individuals
and family members
– Gene discovery
– Screening and surveillance recommendations

Thank you!
Fay Kastrinos, MD, MPH
212-305-1021

Kate McNamara, MD
CCCF Research Scholar
University of Toronto

CCCF Annual Research Scholar Award

Zane Cohen Center for Digestive Diseases
Research Treatment Education Support
Gastrointestinal Cancers
Research Groups
Familial Gastrointestinal Cancer Registry
(FGICR)
Ontario Pancreas Cancer Study (OPCS)
Ontario Familial Colorectal Cancer Registry (OFCCR)
Soft Tissue Sarcoma Research Program (STSRP)
Diseases
Lynch Syndrome (LS)
Familial Adenomatous Polyposis (FAP)
MYH - Associated Polyposis (MAP)
Peutz-Jeghers Syndrome (PJS)
Juvenile Polyposis (JP)
Hereditary Hemorrhagic Telangiectasia (HHT)
Hereditary Diffuse Gastric Cancer Syndrome (HDGC)
Pancreatic Cancer

Genetics of Early Age Onset Colorectal Cancer (EAO-CRC)

age-standardized incidence rate per 100,000 43.7
age-standardized mortality rate per 100,000 15.9
estimated new cases in 2014 136,830
% of all new cancer cases 8.2%
estimated deaths in 2014 50,310
% of all cancer deaths 8.6%
CRC incidence and mortality in the US
● third leading cause of cancer incidence in both males and females
● second leading cause of cancer mortality in both males and females
SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Both Sexes.

EAO-CRC incidence and mortality in the US
● approximately 10% of colorectal cancers have early-onset
NEW CASES DEATHS
Male Female Male Female
Age (yrs) Count % Count % Count % Count %
0-49 7,270 10 6,250 10 1,840 7 1,450 6
50-64 22,890 32 16,570 25 6,780 26 4,590 19
65-79 27,950 39 23,050 35 10,100 38 7,710 32
80+ 13,720 19 19,130 29 7,550 29 10,290 43
Estimated Numbers of New Colorectal Cancer Cases and Deaths by Age and Sex, United States, 2014
Siegel, R., DeSantis, C. and Jemal, A. (2014), Colorectal cancer statistics, 2014. CA: A Cancer Journal for Clinicians, 64: 104–117.
doi: 10.3322/caac.21220

CRC incidence and mortality in Canada
● incidence and mortality rates are higher in Canada than in the US
● second leading cause of cancer incidence and mortality in males
● third leading cause of cancer incidence and mortality in females
age-standardized incidence rate per 100,000 48.9
age-standardized mortality rate per 100,000 17.9
estimated new cases in 2014 24,400
% of all new cancer cases 12.8%
estimated deaths in 2014 9,300
% of all cancer deaths 11.5%
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.

EAO-CRC incidence and mortality in Canada
● approximately 6% of colorectal cancers have early-onset
NEW CASES DEATHS
Male Female Male Female
Age (yrs) Count % Count % Count % Count %
0-29 45 <1% 45 <1% 10 <1% 5 <1%
30-49 720 5 660 6 175 3.5 145 3.5
50-59 2,100 15 1,550 14 580 11.5 390 10
60-69 4,000 29.5 2,500 23 1,250 25 700 18
70-79 4,000 29.5 2,800 26 1,500 30 1,000 25.5
80+ 2,800 20.5 3,300 30.5 1,450 29 1,650 42
Estimated Numbers of New Colorectal Cancer Cases and Deaths by Age and Sex, Canada, 2011

CRC incidence trends in the US
● CRC ASIR have been decreasing on average 3.1% per year since 2002
SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Both Sexes. Rates are Age-Adjusted.

CRC incidence is increasing in young adults
Age (y) 1973
Incidence
1999
Incidence
EAPC
Colon 20-40 1.8 2.1 0.75**
60+ 179 204.4 0.26
Rectum 20-40 0.8 1.4 3.15**
60+ 86 72.1 -0.73**
Race/ethnicity n APC
All races M 10,913 1.5**
F 9,733 1.6**
Non-Hispanic White M 6,748 2.0**
F 5,626 2.2**
Non-Hispanic Black M 1,409 −0.2
F 1,456 −0.6
Hispanic M 1,307 2.7**
F 1,250 1.1
Asian American/ Pacific Islander M 1,284 1.2
F 1,239 0.6
Subsite APC
Rectum 2.6**
Sigmoid 0.4
Descending colon -1.8**
Colon excluding rectum -0.2
• O’Connell et al.
Young adults 20-40y, SEER 1973-1999
• Meyer et al.
Young adults <40y, SEER 1973-2005
• Seigel et al.

CRC incidence trends among young non-hispanic white adults (20-49yrs)
by age and anatomic subsite,1992 to 2005
Age n APC
M 20-29 249 5.2*
30-39 1,419 3*
40-49 5,080 1.5*
F 20-29 240 5.6*
30-39 1,125 2*
40-49 4,261 2.1*
Subsite n APC
M Proximal 2,054 0
Distal 1,609 1.5*
Rectum 2,609 3.5*
F Proximal 1,548 0.8
Distal 1,619 2.3*
Rectum 2,065 2.9*
Seigel et al.
• O’Connell et al.
• Meyer et al.
Young adults <40y, SEER 1973-2005

CRC incidence and mortality trends in Canada
● CRC ASIR has been decreasing on average 0.8% per year in males, 2001-2010
● CRC ASIR has been decreasing on average 0.6% per year in females, 2001-2010

Cancer Care Ontario. Colorectal cancer incidence increasing among adolescents and young adults. August 2009. Available at https://www.cancercare.on.ca/cancerfacts.

Hereditary CRC risk
• familial cases comprise approximately 30% of all CRC
• mutations in highly penetrant CRC susceptibility genes account for 5-10% of all CRC
• etiology of remaining 20-25% of inherited CRC is not completely understood

Hereditary CRC syndromes
POLYPOSIS
adenomatous polyposis syndromes
Familial Adenomatous polyposis (FAP) – AD, mutation in APC
Attenuated FAP (AFAP) - AD, APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9
MUTYH-associated polyposis (MAP) – AR, biallelic mutations in MUTYH
Polymerase-proofreading associated polyposis – AD, mutation in POLE or POLD1
hamartomatous polyposis
Peutz-Jeghers syndrome (PJS) - AD, mutations in STK11
Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1A
Cowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN
hyperplastic/serrated polyposis
Serrated polyposis syndrome – uncertain genetic etiology; unclear hereditary predisposition
Hereditary mixed polyposis syndrome
NONPOLYPOSIS
Lynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2) or EPCAM
Biallelic Mismatch Repair deficiency
Other (Li-Fraumeni, Bloom syndrome)

POLYPOSIS
adenomatous polyposis syndromes
Familial Adenomatous polyposis (FAP) – AD, germline mutation in APC
Attenuated FAP (AFAP) - AD, germline APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9
10 to 99 synchronous adenomas
emergence of adenomas and CRC development delayed 10 to 20 years
CRC risk 70% by age 80
 100s to 1000s of synchronous adenomas beginning in adolescence
 CRC risk >95% by age 50 if untreated
MUTYH-associated polyposis (MAP) - AR, biallelic mutations in MUTYH
 variable phenotype, most commonly 20 to 99 polyps but may present with <10 or >500
 CRC risk >40% by age 60
Polymerase-proofreading associated polyposis (PPAS) – AD, mutation in POLE or POLD1
 10 to 100 adenomas, may present with other polyp histology
 CRC risk undefined

POLYPOSIS
hamartomatous polyposis
Peutz-Jeghers syndrome (PJS) - AD, germline mutations in STK11
 GI polyps in 90-100% of cases
 mucocutaneous pigmentation in >95% of cases most commonly perioral and buccal mucosa
 lifetime CRC risk 40%
 elevated risk for gastric, small bowel , breast, lung, pancreatic, and gynecologic cancers
Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1A
 multiple juvenile polyps in colon, small bowel, and stomach
 CRC risk 20% by age 35 and up to 70% by age 60
Cowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN
 range of phenotypes, colon polyps present in up to 95%, <10 to 100s of polyps, various histology
 lifetime CRC risk may be up to 15%

hyperplastic/serrated polyposis
Serrated polyposis syndrome
 uncertain genetic etiology; unclear hereditary predisposition
Hyperplastic Mixed Polyposis Syndrome
newly described, poorly characterized
oligopolyposis, mixed poly histology including adenomatous,
serrated, hyperplastic and mixed types

NONPOLYPOSIS
Lynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene
(MLH1, MSH2, MSH6, PMS2) or EPCAM
 usually few (<10) early-onset adenomas, accelerated adenoma-carcinoma sequence
 lifetime CRC risk dependent on MMR gene mutation ranging 25-75% for MLH1/MSH2
mutations and lower risks for other gene mutations
 associated with extracolonic malignancies – endometrial, gastric, ovarian, urinary tract,
small bowel, brain, hepatobiliary
 pedigrees characterized by Amersterdam criteria (3 affected, 2 generations, first-degree relatives)
Biallelic Mismatch Repair deficiency – AD, biallelic mutations in MMR genes
 more commonly associated with brain and hematologic malignancies at very early-age
Other (Li-Fraumeni, Bloom syndrome)

Hereditary CRC syndromes and EAO-CRC
Chang et al. 2012 ≤40 surgical patients, Stanford Univ hosp 75 total; 13(17%) IHC def, 2(3%) FAP,
1(1%) JPS, 1(1%) LFS, 3(4%) IBD
Steinhager et al. 2012 <50 surgical patients, MSKCC 198 total; 17 (9%) LS and 7 (3.5%) VUS
Limburg et al 2011 <50 CCFR 155 total; 18 (12%) IHC def
Perea et al. 2010 ≤45 surgical patients ,2 hospitals in Spain 43 total; 8(19%) LS and 1(2%)FAP,
26(60%) sporadic
Jasperson et al. 2010 ≤35 3 US CRC registries 86 total; 21(24%) LS, 1(1%) FAP, 1(1%) LFS
48(56%) sporadic
Losi et al. 2005 <45 surgical patients, 2 hospitals in Italy 71 total; 7 (10%) LS
Terdiman et al. 2002 ≤35 high risk clinic, USCF 43 total; 13(30%) LS
US population based registry 23 total; 0 (0%) LS
hereditary CRC syndromes account for greater proportion of EAO-CRC

FGICR and EAO-CRC
Lynch Syndrome n=87
1.MMR (or EPCAM) gene mutation
2.IHC deficient tumor
• 71 germline mutations
• 12 VUS
Classic FAP n=84
1. >100 adenomas
2. 100 adenomas + 1⁰ relative with FAP
• 43 germline mutations: 41 APC, 2 biallelic MUTYH
• 10 VUS
AFAP n=8
• 8 germline mutations: 4 APC, 4 biallelic MUTYH
JPS n=6
• 2 germline mutations: 1 SMAD4, 1 BMPR1A
• 1 VUS
other
Biallelic MMR deficiency n=4
• 3 germline mutations
• 1 VUS
Bloom syndrome n=1
• 1 germline mutation
IBD n =11
Undefined conditions n=122
• 97 complete testing
• 5 partial testing
• 20 no testing
high-risk familial
▪ FCCTX
common familial risk
non-familial

Br J Surg. 2013 Dec;100(13):1719-31. doi: 10.1002/bjs.9316.
Systematic review of the impact of registration and screening on colorectal cancer
incidence and mortality in familial adenomatous polyposis and Lynch syndrome.
Barrow P1, Khan M, Lalloo F, Evans DG, Hill J.
METHODS
• English-language studies describing CRC incidence and/or mortality in patients with FAP or LS
• comparison of : screened and unscreened patients OR time periods before and after establishment of the registry
RESULTS
 FAP – 33/33 studies report reduction of CRC incidence and mortality with registration and screening
 LS – 9/10 studies report reduction of CRC incidence and mortality with registration and screening

J Exp Clin Cancer Res. 2014 Jan 2;33:1. doi: 10.1186/1756-9966-33-1.
Early-onset colorectal cancer patients without family history
are "at very low risk" for lynch syndrome.
Stigliano V1, Sanchez-Mete L, Martayan A, Diodoro M, Casini B, Sperduti I, Anti M.

Clinicopathologic features of non-familial EAO-CRC
Early-onset (≤40
years) colorectal
adenocarcinoma
(%) (N=55)
Control (>40 years of
age) colorectal
adenocarcinoma (%)
(N=73)
P value
Tumor
location
Right colon 11 (20) 31 (42) 0.007
Left colon
and rectum
44 (80) 42 (58)
Sigmoid 24 (44) 33 (45)
Rectum 20 (36) 9 (12)
Tumor stage
I 6 (11) 14 (19) 0.21
II 14 (26) 21 (29)
III 20 (36) 28 (38)
IV 15 (27) 10 (14)
Tumor grade
Low 40 (73) 63 (86) 0.06
High 15 (27) 10 (14)
Perineural
invasion
16 (29) 8 (11) 0.009
Venous
invasion
12 (22) 4 (6) 0.006
Mucinous histology
present 42 (76) 11 (15) 0.22
absent 13 (24) 62 (85)
Signet ring histology
present 7 (13) 1 (1) 0.021
absent 48 (87) 72 (99)
● more frequent location in distal colon
and rectum
● later stage at presentation
● more frequent aggressive histologic features
 venous invasion
 perineural invasion
 mucinous histology
 signet ring histology
Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma:
an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol 2012 Aug;25(8):1128–1139

PLoS One. 2014 Aug 1;9(8):e103159.
Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a
morphological, molecular and genetics study.
Kirzin S1, Marisa L2, Guimbaud R3, De Reynies A2, Legrain M4, Laurent-Puig P5, Cordelier P6, Pradère B7, Bonnet D8, Meggetto F6, Portier G7,
Brousset P9, Selves J9.
METHODS
• surgical patients at university hospital in France 1999-2005
▪ 39 MSS tumor <45y cases
▪ 9 MSI tumor <45y cases
▪ 36 MSS tumor >60y cases
▪ 14 MSI tumor >60y cases
RESULTS
• absence of BRAF mutations
and methylator phenotype in EAO-CRC
• 49 signaling pathways upregulated in EAO-CRC
CONCLUSIONS
 EAO-CRC is distinct clinico-molecular entity
MSS
young
MSS old MSI
young
MSI old
KRAS mut 14 (37%) 16 (44%) 3 (33%) 4 (29%)
WT 24 (63%) 20 (56%) 6 (67%) 10 (71%)
BRAF
V600E
mut 0 (0%) 5 (14%) 0 (0%) 5 (36%)
WT 39 (100%) 31
(86%)
9 (100%) 9 (64%)
TP 53 mut 17 (44%) 17 (47%) 0 (0%) 5 (36%)
WT 22 (56%) 19 (53%) 9 (100%) 9 (64%)
PIK-
3CA
mut 5 (21%) 2 (6%) 4 (80%) 3 (27%)
WT 19 (79%) 32 (94%) 1 (20%) 8 (73%)
CIMP unmethylated 38 (100%) 29
(81%)
9 (100%) 5 (38%)
methylated 0 (0%) 7 (19%) 0 (0%) 8 (62%)

Am J Surg Pathol. 2009 Apr;33(4):572-82. doi: 10.1097/PAS.0b013e31818afd6b.
Clinical, pathologic, and molecular features of early-onset colorectal carcinoma.
Yantiss RK1, Goodarzi M, Zhou XK, Rennert H, Pirog EC, Banner BF, Chen YT.
METHODS
• surgical patients UMass Memorial Healthcare and
Weill Cornell Medical College 2000-2007
 24 patients <40y
 15 patients 40-40y
 30 patients >50y
RESULTS
• more frequent AMACR expression in patients <40y
• 4 micro-RNA species significantly overexpressed in patients <40y
(miR-21, miR-20a, miR-181b, mi-203)
CONCLUSIONS
 posttranscriptional regulation of mRNA may be particularly important for
the development of CRC in young patients

Exploring the genetics of EAO-CRC
Next-generation sequencing (NGS)

 rare variant hypothesis
▪ undiscovered moderately penetrant genetic variants
cause increased CRC risk
de novo dominant
recessive
biallelic somatic

Whole genome sequencing
vs
Exome sequencing
Whole genome
 expensive
 IT issues
 complete sequence
Exome
 cheaper
 more manageable
 coding regions
 incomplete sequence

Nat Genet. 2011 May; 43(5): 442–446.
Exome sequencing identifies GRIN2A as frequently mutated in
melanoma
Xiaomu Wei,1 Vijay Walia,1,12 Jimmy C Lin,2,12 Jamie K Teer,3 Todd D Prickett,1 Jared Gartner,1 Sean Davis,4 NISC Comparative Sequencing Program,5 Katherine Stemke-
Hale,6 Michael A Davies,6,7 Jeffrey E Gershenwald,8,9 William Robinson,10 Steven Robinson,10 Steven A Rosenberg,11 and Yardena Samuels1
Science. 2009 Apr 10;324(5924):217
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.
Jones S1, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW,
Vogelstein B, Eshleman JR, Goggins M, Klein AP.
Nat Genet. 2011 Jun 19;43(7):663-7.
Exome sequencing identifies MAX mutations as a cause of hereditary
pheochromocytoma.
Comino-Méndez I1, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A, de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse
S, Pica G, Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A, Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo M, Cascón A.
Nature. 2011 Jan 27; 469(7331): 539–542.
Exome sequencing identifies frequent mutation of the SWI/SNF complex
gene PBRM1 in renal carcinoma
Ignacio Varela,1 Patrick Tarpey,1 Keiran Raine,1 Dachuan Huang,2 Choon Kiat Ong,2 Philip Stephens,1 Helen Davies,1 David Jones,1 Meng-Lay Lin,1 Jon
Teague,1 Graham Bignell,1 Adam Butler,1 Juok Cho,1 Gillian L. Dalgliesh,1 Danushka Galappaththige,1 Chris Greenman,1 Claire Hardy,1 Mingming Jia,1 Calli
Latimer,1 King Wai Lau,1 John Marshall,1 Stuart McLaren,1 Andrew Menzies,1 Laura Mudie,1 Lucy Stebbings,1 David A. Largaespada,3 L.F.A. Wessels,4
Stephane Richard,5,6 Richard J Kahnoski,7 John Anema,7 David A. Tuveson,8 Pedro A. Perez-Mancera,8 Ville Mustonen,8 Andrej Fischer,9,10 David J.
Adams,11 Alistair Rust,11 Waraporn Chan-on,2 Chutima Subimerb,2 Karl Dykema,12 Kyle Furge,12 Peter J. Campbell,1 Bin Tean Teh,2,14 Michael R.
Stratton,1,15 and P. Andrew Futreal1
Exome sequencing and cancer genetics

Nat Genet. 2013 Feb;45(2):136-44.
Germline mutations affecting the proofreading domains of POLE and POLD1
predispose to colorectal adenomas and carcinomas.
Palles C1, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M,
Martin L, Kovac MB, Humphray S; CORGI Consortium; WGS500 Consortium, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey
SE, Thomas HJ, McVean G, Houlston RS, Tomlinson I.
• whole genome sequencing and linkage analysis
• COloreRectal Gene Identification (CORGI) study; recruits from UK Clinical Genetics Departments
• 20 discovery phase samples:
 15 unrelated probands diagnosed with ≥10 colorectal adenomas before age 60
 relative with >5 colorectal adenomas for 3 probands, and 2 affected relatives for 1 proband
• 3,805 white UK validation phase samples enriched for family history of CRC and early-onset
• 6,721 white UK control samples without personal history of CRC

POLE L424V variant
• pedigree SM2702, only variant shared by all 3 affected individuals
• present in 12 additional unrelated cases from validation phase and no controls
• additional genotyping in 12 families showed all carriers developed colorectal tumors
POLD1 S478N variant
• pedigree SM1645, shared by both of the 2 affected individuals
• present in additional proband plus additional unrelated case from validation phase and no controls
• additional genotyping in SM1645 and proband family showed all carriers developed colorectal tumors
 dominantly-inherited high penetrance susceptibility for colorectal adenoma and carcinoma
 mutations map to proof-reading (exonuclease) domain of DNA polymerases ε and δ;
predicted to impair correction of mispaired bases inserted during DNA replication

Hum Mutat. 2013 Jul;34(7):1026-34. doi: 10.1002/humu.22333. Epub 2013 May 20.
Exome resequencing identifies potential tumor-suppressor
genes that predispose to colorectal cancer.
Smith CG1, Naven M, Harris R, Colley J, West H, Li N, Liu Y, Adams R, Maughan TS, Nichols L, Kaplan R, Wagner MJ, McLeod HL, Cheadle JP.
METHODS
• exome sequencing of 50 germline DNA samples
• unrelated sporadic CRC patients from UK national multicenter
randomized controlled trials COIN and COIN-B

analysis strategy 1
 search for protein-truncating variants in subset of 1,138 genes from pathways implicated in CRC
 oncogenes excluded
 search for LOH by Sanger sequencing of matched tumor DNA when available
32 variants in 31 genes
5 variants with somatic biallelic inactivation
FANCM, LAMB4, PTCHD3, LAMC3, TREX2
analysis strategy 2
 search for protein-truncating variants in all genes
 initially limited search to 18 EAO-CRC cases in sample set
 expanded to include all cases
173 variants in 159 genes in EAO-CRC
additional 331 variants in additional 305 genes in remainder

Cancer Genetics 208 (2015) 35-40
Systematic search for rare variants in Finnish
early-onset colorectal cancer patients
Tomas Tanskanen a, Alexandra E. Gylfe a, Riku Katainen a, Minna Taipale b,e, Laura Renkonen-Sinisalo a,c, Heikki J€arvinen c, Jukka-Pekka Mecklin d,
Jan B€ohm d, Outi Kilpivaara a, Esa Pitk€anen a, Kimmo Palin a, Pia Vahteristo a, Sari Tuupanen a, Lauri A. Aaltonen a,*
METHODS
• exome sequencing
• unselected surgical patients from 9 Finnish hospitals 1994-1998
• discovery set of 22 non-familial EAO-CRC cases <40y
• validation set of 95 familial CRC cases

RESULTS
 no genes with rare loss-of-function (LoF) variants present in more than one EOA-CRC patient
 ADAMTS4, CYTL1, SYNE1 LoF variants in one EAO-CRC patient and familial CRC cases
 ACSL5 p.Pro71Leu, INTS5 p.Pro922Leu missense variants in 2 EAO-CRC patients and no familial CRC cases
 MCTP2, ARHGAP12, ATM, DONSON, ROS1 each with homozygous variants in one EOA-CRC patient
 no compound heterozygous LoF variants
CONCLUSIONS
 results suggest genetic heterogeneity in unexplained EAO-CRC

The Toronto EAO-CRC cohort
FGICR
Undefined conditions n=122
• 97 complete testing
• 5 partial testing
• 20 no testing
• complete testing
• no polyposis
• no significant family history:
▪ pedigree does not meet Amsterdam
or Revised Bethesda criteria
▪ no relative with EAO-CRC (≤35y)
▪ no first degree relative with CRC
• germline and tumor DNA available
 30 EAO-CRC germline and tumor exomes

rare variant hypothesis
▪ undiscovered moderately penetrant genetic variants
cause increased CRC risk
perhaps not one single variant but unique combinations ;
OR the interaction of certain variant(s) with environmental exposures
and/or epigenetic alterations, etc….

References
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available
from: http://globocan.iarc.fr, accessed November 15, 2014.
American Cancer Society. Colorectal Cancer Facts and Figures 2014-2016. Atlanta: American Cancer Society; 2014.
Canadian Cancer Society's Advisory Committee on Cancer Statistics (2014). Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society.
Siegel R, Desantis C, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Mar-Apr 64(2):104-17.
Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future
rates. Cancer. 2010 Feb 1;116(3):544-73.
Cheng L, Eng C, Neiman LX, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976-2005. Am J Clin Oncol. 2011 Dec;34(6):573-80
Surveillance Epidemiology and End Results. Fast Stats, http:// seer.cancer.gov/faststats. Accessed November 15, 2014.
Bailey CE, Hu CY, You YN, et al. Increasing Disparities in the Age-Related Incidences of Colon and Rectal Cancers in the United States, 1975-2010. JAMA Surg. 2014 Nov 5:1-6.
Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1695-8.
You YN, Xing Y, Feig BW, Chang GJ, Cormier JN. Young-onset colorectal cancer: is it time to pay attention? Arch Intern Med. 2012 Feb 13;172(3):287-9.
Pignone M, Rich M, Teutsch SM, et al. Screening for colorectal cancer in adults at average risk: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002 Jul 16;137(2):132-41.
Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008 Nov 4;149(9):638-58.
Myers EA, Feingold DL, Forde KA, et al. Colorectal cancer in patients under 50 years of age: A retrospective analysis of two institutions' experience. World J Gastroenterol. 2013 Sep 14;19(34):5651-7.
Kirzin S, Marisa L, Guimbaud R, et al. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study. PLoS One. 2014 Aug 1;9(8):e103159.
Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid
involvement, and adverse morphologic features. Mod Pathol 2012 Aug;25(8):1128–1139
Yantiss RK, Goodarzi M, Zhou XK, et al. Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Am J Surg Pathol 2009 Apr;33(4):572–582
Fante R, Benatti P, di Gregorio C, et al. Colorectal carcinoma in different age groups: a population-based investigation. Am J Gastroenterol. 1997;92:1505–1509.
Minardi AJ, Sittig KM, Zibari GB, McDonald JC. Colorectal cancer in the young patient. Am Surg. 1998;64:849–853.
Domergue J, Ismail M, Astre C, et al. Colorectal carcinoma in patients younger than 40 years of age. Montpellier Cancer Institute experience with 78 patients. Cancer. 1988;61:835–840.
Palmer ML, Herrera L, Petrelli NJ. Colorectal adenocarcinoma in patients less than 40 years of age. Dis Colon Rectum. 1991;34:343–346.
Chiang JM, Chen MC, Changchien CR, et al. Favorable influence of age on tumor characteristics of sporadic colorectal adenocarcinoma: patients 30 years of age or younger may be a distinct patient group. Dis Colon Rectum.
2003 Jul;46(7):904-10.
Parramore JB, Wei JP, Yeh KA (1998) Colorectal cancer in patients under forty: presentation and outcome. Am Surg 64: 563–567 discussion 567–568
Liang JT, Huang KC, Cheng AL, Jeng YM, Wu MS, et al. (2003) Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age. Br J Surg 90: 205–214
Berg M, Danielsen SA, Ahlquist T, Merok MA, Agesen TH, et al. (2010) DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS One. 2010 Nov
12;5(11):e13978.
Alsop K, Mead L, Smith LD, Royce SG, Tesoriero AA, et al. (2006) Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. Eur J Cancer 42: 1357–1361
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.
Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17:502–10.
Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet. 2005;6:109–118.
Bodmer W1, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008 Jun;40(6):695-701. doi: 10.1038/ng.f.136.
Frayling I, Beck NE, Ilyas M, Dove-Edwin I, Goodman P, Beck JA, et al. The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci USA. 1998 Sep
1;95(18):10722–7.
Fearnhead N, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, et al. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci USA. 2004 Nov
9;101(45):15992–7.
Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011 Jun 19;43(7):663–7.
Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. 2009 Science Apr 10;324(5924):217
Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013
Feb;45(2):136-44.
Smith CG, Naven M, Harris R, Colley J, West H, Li N, et al. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Hum Mutat. 2013 Jul;34(7):1026-34.
Newcomb PA, Baron J, Cotterchio M, Gallinger S, Grove J, Haile R, et al. Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev. 2007
Nov;16(11):2331-43.

Jiyoung Ahn, PhD, RD
Associate Professor
Dept. of Population Health
NYU School of Medicine
Early Age Onset Colorectal Cancer Summit, March 2005
Gut Microbiome, Fiber Intake,
and Risk of Colorectal Cancer

16
3
Human microbiome
• Human microbiome, totality of human microbiota.
• Our understanding of microbiome has been limited.
• Bacterial DNA sequencing opened new possibility
to study microbiome comprehensively and accurately.
Ahn et al, Cancer Cause and Control, 2012

16
4
World Health Organization
Group 1 infectious agents that cause cancer
Bacteria
Helicobacter pylori (H. pylori)
Viruses
Epstein-Barr Virus (EBV)
Hepatitis B Virus (HBV)
Hepatitis C Virus (HCV)
Human Herpesvirus 8 (HHV-8)
Human Immunodeficiency Virus (HIV)
Human Papillomavirus (HPV)
Human T-Cell Lymphotrophic/Leukemia Virus Type 1
(HTLV-1)

16
5
• Recently completed study of microbiome and
colorectal cancer
- published in Journal of National Cancer Institute
• Large scale on-going effort on
- NYU Human Microbiome Study Cohort
Overview of talk

16
6
Gut microbiome and CRC
• Gut microbiome plays key roles in inflammation and in the
breakdown of otherwise indigestible food compounds,
such as fiber.
• Animal studies (Infect Immun 1998, mBio 2013)
- mice develops fewer colon tumors under germ-free conditions
- fecal transplant from CRC mice results in tumor formation
• Systematic epidemiologic surveys of gut microbiome with
cases and controls are lacking.
• We tested the hypothesis that altered gut microbiome is
associated with risk of CRC.

16
7
• Hospital based case-control study
- 47 CRC cases and 94 non-cancer controls
- recruited 3 hospitals in Washington DC area
- matched by age, gender, and BMI
• Diet and demographic questionnaires
• In-home 2 day fecal collection
• 16s rRNA gene sequencing microbiome assay
Study Design

16
8
Microbiome Assay and Data Analysis
- Compared overall gut microbiome diversity and microbial taxa
abundances in CRC cases and controls

16
9
Inter-individual variability of gut microbiome
Ahn et al, JNCI, 2013
20 different health subjects

17
0
Gut microbiome diversity in CRC and controls
500 1000 1500 2000 2500 3000
6
7
8
9
Shannon Index in Colorectal Cancer Cases and Controls
Sequences Per Sample
ShannonIndex
Controls
Cases
Less diverse in cases than in controls
P = 0.02

17
1
Taxonomic differences in CRC and controls
Case
Cont

17
2
Fusobacterium increases CRC risk
• Multivariate OR=3.74, p=0.0035.
• Fusobacterium is gram negative
inflammatory bacteria.
• Consistent with our result, two studies
reported that Fusobacterium is enriched in
human colorectal cancer tissue compared to
adjacent normal tissue
(Genome Research 2012 and Science 2013).

17
3
Clostridia decreases in CRC patients
• Clostridia depleted in CRC cases
(Multivariate OR = 0.8, P=0.005).
• Clostridia ferment dietary fiber
to short chain fatty acid (butyrate),
anti-carcinogenic components.

17
4
High fiber intake decreases CRC risk
0.6
0.7
0.8
0.9
1
1.1
CRC Risk
<15 g/day, 15-20 g/day, 20-24 g/day, 24-30 g/day 30+ g/day
Dietary Fiber Intakes
Lancet 2003, JAMA 2005
• Non-digestible plant component of complex carbohydrates

17
5
Low Fiber Intake
High fiber intake and high clostridia
High Fiber Intake
High fiber intake - for high vs. low Clostridia:
multivariate OR=1.24 (p=0.009)
Domminiani et al, PLOS ONE, 2015
Clostridia
Overall diversity Genera (unsupervised clustering)

17
6
Summary
• CRC risk was associated
- with decreased gut microbiome diversity;
- increased presence of Fusobacterium;
- depletion of fiber–fermenting Clostridia.
• High fiber intake  Clostridia  CRC.

17
7
NYU Human Microbiome Cohort:
Human Microbiome and Colorectal Tumor (HMAC) Study
(supported by Dept. Population Health, NYU Cancer Institute, and NCI)
Ongoing Recruitment (~ 500 recruited, 3000 planned)
- GI clinic and colonoscopy centers at NYULMC and other 3 sites in US.
- Fecal/oral/tissue sample collection
- Comprehensive diet/demographic questionnaires
- Detailed clinical and pathology information
Follow up for future tumor assessment
- Annual follow up questionnaire and medical chart verification

17
8
Implications
• Learn about the causes of CRC.
• Identifying people at high risk for CRC.
• Possible prevention of CRC by tailored bacterial
and diet modifications.

17
9
Research Team
• NYU: Richard Hayes, Mitchell Bernstein, George Miller, Zhiheng Pei
• My group: Christine Domminiani, Xiaozhou Fan, Jing Wu, Ryan Shanly, Elong Zhang
• NCI: Mark Purdue, Rashimi Sinha, Jim Goedert, Neal Freedman
• ACS: Susan Gapstur, Eric Jacobs
• CDC: Jean Shapirio
Grant Support
• NIH R01 CA 164964 (PI. Ahn): Microbiome-pancreas cancer
• NIH U01 CA182370 (MPI. Ahn/Pei): Microbiome-esophagus cancer
• NIH R03 CA159414 & NIH R21 CA183887 (PI. Ahn): Microbiome-CRC
• NIH R01 CA 164964 (PIs. Hayes/Pei): Microbiome-HNC
• NYU Abu Dhabi (PI. Ahn): Microbiome - CVD
• NIH R21 ES021194 (PI. Ahn) & NIH R21 ES021242 (PI. Ahn): Diet studies
www.NYUMGEL.org
(Ahn – Diet, microbiome and genetic epidemiology lab)

18
0
Each body site
has a different
and unique
microbiome
HMP data

18
1
Shared common structure of human microbiome
Catonella
Dialister
Eubacterium
Filifactor
Gemella
Granulicatella
Megasphaera
Parvimonas
Selenomonas
Streptococcus
Veillonella
Aggregatibacter
Camplylobacter
Haemophilus
Kingella
Neisseria
Capnocytophaga
Porphyromonas
Prevotella
Tannerella
Actinomyces
Bifidobacterium
Slackia
Fusobacterium
LeptotrichiaFusobacteria (5.0%)
Firmicutes
(52.3%)
Proteobacteria
(19.7%)
Bacteroidetes
(15.6%)
Actinobacteria(7.3%)
SR1 (0.07%)
TM7 (0.06%)
Cyanobacteria (0.01%)
Spirochaetes (0.01%)
Tenericutes (0.01%)
Synergistetes (0.0001%)
HumanOralBacteria
Ahn et al, PLoS ONE, 2011
Phyla Genera

Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Thomas K Weber, MD FACS
Professor of Surgery
State University of New York
Health Sciences Center
Brooklyn, New York

Incidence trends by age: 50+ versus 20-49
0
2
4
6
8
10
12
14
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Rateper100,000
Men
Women
45%
2% per year
Since 1993-1994
0
50
100
150
200
250
300
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Rateper100,000
Men
Women
Ages 50+ Ages 20-49

• We have a major cancer control /
epidemiologic challenge
• The “seismic” nature of this challenge are
illustrated by very simple “30,000 feet”
observations.

• “A study of initial presentation of young
onset CRC patients without established risk
factors found that 86% were symptomatic
at the time of diagnosis” *
• Siegel et al Can Epi Biomark 18(6) 1695-8

• For almost a quarter of a century our
collective “conditioned reflexes” have been
wired to think “genetic hereditary
syndrome” when we see a young (under
50) solid tumor patient in general and
especially with breast and colorectal
cancer.
• However…………..

• However…………..
• At least 75% of EAO-CRC patients DO NOT
report positive family history of the
disease
• Dr Kastrinos shared Dr Limburg’s Colorectal
CFR data indicating less than 6% of < 50
patients carried a Lynch Syndrome gene
mutation.

• So…………..
• We are facing a new problem…
• A Fresh Challenge…....
• A novel opportunity to advance our
understanding of the basic biology of the
pathophysiology of solid tumor malignancy
in the young.

• I have no links whatsoever to this man…

HOWEVER……
• A Potentially Useful Construct:
• “There are known knowns. These are things
we know that we know.
• There are known unknowns. That is to say,
there are things that we know we don't
know.
• But there are also unknown unknowns.
There are things we don't know we don't
know.”

Known Knowns……The Basics
• Health Insurance: what are the dimensions of
this problem? What specific strategies could
address this? Do related pre-existing issues
impact it”
• No Primary Care Physician: again – the
dimensions?
• Remember – in NYC > 80% unscreened had
insurance AND a primary care physician

Known Knowns……The Basics
• A POSITIVE family history for CRC and or
Lynch related malignancies
• A positive history for Inflammatory Bowel
Disease - IBD

Unknown Knowns……What is the true risk –
in YOUNG ADULTS?

especially in the young?
• Exercise vs. Sedentary Lifestyle??
• Obesity?
• Red Meat?
• Milk?
• Fast Foods?
• That’s NOT ME!

• Diabetes
• Sleep Patterns?
• Sitting Position?
• Alcohol?
• Tobacco?
• Recreational Drugs ?

• Microbiome?
• Periodontal Disease?
• Our Environment?
• The Exposome?

What DO we know about the
Unknown Knowns……?
• Any Data?

COloRECtal Transdisciplinary Study NCI
GAME-ON Consortium
• •Global study n= 52,649
• •OncoArray consortium n= 45,000
• •Diverse populations
• •Harmonizing epidemiologic data
• •Developing integrated risk prediction model

• Genetics……………………………..
• “Known Syndromes?
• Unknown Genetic Elements and
Syndromes
• Unknown Unknowns?

GWAS, SNPS,THE “EXPOSOME” and
Colorectal Cancer
• GWAS SNP studies have been…..disappointing
• If 21,000 is “underpowered” then ….?
• GWAS / SNP approach has not focused on
EAO-CRC (“enriched”)
• The GWAS SNP approach contrasts with the
whole exome / whole genome work discussed
by Drs McNamara and Kastrinos.

• “But there are also unknown unknowns.
know.”
• ?
• ?
• ?
• ?

• “But there are also unknown unknowns.
know.”
• Changing patterns of: Antibiotic Usage
• Aspirin Use?
• Attention Deficit Meds
• In Utero Exposures – “Exposome”
• Statins?

• How Can We Move Forward?

• No Health Insurance
• No Primary Physician
• INEFFECTIVE PRIMARY CARE & OTHER
PHYSICIANS
• Positive Family History
• Inflammatory Bowel Disease
• Diabetes
• High Calorie / Red Meat Containing / Processed
Foods

• “There are also unknown unknowns.
know.”
• ?
• ?
• ?
• ?

• “There are also unknown unknowns.
know.”
• Changing Patterns of: Antibiotic usage?
• Aspirin?
• Puberty and Menarche?
• Attention Deficit Meds?
• In-Utero Exposures?

And How Do We Advance Knowledge About
Young Adult CRC Unknowns?
• Little or none of what we have reviewed
has been directed to EAO-CRC
• Our NCI / CDC Cancer Registries do NOT
collect family history or other basic risk
factor data

• Little or none of what we have reviewed
has been directed to YOUNG ADULTS!
• Our NCI / CDC Cancer Registries do NOT
collect family history or other basic risk
factor data.

• As Discussed at Yesterday’s Never Too
Young Coalition Meeting:
• An IRB guided, HIPAA Compliant, State of
the Art Epidemiologic SURVEY of Young
Adult Survivors – (and Families?)
• MSKCC & MD Anderson – Genetic Alliance

One Thing We All SHOULD Know:
• If you are symptomatic – or have positive
“physical signs”
• You Need / Your Patient Needs……..
• A DIAGNOSTIC EVALUATION!
• Rectal Bleeding, Abdominal Pain, Change in
Bowel Habit

SUMMARY?

“You Never Know…”

• We know a great deal
• There are clear opportunities to use
that knowledge to inform patient
choice and provider response / action.
• Knowledge of RISK FACTORS can be
immediately deployed to RISK
REDUCTION strategies.

• Known RISK FACTORS need to be
validated in YOUNG ADULTS.
• Tackling UNKOWNS – requires
resourcing our national / international
cancer registries to address the
problem
• EAO-CRC Survivor Survey Project

RISK
• Identification
• Clarification
• Mitigation / Reduction

THANK YOU!

Martha Raymond, MA, CPN
Early Age Onset Colorectal Cancer Summit
March 21, 2015
Memorial Sloan Kettering Cancer Center
New York, New York
The Patient Perspective:
Exploring the ‘New Normal’ of the Young
Colon Cancer Patient

Quality of Life After an EAO-CRC
Diagnosis:
Knowledge Gaps and
Opportunities
Susan K. Peterson, PhD, MPH
Professor, Behavioral Science
1st Early Age Onset Colorectal Cancer Summit
New York, NY
March 21, 2015

Cancer Survivorship
• Cancer survivorship = the state or process
of living after a diagnosis of cancer
• Encompasses not only the physical but also
the social, psychological, and
spiritual/existential impact of cancer on one’s
life and for the remainder of one’s life.

Measuring Quality of Life
• Physical functioning
• Health status
• Sexuality and fertility
• Emotional adjustment
• Psychological and
behavioral functioning
• Spiritual/existential
domains
• Future outlook
• Independence
• School performance
• Work performance
• Social relationships
• Family relationships

• Establish autonomy and independence
– Achieve emotional independence from adults
– Self-esteem and identity development
– Acquire a set of values and an ethical system as a
guide to behavior
• Social and intimate relationships
– More mature relations with peers
– Prepare for marriage and family
• Establish financial independence
– Completion of school
– Prepare for a career.
Crucial Developmental
Milestones in Young
Adulthood

The Impact of an Illness
• Changes in mobility and physical functioning
• Changes in physical appearance
• Separation from peers and usual activities
• Increased dependence on parents at a
time they would usually be practicing
independence

Research on Quality of Life (QOL)
in
Young Adult Cancer Survivors

N=523 young survivors, age 15-39
• Compared to peers, YCS had lower physical and
social functioning; psychosocial, emotional, and
work/school functioning were similar to peers
• Worse HRQOL associated with: < high school, no
insurance, Hispanic ethnicity, active treatment (esp.
chemo), younger age, greater symptom burden
• Demands of normal physical, hormonal, cognitive
changes + other normal developmental changes
may contribute to lower levels of physical functioning
and fatigue
Smith, JCO, 2013
Health-related QOL in Young Cancer
Survivors

N=8375 survivors, diagnosed age 15-39
• Compared to peers, 30% of those age 40-64 report
poor/fair health vs. controls
• > 1 diagnosis associated with poorer QOL
• 45% of female CRC survivors report fair/poor health
– Long-term issues with infertility, bowel function
• Earlier age of diagnosis associated with more days
of poor mental health compared with older age at
diagnosis
– Gap in psychological support for youngest survivors
• Young age at diagnosis may have long-term QOL
impact across lifespan
Kirchhoff, JAYAO, 2014
Health-related QOL in Young Cancer
Survivors

• About half or fewer may achieve
recommended levels of physical activity (PA)
(ages 20-44)
• About half may be overweight or obese
• More physically active compared to older
survivors, less compared to age-related
peers
• Benefits of PA include improved QOL, symptom
reduction, and improved survival/reduced
recurrence risk in some cancers
• Tobacco use may be higher compared to older
survivors
Health Behaviors in Young Adult Cancer
Survivors

20
32
39 39
12
29
18
21
9
0
1
0
2
0
3
0
5
0
4
0
0 1 2 3
Number of Risk Factors
4
Percent Affected Unaffected
Prevalence of Risk Behaviors* for Colorectal Cancer
Among Persons at Risk for Lynch Syndrome
(n=429)
Risk Behavior Index Score (M), Cancer-affected vs. unaffected
1.4 vs. 1.7 (p<0.01)
*Smoking, alcohol use, dietary factors Burton, 2011

Unmet need rated by
70% or more
- Sexuality/intimacy-related
counseling
- Adoption services
- Retreats, camps
N=879 young cancer survivors
Needs were greater for younger
survivors and those diagnosed at
younger ages
Unmet need rated by
50% or more
- Diet, nutrition, exercise
- Family counseling
- Substance abuse
counseling
- Assistance with
transportation, child care
Unmet Information and Service Needs
of Young Cancer Survivors

• Medical care
– Perceived excellence in care after diagnosis
– Dissatisfaction with initial diagnosis delay
• Patient factors - still-maturing cognitive function,
reliance on peers for information
• Provider factors – not attributing symptoms to
cancer, poor provider-patient communication
– Side effects and symptoms
• Fatigue, depression, nausea, weight gain/loss, bowel function,
sexuality/fertility, changes in eating, decreased energy, body
image concerns
Zebrack, Psychosoc Onc, 2014
QOL Domains for Young Cancer Survivors

• Practical
– Financial
• Inadequate or gaps in health insurance
• Difficulty navigating health insurance coverage
• Work interruptions
• Acquiring early debt & limited financial resources
– School/ work disruption
• Treatment takes precedence over work, school

• Psychological and Spiritual
– Managing distress & emotions related to cancer,
treatment, and fear of recurrence
– Social functioning and isolation
• Disclosure and communication
– Maintain/re-establish normalcy
– Loss: job/school, appearance change,
relationship changes
***Positive attitudes, beliefs, feelings emerge from
cancer experience

Cancer Can Promote Psychological
Growth: Resilience Concept
• Some people can transform their lives by
responding to an illness in ways that
enhance the quality and meaning of their
lives
• Resilience = process for identifying and
developing resources or strengths to manage
stressors in order to gain positive outcome
from the experience
• Positive growth: greater maturity, appreciation
for life than population norms

• Racial/ethnic minority and medically underserved cancer
survivors have greater disparities in cancer outcomes
and access to survivorship care
– AfricanAmericans: higher mortality for CRC
– Uninsured or underinsured persons → more likely to
be diagnosed with advanced cancer → less likely to
receive standard care and survive → less likely to
adhere to surveillance and survivorship care
regimens
• Uninsured/underinsured = predominantly Hispanic,
recent immigrants, and the working poor
– Lifestyle behaviors (e.g., obesity, low physical activity,
tobacco use) related to cancer recurrence or mortality
are more prevalent among racial/ethnic minority, lower
resourced, and less educated survivors
CDC, 2011; American Cancer Society, 2012
Health disparities in U.S. cancer survivors

Including “Previvors” in the Discussion
About EAO-CRC
• Previvors = at increased risk of hereditary CRC, no CRC diagnosis
• Bowel function and QOL in children with FAP who underwent colectomy
at age < 14 y
• n=28, 56% female, mean colectomy age=12 y, current age=24 y
• Reported more night incontinence, nighttime stools (p<0.05); daytime
incontinence not different from adult sample
• 60% reported feeling embarassed “always or sometimes” due to bowel
concerns
• 20% reported restrictions at school or work, 30% restrictions in sports
due to bowel concerns
• 36% worried ‘at least some’ about post-surgery cancer risk; greater
in younger patients had greater worry
• Younger patients reported more FAP surgery-related distress
– Number of FAP-affected family members associated with higher distress
• Body image and self-esteem scores in normal ranges
Durno, Dis Colon Rectum (2012)

72% seek health information online
-Used phone: 31% cell phone, 52%
smartphone
- 19% smartphone owners
download Pew Internet Research Project, 2012; 2014
Social and mobile media to
reach EAO-CRC survivors

Computer and mobile technology use in the U.S.
Pew Internet Research Project, 2014

• In general, young adult cancer survivors not well-
represented in QOL studies of survivors
– Especially EAO-CRC
• QOL needs for young adult survivors are specific and
differ from older survivors
e.g., social functioning, financial stress, sexuality,
health information
→ Need better understanding of QOL in EAO-CRC
→ QOL measures specific to EAO-CRC
→ Resources targeted toward specific QOL support
in EAO-CRC
Gaps and Opportunities

• Subgroups of young adult cancer survivors
have specific needs
– Those diagnosed at youngest ages
– Underserved
– Fertility, sexuality considerations
– Pre-vivors
→ Need better understanding of life-stage specific
QOL in EAO- CRC
→ Resources targeted toward specific QOL
support in EAO-CRC

• Health care system may not be responsive to needs
of EAO-CRC
– Cancer treatment settings may reflect pediatric vs. older
adult divisions in care
– Delay in initial diagnosis and treatment, despite
persistent symptoms & health concerns
• Delays in diagnosis → skepticism, mistrust → poor
adherence to treatment, failure to seek future care
→ Resources needed for EAO-CRC that are
appropriate for varied stages of life, development
→ Support for providers who care for EAO-CRC
e.g., Focus Under Forty (ASCO, Livestrong), EAO-
targeted survivorship care plans and services

National Cancer Institute, National Institutes of Health, 1R42 CA126453,
1R41-CA126453-01
Seed Money Grant, Duncan Family Institute for Cancer Risk Assessment
and Prevention
Cancer Center Support Grant (CA016672, PI: R. DePinho)
National Cancer Institute, National Institutes of Health
MarthaAskins, PhD
Associate Professor and Pediatric Psychologist Psychosocial
Director,Adolescent and Young Adult Program
The Children’s Cancer Hospital at MD Anderson Cancer Center
Acknowledgements

*
• Cancer survivorship = the state or process
of living after a diagnosis of cancer
• Encompasses not only the physical but also
the social, psychological, and
spiritual/existential impact of cancer on one’s
life and for the remainder of one’s life.

*
• Physical functioning
• Health status
• Sexuality and fertility
• Emotional adjustment
• Psychological and
*behavioral functioning
• Spiritual/existential
*domains
• Future outlook
• Independence
• School performance
• Work performance
• Social relationships
• Family relationships

• Establish autonomy and independence
– Achieve emotional independence from adults
– Self-esteem and identity development
– Acquire a set of values and an ethical system as a
guide to behavior
• Social and intimate relationships
– More mature relations with peers
– Prepare for marriage and family
• Establish financial independence
– Completion of school
– Prepare for a career.
*

*
• Changes in mobility and physical functioning
• Changes in physical appearance
• Separation from peers and usual activities
• Increased dependence on parents at a
time they would usually be practicing
independence

N=523 young survivors, age 15-39
• Compared to peers, YCS had lower physical and
social functioning; psychosocial, emotional, and
work/school functioning were similar to peers
• Worse HRQOL associated with: < high school, no
insurance, Hispanic ethnicity, active treatment (esp.
chemo), younger age, greater symptom burden
• Demands of normal physical, hormonal, cognitive
changes + other normal developmental changes
may contribute to lower levels of physical functioning
and fatigue
Smith, JCO, 2013
*

N=8375 survivors, diagnosed age 15-39
• Compared to peers, 30% of those age 40-64 report
poor/fair health vs. controls
• > 1 diagnosis associated with poorer QOL
• 45% of female CRC survivors report fair/poor health
– Long-term issues with infertility, bowel function
• Earlier age of diagnosis associated with more days
of poor mental health compared with older age at
diagnosis
– Gap in psychological support for youngest survivors
• Young age at diagnosis may have long-term QOL
impact across lifespan
Kirchhoff, JAYAO, 2014
*

• About half or fewer may achieve
recommended levels of physical activity (PA)
(ages 20-44)
• About half may be overweight or obese
• More physically active compared to older
survivors, less compared to age-related
peers
• Benefits of PA include improved QOL,
symptom reduction, and improved
survival/reduced recurrence risk in some
cancers
• Tobacco use may be higher compared to
*

20
32
39 39
12
29
18
21
9
0
1
0
2
0
3
0
5
0
4
0
0 1 2 3
Number of Risk Factors
4
Percent Affected Unaffected
*
Risk Behavior Index Score (M), Cancer-affected vs. unaffected
1.4 vs. 1.7 (p<0.01)
*Smoking, alcohol use, dietary factors Burton, 2011

Unmet need rated by
70% or more
- Sexuality/intimacy-related
counseling
- Adoption services
- Retreats, camps
N=879 young cancer survivors
Needs were greater for younger
survivors and those diagnosed at
younger ages
Unmet need rated by
50% or more
- Diet, nutrition, exercise
- Family counseling
- Substance abuse
counseling
- Assistance with
transportation, child care
*

• Medical care
– Perceived excellence in care after diagnosis
– Dissatisfaction with initial diagnosis delay
• Patient factors - still-maturing cognitive function,
reliance on peers for information
• Provider factors – not attributing symptoms to
cancer, poor provider-patient communication
– Side effects and symptoms
• Fatigue, depression, nausea, weight gain/loss, bowel function,
sexuality/fertility, changes in eating, decreased energy, body
image concerns
Zebrack, Psychosoc Onc, 2014
*

• Practical
– Financial
• Inadequate or gaps in health insurance
• Difficulty navigating health insurance coverage
• Work interruptions
• Acquiring early debt & limited financial resources
– School/ work disruption
• Treatment takes precedence over work, school
*

• Psychological and Spiritual
– Managing distress & emotions related to cancer,
treatment, and fear of recurrence
– Social functioning and isolation
• Disclosure and communication
– Maintain/re-establish normalcy
– Loss: job/school, appearance change,
relationship changes
***Positive attitudes, beliefs, feelings emerge from
cancer experience
*

*
• Some people can transform their lives by
responding to an illness in ways that
enhance the quality and meaning of their
lives
• Resilience = process for identifying and
developing resources or strengths to manage
stressors in order to gain positive outcome
from the experience
• Positive growth: greater maturity, appreciation
for life than population norms

• Racial/ethnic minority and medically underserved cancer
survivors have greater disparities in cancer outcomes
and access to survivorship care
– African Americans: higher mortality for CRC
– Uninsured or underinsured persons → more likely to
be diagnosed with advanced cancer → less likely to
receive standard care and survive → less likely to
adhere to surveillance and survivorship care
regimens
• Uninsured/underinsured = predominantly Hispanic,
recent immigrants, and the working poor
– Lifestyle behaviors (e.g., obesity, low physical activity,
tobacco use) related to cancer recurrence or mortality
are more prevalent among racial/ethnic minority,
lower resourced, and less educated survivors
CDC, 2011; American Cancer Society, 2012
*

*
• Previvors = at increased risk of hereditary CRC, no CRC diagnosis
• Bowel function and QOL in children with FAP who underwent colectomy
at age < 14 y
• n=28, 56% female, mean colectomy age=12 y, current age=24 y
• Reported more night incontinence, nighttime stools (p<0.05); daytime
incontinence not different from adult sample
• 60% reported feeling embarassed “always or sometimes” due to bowel
concerns
• 20% reported restrictions at school or work, 30% restrictions in sports
due to bowel concerns
• 36% worried ‘at least some’ about post-surgery cancer risk; greater
in younger patients had greater worry
• Younger patients reported more FAP surgery-related distress
– Number of FAP-affected family members associated with higher distress
• Body image and self-esteem scores in normal ranges
Durno, Dis Colon Rectum (2012)

72% seek health information online
-Used phone: 31% cell phone, 52%
smartphone
- 19% smartphone owners
download Pew Internet Research Project, 2012; 2014
* Social and mobile media
to reach EAO-CRC
survivors

* Computer and mobile technology
use in the U.S.
Pew Internet Research Project,
2014

Early age onset_colorectal_cancer_2015

Early age onset_colorectal_cancer_2015

Recomendados

Recomendados

Más contenido relacionado

La actualidad más candente

La actualidad más candente (20)

Similar a Early age onset_colorectal_cancer_2015

Similar a Early age onset_colorectal_cancer_2015 (20)

Más de Colon Cancer Challenge Foundation

Más de Colon Cancer Challenge Foundation (6)

Último

Último (20)

Early age onset_colorectal_cancer_2015