cancer and genetics

1. GENETIC PREDISPOSITION
TO CANCER

2. OBJECTIVES
 Review the role of genetic susceptibility in
various cancer types
 Discuss the genetic syndromes and testing
options of various cancer types

3. GENETICS IN CANCER
 5-10% of all malignancies are due to highly
penetrant hereditary cancer predisposition
syndromes [Ballinger, 2012]
 Over 400 cancer-related genes have been identified
May account for many familial cancers
Caution! Current clinical testing may
include some of these genes of lower-risk

4. BREAST CANCER
•
•
•
•
Most prevalent type of cancer in women
2nd leading cause of cancer death in the US
New cases in 2012: 229,060 (estimated)
Deaths in 2012: 39,920 (estimated)
15%−20%
5%–10%
Sporadic
Family clusters
Hereditary

5. OVARIAN CANCER
•
•
•
•
22,000 newly diagnosed in the US annually
1.4% lifetime risk
~45% 5-year survival rate
4.6x RR if mother had ovarian cancer and 1.6x RR
is sister [Ziogas et al., 2009]
5%–10%
Sporadic
Hereditary

6. ENDOMETRIAL CANCER
• 47,130 newly diagnosed in 2012 (estimated)
• Lifetime risk is estimated to be 2.5%
• 8,010 estimated deaths in 2012
• Most common heritable form is Lynch syndrome
(a.k.a. hereditary non-polyposis coli) which
represents 2-3% of all cases
• May also be related to Cowden (PTEN Hamartoma
Tumor syndrome) and Peutz-Jeghers

7. COLORECTAL CANCER
•
•
•
•
•
4th most common cancer diagnosis in US
1 in 20 Americans will develop CRC
In 2012, expected number of new cases: 143,460
Expected deaths due to CRC: 51,690
Death rate is declining – early detection and
prevention
5%
General population
15%-20%
Personal h/o CRC
15%–40%
Inflammatory bowel disease
HNPCC mutation
70%–80%
FAP
>95%
0
20
40 60 80 100
Lifetime risk (%)

8. GASTRIC CANCER
•
Estimated 21,320 new diagnoses in the US (2012)
•
Estimated 10,540 deaths in the US (2012)
•
4th leading cause of cancer deaths worldwide
•
5 year survival of 20%
•
3-10% are hereditary
– Hereditary diffuse gastric cancer
– Hereditary breast/ovarian cancer
– Lynch syndrome
– Li-Fraumeni syndrome
– Familial Adenomatous Polyposis
– Juvenile polyposis
– Peutz-Jeghers

9. PANCREATIC CANCER
•
Estimated 43,920 new diagnoses in the US (2012)
•
4th leading cause of cancer-related deaths in the US
– Estimated deaths 37,390 in 2012
•
5-10% are hereditary
– Associated with familial forms of pancreatitis
– Breast-ovarian cancer syndrome (BRCA2 and PALB2)
– Familial multiple melanoma with 0.6-31% lifetime risk
•
Higher risk if first-degree relative with pancreatic ca.
– Lynch syndrome 0.4-4% lifetime risk
– Peutz-Jeghers 8-36% risk

10. MELANOMA
•
•
76,250 new cases in the US in 2012 (estimated)
9,180 estimated attributable deaths in 2012
•
~10% hereditary
– Familial atypical mole-melanoma syndrome
• Accounts 5-7% of all melanoma
– May be associated with HBOCS (BRCA2)

11. PROSTATE CANCER
• Most frequently diagnosed cancer in US men
- 36% of all cancers
• Lifetime risk for men in US: 15-20%
• 241,000 new cases diagnosed in 2012
(estimated)
• 5-10% is heritable
– ~40% under 55y
– Higher in families with
breast/ovarian cancer
5-10%

12. CANCER SYNDROMES

13. GENETIC SYNDROMES
•
There are those with dysmorphic or characteristic features that also have a
tumor predisposition
–
–
–
–
–
–
–
–
–
–
Beckwith-Wiedemann syndrome
Bloom syndrome
Diamond-Blackfan
Down syndrome
Fanconi anemia
Neurofibromatosis type I and II
Gorlin syndrome (basal cell nevus syndrome)
Rothmund-Thomson syndrome
Tuberous sclerosis
Werner syndrome

14. HEREDITARY BREAST CANCER SYNDROMES
•
Hereditary breast-ovarian cancer (5% of all breast cancer)
•
Li-Fraumeni (~1%)
•
PTEN hamartoma (<1%)
•
Peutz-Jeghers (<1%)
•
Hereditary diffuse gastric cancer syndrome
•
Also:
– Autoimmune lymphoproliferative (ALPS)
– Ataxia telangiectasia
– Bloom syndrome
– Familial melanoma
– Werner syndrome
– Xeroderma pigmentosa

15. HERITABLE OVARIAN
CANCER
• Lifetime risk varies from 12-60%
• Often earlier than those of the general population
• 6-15% breast/ovarian cancer syndrome
• Also includes:
– Lynch syndrome
– Peutz-Jeghers syndrome

16. BREAST/OVARIAN CANCER
SYNDROME
• Primarily BRCA1 and BRCA2
• Frequency of carriers 1 in 300 (BRCA1) to 1 in 800 (BRCA2)
– Ashkenazi Jewish (1 in 40)
• Accounts for >90% of families with breast and ovarian cancers

17. BREAST-OVARIAN CANCER
SYNDROME
•
Of those with BRCA1 mutations:
– 50-80% risk of invasive breast carcinoma-females
• ~1% risk for males
– Up to 60% risk of serous ovarian carcinoma
– Up to 30% risk of prostate cancer
– 1-3% risk of pancreatic
•
Of those with BRCA2 mutations:
– 40-85% risk of invasive breast carcinoma-females
• 6-7% risk for males
– Up to 35% risk of serous ovarian carcinoma
– Up to 39% risk of prostate cancer
– 2-7% risk of pancreatic

18. HBOCS- TUMOR
CHARACTERISTICS
• Breast tumor often originates from breast
epithelia cells
– Basal keratin positive
• More commonly a/w with invasive lobular
and ductal carcinoma as well as DCIS
• More likely to be high-grade malignancies
and lymph node positive
– Estrogen receptor negative
– Progesterone receptor negative
– Her2/neu negative
• >90% ovarian serous adenocarcinoma

19. HEREDITARY CRC
SYNDROMES
•
Accounts for 5-10% of all CRC cases
•
Polyposis types:
– Adenomatous
• Familial adenomatous polyposis (<1%)
• MYH-associated polyposis (<1%)
– Hamartomatous
• Juvenile polyposis (<1%)
• Peutz-Jeghers
• Cowden (PTEN)
•
Lynch syndrome (2-3%)
– Often not polyps but can have and still increased cancer risk
•
Seldom in:
– Bloom, hereditary diffuse gastric cancer syndrome, and Li-Fraumeni

20. LI-FRAUMENI SYNDROME
•
Prevalence: Up to 1 in 20,000
•
Inheritance: Autosomal dominant
•
Gene: TP53
•
Lifetime risk of cancer:
– 50% by age 30-35y
– 90% by 60y
– Female lifetime risk is 90%
– Male lifetime risk is 70%
– 57% risk of a second primary

21. LFS- DIAGNOSTIC CRITERIA
•
Proband with sarcoma <45yoa
•
First-degree relative with any cancer <45yoa
•
First- or second-degree relative with any cancer <45yoa or sarcoma at any age
•
LFS-related cancers include:
– Breast cancer
• Most common LFS-related cancer
• Lifetime risk 49%
• <1% overall of total breast cancers; however, more likely with diagnosis <30yoa (up
to 7%)
• More likely to be triple positive
– Soft tissue and bone sarcomas
– Brain tumors Choroid plexus tumors
– Adrenocortical carcinoma
– Leukemia
– Bronchoalveolar cancer
LFS accounts for 80% of childhood ACC

22. PTEN HAMARTOMA SYNDROME
• Prevalence: 1 in 200-250,000
• Inheritance: Autosomal dominant
• Gene: PTEN
Planchon S M et al. J Cell Sci 2008;121:249-253

23. PTEN HAMARTOMATOUS
SYNDROME
•
25-85% lifetime risk of breast cancer
– <1% overall of all breast cancer
– Average age of diagnosis 38-46y
•
5-28% lifetime risk of endometrial cancer
•
3-35% lifetime risk of non-medullary thyroid (follicular) cancer
•
40-93% lifetime risk of polyps (hamartomatous)
– 9% lifetime risk of CRC
– Ganglioneuroma
– 13% of PTEN mutation-associated Cowden
syndrome patients developed CRC <50yoa
•
Strongly a/w Lhermitte-Duclos (dysplastic gangliocytoma)
•
May also be associated with renal cancer and melanoma

24. PTEN PHYSICAL
FEATURES
•
•
Macrocephaly
•Macrocephalic
Facial papules
(trichilemmomas)
•No unusual skin
lesions or
pigmentation
– ≥2
pathognomic?
•
Oral mucosal
papillomatosis
– 99% incidence
•
Acral keratoses
•BrCa at 42yoa

25. BREAST CANCER- WHEN TO
REFER
•
•
Breast cancer <50yoa
Triple negative breast cancer
– 11-28% have BRCA1 mutations
•
Two breast cancer primaries in a single individual
– ~30% risk of second primary in 10 years for
BRCA1/2
•
•
Breast or ovarian cancer at any age in those of Ashkenazi Jewish
ancestry
Breast cancer at any age and…
– ≥1 close relative* with breast cancer <50yoa
– ≥1 close relative* with epithelial ovarian cancer at
any age
– ≥2 close relatives* with breast cancer and/or
pancreatic cancer at any age

26. ( WHEN TO REFER (2
•
A combination of breast cancer with one or more of the following in close relatives:
– Thyroid cancer
– Sarcoma
– Endometrial cancer
– Pancreatic cancer
– Brain tumors
– Diffuse gastric cancer
– Dermatologic manifestations and/or macrocephaly
– Leukemia/lymphoma
•
Ovarian cancer with a family history of breast and/or ovarian cancer
•
Male breast cancer
– 4-14% due to BRCA2

27. LYNCH SYNDROME
•
A.k.a. hereditary nonpolyposis colorectal cancer; includes Muir-Torre
(sebaceous adenomas)
•
Incidence: 1 in 440
•
Accounts for:
MSH6
– 2-10% of all CRC
MSH2
– 2% of ovarian cancers
– 2-5% of endometrial
• 9-20% of those <50y
•
Autosomal dominant
•
Multiple genes (MLH1, MSH2, MSH6,
PMS1
MSH3, PMS1, PMS2, TACS (EPCAM), TD1)
Chr 2

28. LYNCH SYNDROME- CANCER
RISKS
•
22-92% lifetime risk of CRC
– Mean age of 44yo (MLH1 or MSH2)
•
6-19% lifetime risk of gastric cancer
– More common in Japan
•
20-70% risk of endometrial cancer
– MSI-IHC testing recommended
•
•
•
•
4-12% risk of ovarian cancer
18% hepatobiliary
5-10% urinary tract cancers
May also develop:
– Small bowel, pancreatic cancer
– Skin: (sebaceous carcinomas, keratocanthomas,
and epitheliomas)
– Brain tumors, especially glioblastoma

29. LYNCH SYNDROME- AMSTERDAM
II
• Amsterdam II criteria (all have to be
met):
– ≥3 family members, one of whom is a firstdegree relative of the other two, with
HNPCC-related
cancers
(CRC,
endometrial, stomach, small bowel,
hepatobiliary, renal pelvic, or ureteral
cancer)
– Two successive generations
– One or more HNPCC-related
diagnosed before 50yoa
cancer

30. LYNCH SYNDROME- BETHESDA
• Modified Bethesda
following):
criteria
(any
of
the
– CRC diagnosed <50yoa
– Presence of synchronous or metachronus CRC, or
other HNPCC-related tumors (CRC, endometrial,
gastric, ovarian, pancreatic, ureteral, biliary tract and
brain tumor) regardless of age
– CRC with microsatellite instability-high <60yoa
– CRC in ≥1 first-degree relatives with HNPCC-related
tumor with one cancer <50yoa
– CRC in ≥2 first- or second-degree relatives at any age

31. LYNCH SYNDROME- MSI
• Microsatellite instability
– Microsatellites are highly-repetitive DNA
sequence
– Susceptible to dynamic changes if not for
the mismatch repair genes
• MSI-high= instability >30% of cells
• MSI-low= instability <30% of cells
• MSI stable= no evidence of MSI

32. LYNCH- MSI CAVEATS
• 90% of inherited tumors are MSI-high
• MSI-high can be caused by many somatic (not
inherited)
events,
most
notably
BRAF
methylation/mutation
• Some Lynch syndrome patients will have MSI-low or
MSI-stable testing
• Immunohistochemistry for mismatch repair proteins
(MLH1, MSH2, MSH6, PMS1, PMS2) recommended
as adjunctive analysis

33. LYNCH- GENETIC
TESTING
• If met Amsterdam II criteria, recommend genetic
testing
• If met Bethesda, testing of the tumor sample by
MSI/IHC recommended initially with consideration of
genetic testing
• If MSI-high and IHC positive (i.e. absence of one of
the proteins) the probability of Lynch is high therefore
genetic testing recommended

34. FAMILIAL ADENOMATOUS
POLYPOSIS
•
A.k.a Turcot or Gardner syndromes
•
1 in 6-20,000 live births
•
Due to genetic defect in APC
– If negative, consider MYH
testing
•
Accounts for <1% of all CRC
•
Hallmark is the adenomatous polyposis
– 20-100% penetrance in the
duodenum
•
100% lifetime risk of CRC with average
age of cancer diagnosis of 39y

35. FAP: AGE AND DEVELOPMENT
OF ADENOMAS AND CRC
100
% of patients
with neoplasia
FAP
Adenomas
80
CRC
60
40
General population
20
0
20
40
Age
60
80

36. FAP- ASSOCIATED RISKS
•
4-12% lifetime risk of other intestinal cancers
– 0.5-2% gastric
– 5% duodenal
•
1-2% risk of pancreatic and non-medullary thyroid
•
0.6% risk of hepatoblastoma before 6yoa with 1-2% lifetime
•
10-30% lifetime risk of desmoid tumors
•
Also a/w medulloblastoma as well as gliomas and ependymoma
•
CHRPE- congenital hypertrophy of the retinal pigmented epithelium

37. PEUTZ-JEGHERS SYNDROME
•
•
•
•
•
Prevalence: 1 in 25-280,000
Inheritance: Autosomal dominant
Gene: STK11
Hamartomatous and adenomatous polyposis especially
of the small intestine
37-93% lifetime risk of cancer
– 38-66% risk of gastrointestinal
•
•
29% gastric
•
–
–
–
–
2-39% CRC
11-36% pancreatic
30-54% risk of breast cancer
Lifetime uterine cancer risk is 9-21%
Lung 15% lifetime risk
Includes ovarian and sex cord tumors
Labial and oral mucosal
hyperpigmentation- may
fade with time

38. LETTERMAN’S TOP 10 GENETIC
CANCERS
1.
2.
3.
4.
5.
6.
7.
8.
Adrenocortical carcinoma (LiFraumeni and BWS)
Carcinoid tumors (MEN I)
Diffuse gastric cancer (Hereditary Diffuse Gastric Cancer)
Fallopian tube (HBOCS)
Leiomyosarcoma (HLRCC, Lynch, Rb)
Medullary thyroid carcinoma (MEN 2)
Paraganglioma/pheo (MEN 2, VHL, NF1, PGL)
Renal cell carcinoma- chromophobe, hybrid oncocytotic,
oncocytoma histology (Britt-Hogg-Dube)
9. Sebaceous carcinoma (Lynch)
10. Sex cord tumor with annular tubule (PJS)