2. All cancer involves changes in genes….
Threshold effect:
 During mitosis & DNA replication
 mutations occur in the cell’s genetic code
 Mutations are normally corrected by DNA repair
mechanisms
 If repair mechanism or cell cycle regulation is
damaged
 Cell accumulates too many mutations
 reaches ‘threshold’
 tumour development

3. Somatic mutations
 Occur in a single cell in the tissue
 Are not passed down to offspring
 Sporadic cancers

4. Germline mutations
 May be passed to offspring
 Inherited cancer syndromes

5. Knudson ‘two-hit’ Model
Sporadic Cancer ONE HIT
(hit=mutation)
Birth: Two non-mutated
copies of the gene
SECOND
HIT
One mutation in one gene;
Second gene non-mutated
Two mutations - one in
each gene
CANCER

6. Knudson ‘two-hit’ Model
Inherited Cancer
Born with one hit
(hit = mutation)
Birth: Two 2 non-
mutated copies of the
gene
SECOND
HIT
One mutation in one gene; One
non-mutated copy
Two mutations - one in
each gene
CANCER

7.  Cancer in 2 or more close relatives
(on same side of family)
 Early age at diagnosis
 Multiple primary tumors
 Bilateral or multiple rare cancers
 Constellation of tumors consistent with specific
cancer syndrome (e.g., breast and ovary)

8.  Personal or family history features
suggestive of hereditary cancer risk
 Test can be adequately interpreted
 Test result will aid in diagnosis or influence
medical management of the patient and/or
family
J Clin Oncol 2003;21:2397-406

9. Benefits Risks and Limitations
• Identifies high-risk • Does not detect all mutation
individuals • Continued risk of sporadic
• Identifies non-carriers in cancer
families with a known • Efficacy of interventions
mutation unproven
• Allows early detection and • May result in or economic harm
prevention strategies • False sense of security
• May relieve anxiety, and • Change in family dynamics
uncertainity • Discrimination by employer, and
insurer
• Loss of privacy

10.  Hereditary Breast Cancer Syndromes
 BRCA1, BRCA2, Cowden, Li-Fraumeni
 Hereditary Colorectal Cancer Syndromes
 HNPCC
 FAP
 Endocrine Syndromes –
VHL, MEN1, MEN2, FMTC

14. % of Hereditary Breast
Gene Cancer
BRCA1 20%–40%
BOCS
BRCA2 10%–30%
TP53 Li-Fraumenni <1%
PTEN Cowden’s <1%
CHEK2 <1%
Undiscovered genes 30%–70%
ASCO

15.  1 in 800 women in the general population
 5-10% of all women with breast CA
 18% of women with breast CA <50 and
one close relative with breast CA <50
 2% of all women of Ashkenazi Jewish
ancestry
 25% of all Ashkenazi Jewish women with
ovarian cancer

16.  Tumor suppressor
 Tumor suppressor
gene on 17q21
gene on 13q12
 Protein has role in
 Protein has role in
genomic stability –
genomic stability –has
facilitates DNA repair
a role in meiosis and
by recognition of
repair of double-strand
double strand breaks
breaks
during homologous
recombination  ~1,300 different
mutations reported
 > 1,200 different
mutations reported

19. Hereditary Cancer Sporadic Cancer
Breast - 41 Breast - 62
Ovarian - 40-50 Ovarian - 60
Prostate - 63 Prostate- 71

20.  Multiple cases of breast or ovarian cancer on
same side of family, especially
 in closely related relatives
 in more than one generation
 when breast cancer is diagnosed before age 50
 A family member with breast cancer
diagnosed before age 35
 A family member with both breast and ovarian
cancers
 An Ashkenazi Jewish heritage, particularly with
relatives with breast or ovarian cancer

21.  A family member with primary cancer in both
breasts
(especially if before age 50)
 A family member with ovarian cancer
 A family member with male breast cancer
 A family member with an identified
BRCA1 or BRCA2 mutation

22. Positive BRCA1 or BRCA2
test result
Possible testing for
other adult relatives
Increased Lifestyle Chemo- Prophylactic
surveillance changes prevention surgery

23. Breast Cancer
 Monthly BSE (begin by age 18) and
 Early clinical surveillence (begin by age
25)
 Clinical breast examination every 6 months
 Mammogram yearly
 MRI yearly(ACS 2007)
 Prompt evaluation of abnormal findings

24. Ovarian Cancer
 No proven metholdology
 Annualy or semiannualy (begin by age 25-
35)
 Ca-125
 Trans vaginal color-doppler ultrasound
 Pelvic examination

25. Breast Cancer
 Blocking the effects of Oestradiol by Tamoxifen, or
Raloxifen.
 Reducing circulating levels of Oestradiol from fat
cells, and adrenal cells by
 Aromatase inhibitors (Anastrazole, Letrozole, and
Exemestane ) in postmenopausal women
 LHRH agonists (Deslorelin) in premenopausal women,
Deslorelin reduces the risk by stopping estrogen
production from ovaries in, and by reducing breast
density.
 Fenretinide ( vitamin A) In premenopausal women
under the age of 40
.

26. Ovarian Cancer
 Oral contraceptives have been shown to decrease
the risk of ovarian cancer in the general population.
 In women with mutations in BRCA1 or BRCA2 that
risk reduction was also documented, with 60%
reduction (RR=0.4) with use of 6 years or more.
Narod SA, Risch H, Moslehi R, et al. NEJM 1998, Aug 13;339(7):469-71.
Fisher B, Costantino JP, Wickerman DL, et al. JNCI, 1998; 90(18):1371-1388.

27.  Cowden’s (TP53) – 25-50% breast ca risk
 Oral lesions, GI hamartomas, benign breast dz
 Thyroid, uterine lesions or CA, macrocephaly
 Li-Fraumeni (PTEN)– breast ca < age 40
 Often childhood cancers
 sarcoma, leukemia, brain adrenocortical CA
 HDGC(CDH1) -gastric, lobular breast and
colon cancers
 Lower risk genes: ATM, PALB2, CHEK2

30. Two common syndromes:
 Lynch syndrome
 Also known as Hereditary Non Polyposis Colorectal
Cancer or HNPCC
 ~2 - 5% of colorectal cancer
 Prevalence of 1 in 200 - 2,000*
 Familial Adenomatous Polyposis (FAP)
 <1% of colorectal cancer
 Prevalence of 1 in 8,000 – 14,000*
 Autosomal dominant inheritance
*Prevalence depends on population

31. when mutated
 Lynch syndrome (HNPCC):
 Mutations in DNA repair genes lead to an
accumulation of mutations which may result
in malignancy.
 FAP:
 Mutations in a tumour suppressor gene
cause an increase in cell proliferation and a
decrease in cell death.

33. HNPCC is associated with germline mutations
in any one of at least four genes

34.  Early but variable age at CRC
diagnosis (~45 years)
 Tumor site in proximal colon
predominates
 Patients rarely exhibit polyps,
making early detection difficult
 Extracolonic cancers:
endometrium , ovary, stomach,
urinary tract, small bowel, bile
ducts, sebaceous skin tumors

35. Cancer Site General Lynch
Pop Syndrome
Colon 5-6% 80%
Avg age dx 44
~75% right-sided
Endometrium 2-3% 40-60%
Stomach 1% 13%
Ovaries 1-2% 12%
Lesser increased risks for:
small bowel, hepatobiliary tract, urinary tract, and brain cancers

36.  Individuals with colorectal or endometrial
cancer diagnosed <50
 Individuals with 2 Lynch syndrome related
cancers diagnosed at any age
 Includes multiple synchronous or metachronous
colorectal cancers
 Individuals with colorectal or endometrial
cancer who have a 1st degree relative with any
Lynch associated malignancy
 One of the cancers dx < 50
 Relatives of individuals with a known Lynch
syndrome mutation
Modified from Bethesda Guidelines JNCI 89:1758-1762

37. Recommendations for Individuals with Lynch Syndrome
Cancer Site Procedure Age to Begin Interval
COLON1 Colonoscopy 20-25 Every 1-2 years
or 5-10 yrs before the until age 40;
earliest CRC dx in the annually
family; whichever is
younger
thereafter
Endometrial Bx
ENDOMETRIUM and/or 30-35 Every 6-12
& OVARIES2 Transvaginal months
ultrasound and
CA-125
STOMACH3 EGD 30-35 Every 1-2 yrs
URINARY Ultrasound and 30-35 Every 1-2 yrs
TRACT3 Urine Cytology
1 Sub-total colectomy could be considered (not standard of care)
2 Could also consider prophylactic hysterectomy and BSO
3 Some advocate only if there is a positive family hx of these types of cancers

38.  Chromosome 5, APC gene
 High penetrance
 Characterized by:
 Early onset
 >100 adenomatous polyps
 Variant form:
 Attenuated FAP may occur with >10 but <100
polyps.

39.  Colorectal adenomatous polyps begin to appear at
an average age of 16 years (range 7-36 years)
 Average age at diagnosis: 34-43 years, when >95%
have polyps
Age Individuals with colon
cancer
21 7%
45 87%
50 93%
From: http://www.genetests.org

40.  ~50-90% develop small bowel polyps
 lifetime risk of small bowel malignancy is 4-
12%
 ~50% develop gastric polyps
 ~10% gastric cancer
 ~10% develop desmoid tumours

41.  Colon
 Annual sigmoidoscopy or colonoscopy beginning at
age 10-15 yrs
 Prophylactic colectomy following polyp detection
w/continued surveillance of rectum/ileal pouch
 Consider use of NSAIDs to decrease polyp burden
 Duodenum/stomach
 EGD age 25, repeat 1-3 yrs depending on findings
 Hepatoblastoma
 Abdominal U/S & AFP every 6 mos from birth to 5
yrs.
NCCN Practice Guidelines & Gastroenterology 2003; 124 AGA Statement

42.  Prophylactic colectomy is necessary for patients
with FAP once polyps develop
 Colectomy may become necessary in patients with
AFAP if polyps become too numerous to manage via
colonoscopy

43.  Lifetime polyp burden of 20 to 100, usually more
proximal located
 Polyps may not appear until mid life
 Lifetime risk of CRC = 80%
 Extracolonic tumors occur at same rate as FAP
 Surveillance:
 annual colonoscopy starting late teens or early 20’s
 EGD every 1 to 3 years beginning around age 25

44. • 5-10% of cancers are Hereditary.
• Hereditary cancers are caused by germ-
line mutation.
• Life time risk for cancer is significantly high
in an individual with positive mutant genes.
• Possible to diagnose mutant genes.
 Possible to prevent cancer by high
surveillance, chemoprevention, and
surgical intervention.