CANCER SUSCEPTIBILITY SYNDROMESDR. VARUN GOELMEDICAL ONCOLOGISTRAJIV GANDHI CANCER INSTITUTE, DELHI
CancerAll 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
Cancer Arises from Gene Mutations
Somatic mutations
Occur in a single cell in the tissue Are not passed down to offspring Sporadic cancers
Cancer Arises from Gene Mutations
Germline mutations
May be passed to offspring Inherited cancer syndromes
Knudson ‘two-hit’ Model
Sporadic Cancer
Birth: Two non-mutated copies of the gene
One mutation in one gene; Second gene non-mutated
ONE HIT
(hit=mutation)
SECOND HIT
Two mutations - one in each gene
CANCER
Knudson ‘two-hit’ Model
Inherited Cancer
Birth: Two 2 non-mutated copies of the gene
One mutation in one gene; One non-mutated copy
SECOND HIT
Two mutations - one in each gene
CANCER
Born with one hit
(hit = mutation)
When to Suspect Hereditary Cancer Syndromes
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)
Genetic Testing
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
Benefits, Risks, and Limitationsof geneTesting
Benefits
• Identifies high-risk individuals
• Identifies non-carriers in families with a known mutation
• Allows early detection and prevention strategies
• May relieve anxiety, and uncertainity
Risks and Limitations• Does not detect all mutation• Continued risk of sporadic
cancer • Efficacy of interventions
unproven• May result in or economic harm• False sense of security• Change in family dynamics• Discrimination by employer, and
insurer• Loss of privacy
Cancer Syndromes Hereditary Breast Cancer Syndromes
BRCA1, BRCA2, Cowden, Li-Fraumeni Hereditary Colorectal Cancer Syndromes
HNPCC FAP
Endocrine Syndromes – VHL, MEN1, MEN2, FMTC
HEREDITARY BREAST CANCER SYNDROMES
How Much Breast and Ovarian Cancer Is Hereditary?
Causes of Hereditary Susceptibility to Breast Cancer
ASCO
Causes of Hereditary Breast Cancer
Gene
BRCA1
BRCA2
TP53 Li-Fraumenni
PTEN Cowden’s
CHEK2
Undiscovered genes
% of Hereditary Breast Cancer
20%–40%
10%–30%
<1%
<1%
<1%
30%–70%
BOCS
BRCA1/2 Mutation Incidence
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
BRCA 1 BRCA 2
Tumor suppressor gene on 17q21
Protein has role in genomic stability – facilitates DNA repair by recognition of double strand breaks during homologous recombination
> 1,200 different mutations reported
Tumor suppressor gene on 13q12
Protein has role in genomic stability –has a role in meiosis and repair of double-strand breaks
~1,300 different mutations reported
BRCA1 Associated Cancers: Lifetime Risk
BRCA2 Associated Cancers: Lifetime Risk
Average Age of Diagnosis
Hereditary Cancer Sporadic Cancer
Breast - 41 Breast - 62
Ovarian - 40-50 Ovarian - 60
Prostate - 63 Prostate- 71
Who should be offered for genetic testing?....
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
…Who should be offered for genetic testing?....
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
Clinical Management of BRCA Mutation-Positive Patient
Positive BRCA1 or BRCA2 test result
Possible testing for other adult relatives
Increasedsurveillance
Prophylacticsurgery
Lifestyle changes
Chemo-prevention
BRCA mutation carriers Increased Surveillance
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
BRCA mutation carriers Increased Surveillance
Ovarian Cancer No proven metholdology Annualy or semiannualy (begin by age 25-
35) Ca-125 Trans vaginal color-doppler ultrasound Pelvic examination
Medical InterventionsBreast 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
.
Medical Interventions
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.
More Breast Cancer Syndromes (<1%)
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
HEREDITARY COLORECTAL CANCER SYNDROMES
Causes of Hereditary Susceptibility to CRC
Inherited Colorectal CancerTwo 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
Colorectal cancer genes…
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.
when mutated
Risk of Colorectal Cancer (CRC)
Genetic Heterogeneity in HNPCC
HNPCC is associated with germline mutations in any one of at least four
genes
Clinical Features of HNPCC
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
Lynch Syndrome -- Lifetime Cancer Risks
Cancer Site General Pop
Lynch 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
…Who should be offered for genetic testing?.... 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
Recommendations for Individuals with Lynch Syndrome
Cancer Site Procedure Age to Begin Interval
COLON1 Colonoscopy 20-25 or 5-10 yrs before the earliest CRC dx in the family; whichever is
younger
Every 1-2 years until age 40;
annually thereafter
ENDOMETRIUM & OVARIES2
Endometrial Bx and/or
Transvaginal ultrasound and
CA-125
30-35 Every 6-12 months
STOMACH3 EGD 30-35 Every 1-2 yrs
URINARY TRACT3
Ultrasound and Urine Cytology
30-35 Every 1-2 yrs
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
Familial Adenomatous Polyposis Chromosome 5, APC gene High penetrance Characterized by:
Early onset >100 adenomatous polyps Variant form:
Attenuated FAP may occur with >10 but <100 polyps.
Consequences of FAP 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
Consequences of FAP
~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
FAP Surveillance 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
Surgical Management for FAP 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
Attenuated FAP Variant of FAP
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
summary
• 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.