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.