Cancer susceptibility syndromes dr. varunPresentation Transcript
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
Somatic mutations Occur in a single cell in the tissue Are not passed down to offspring Sporadic cancers
Germline mutations May be passed to offspring Inherited cancer syndromes
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 geneCANCER
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 geneCANCER
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)
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 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
Hereditary Breast Cancer Syndromes BRCA1, BRCA2, Cowden, Li-Fraumeni Hereditary Colorectal Cancer Syndromes HNPCC FAP Endocrine Syndromes – VHL, MEN1, MEN2, FMTC
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
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
Hereditary Cancer Sporadic CancerBreast - 41 Breast - 62Ovarian - 40-50 Ovarian - 60Prostate - 63 Prostate- 71
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
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
Positive BRCA1 or BRCA2 test resultPossible testing forother adult relatives Increased Lifestyle Chemo- Prophylacticsurveillance changes prevention surgery
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
Ovarian Cancer No proven metholdology Annualy or semiannualy (begin by age 25- 35) Ca-125 Trans vaginal color-doppler ultrasound Pelvic examination
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.
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.
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
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
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.
HNPCC is associated with germline mutations in any one of at least four genes
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
Cancer Site General Lynch Pop Syndrome Colon 5-6% 80% Avg age dx 44 ~75% right-sidedEndometrium 2-3% 40-60% Stomach 1% 13% Ovaries 1-2% 12% Lesser increased risks for:small bowel, hepatobiliary tract, urinary tract, and brain cancers
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 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 BxENDOMETRIUM 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
Chromosome 5, APC gene High penetrance Characterized by: Early onset >100 adenomatous polyps Variant form: Attenuated FAP may occur with >10 but <100 polyps.
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
~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
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
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
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
• 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.