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An Overview of Clinical Cancer Genetics

An Overview of Clinical Cancer Genetics. M ónica Alvarado, MS, CGC Certified Genetic Counselor Regional Administrator, Genetic Services Kaiser Permanente, Southern California. New cases in U.S. each year. Breast cancer: >185,000 Colorectal cancer: >150,000 Ovarian cancer: > 25,000

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An Overview of Clinical Cancer Genetics

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  1. An Overview of Clinical Cancer Genetics Mónica Alvarado, MS, CGC Certified Genetic Counselor Regional Administrator, Genetic Services Kaiser Permanente, Southern California

  2. New cases in U.S. each year • Breast cancer: >185,000 • Colorectal cancer: >150,000 • Ovarian cancer: > 25,000 If 5% to 10% of these are due to hereditary cancer syndromes then…Each year between18,000 to 36,000newly diagnosed patients would be appropriate for referral to a cancer genetic counselor • Reports indicate that only about 5% to 7% of patients who have a personal/family history of cancer suggestive of hereditary cancer are ever referred for genetic counseling.

  3. GENETIC vs. INHERITED CANCER IS ALWAYS GENETIC BUT RARELY INHERITED

  4. Cancer Arises From Gene Mutations Germline mutations Somatic mutations Parent Child All cells affected in offspring Somatic mutation (eg, breast) Mutation in egg or sperm • Occur in nongermline tissues • Are nonheritable • Present in egg or sperm • Are heritable • Cause cancer family syndromes

  5. When to Suspect Hereditary Cancer Syndrome • Cancer in 2 or more close relatives (on same side of family) • Early age at diagnosis (< 45 yrs) • Multiple primary tumors • Bilateral or multiple rare cancers • Constellation of tumors consistent with specific cancer syndrome (eg, breast and ovary, colon & endometrium) • Evidence of autosomal dominant transmission • Triple negative breast cancer plus any one of the above

  6. Normal Affected Autosomal Dominant Inheritance • Each child has 50% chance of inheriting the mutation • No “skipped generations” • Equally transmitted by men and women

  7. Sporadic(~60%) Familial (~30%) Rare syndromes (~4%) HNPCC (3-5%) FAP (<1%) Colorectal Cancer: >150,000 cases annually in the US Nat Med 1996; 2:169-74

  8. Familial Risk for Colorectal Cancer 70% Approximate lifetime CRC risk to age 70 yrs (%) 17% 10% 8% 6% 2% One 1° and two 2° One 1° age <45 HNPCC mutation None One 1° Two 1° Aarnio M et al. Int J Cancer 64:430, 1995 Houlston RS et al. Br Med J 301:366, 1990 St John DJ et al. Ann Intern Med 118:785, 1993 Affected family members

  9. Lynch Syndrome (HNPCC)- About 3% of all Colorectal Cancer • Early (but variable) onset of CRC: • Average age of onset of CRC is 45 years • Defects in one of 4 mismatch repair genes: • MLH1, MSH2, MSH6, PMS2 • Tumors tend to be right sided • 90% or more of CRC tumors exhibit microsatellite instability • Muir-Torre syndrome is a variant of HNPCC associated with sebaceous adenomas

  10. LS Risk >25% 80% LS Increases the Risk ofColorectal Cancer By age 50 By age 70 Population Risk 0.2% 2% Gastroenterology 1996;110:1020-7 Int J Cancer 1999;81:214-8

  11. LS Risk 20% 60% LS Increases the Risk of Endometrial Cancer By age 70 By age 50 Population Risk 0.2% 1.5% Gastroenterology 1996;110:1020-7 Int J Cancer 1999;81:214-8

  12. The Family History Is Key to Diagnosing LS CRC dx 50s CRC dx 45 CRC dx 61 CRC dx 75 OvarianCa, dx 64 CRC dx 48 CRC dx 52 EndometrialCa, dx 59 45 CRC dx 42

  13. Early age of diagnosis mean age <45 yrs Predominantly proximal (right) colon cancer Improved survival Patients develop similar numbers of adenomas as the general population LS: Clinical Characteristics of Colorectal Cancer

  14. LS Cancer Risks Colorectal: Up to 80% lifetime risk Endometrial: 30% to 60% lifetime risk Ovary: 12% by age 70 Stomach: 13% by age 70 Other Urinary tract (4% by age 70) Small intestine (100-fold relative risk, but < 5%) Biliary tract (2% by age 70) Brain (~4% by age 70) Gastroenterology 1996;110: 1020-7 Int J Cancer 1999;81:214-8

  15. Management of LS

  16. Surveillance No surveillance 81.7% 57.8% Colonoscopy Prevents Cancer in Mutation Carriers Proportion free of CRC 100 80 60 40 15 0 5 10 Follow-up time (years) Gastroenterology 118:829, 2000

  17. Microsatellite Instability (MSI) • 10% to 15% of sporadic tumors have MSI • 95% of LS colon tumors have MSI • Can be used as a screening test • If colorectal tumor is MSI-H and family history is positive for CRC very high likelihood of LS

  18. IHC tumor test for LS

  19. IHC Test & Results Rationale for IHC tumor test • Universal IHC screening detects nearly twice as many cases of LS as targeting younger patients • Cost effective • can be internalized • results point to which MMR genes to analyze Results • 80% all proteins present • Most likely not LS • 20% one or more proteins absent • Most will not have LS • Approximately a third of these patients will test positive for a MMR mutation

  20. 2011 KPSC IHC Pilot Proposal • Surgery • provide the “IHC fact sheet” to patients scheduled for CRC tumor surgery • Pathology • order reflex IHC testing on all CRC≤ 50 yrs at diagnosis(~185 to 200 cases/yr) • Immunohistochemistry lab • performs IHC on tumor specimens per protocol • sends all abnormal IHC tumor results (~20% of cases) to surgeon and local genetics contact • Genetics • Arranges follow-up of all abnormal IHC MMR results including: • Contacts patient to offer genetics consultation as needed • Coordinates follow-up tumor & germ line testing andappropriate counseling

  21. Lynch Syndrome: Key Points • Most common form of hereditary CRC. Autosomal Dominant inheritance • About 3% or colorectal and endometrial cancers • Uterine/Endometrial cancer second most common after CRC in HNPCC families • Family/Personal history and IHC and/or MSI can help identify affected individuals • Identifying individuals with LS can minimize impact of disorder for them and their family members • High risk of multiple primary CRC and extra-intestinal tumors • Colonoscopic surveillance can improve survival in at-risk individuals For every individual identified with LS there are approx. 3 affected family members. Potential for preventing CRC in unaffected persons

  22. Familial Adenomatous Polyposis (FAP) • About 1% of all CRC; Incidence 1 in 8,000 • Multiple colonic adenomas (100s) beginning in childhood or teen years • Autosomal dominant pattern of CRC: • Average age of CRC is 36 • Risk of CRC by age 40 nearly 100% • Mutations in APC gene on 5q • 80% are protein truncating mutations • Up to 30% are new mutations

  23. Family with FAP Colon CA dx. 47 Age 45 FAP, dx. 27 Colectomy FAP, dx. 25 CRC dx. 31, d. 35 Age 42 FAP dx.38 APC+ Colectomy Age 40 APC - Age 18 APC+ FAP dx. 15 Surveillance

  24. Clinical Features of FAP • Estimated penetrance for adenomas >90% • Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) • CHRPE may be present • Untreated polyposis leads to 100% risk of cancer

  25. Other Cancers Associated with FAP Duodenal & periampullary cancer 5-12 % Thyroid cancer 2 % Pancreatic cancer 2 % Hepatoblastoma (childhood) 2 % Gastric cancer 0.5 % CNS tumors <1 % Cancer Risk Lifetime Risk Burt, Gastroenterology 2000; 119:837-53

  26. Desmoid tumors Osteomas Dental abnormalities CHRPE Soft tissue skin tumors Gardner’s Syndrome:A Variant of FAP Features of FAP plus extraintestinal lesions: Epidermoid cyst Jaw osteoma

  27. Medical Management of FAP • Annual flexible sigmoidoscopy beginning at age 101 • Prophylactic total colectomy after polyp detection chemoprevention: • celecoxib after surgery2 • NSAIDs (eg., sulindac) after surgery (investigational) • Subsequent surveillance for rectal and extracolonic tumors 1Gastroenterology 2001; 121:197-7 2Steinbach, NEJM 2000; 342:1946-52

  28. FAP: Key Points • Autosomal dominant with early onset of polyposis • However, up to 30% new mutations (no family hx) • Severe polyposis makes it easier to identify affected individuals • CRC risk is 100% in untreated patients • Genetic testing identifies most APC mutation carriers • Endoscopic surveillance and colectomy can significantly improve survival • Noncarriers can avoid anxiety and unnecessary tests • Genetic testing of children has medical benefit

  29. Tumor Suppressor Genes Normal genes (prevent cancer) 1st mutation (susceptible carrier) 2nd mutation or loss (leads to cancer)

  30. BRCA1 • Approximately 1 in 500 women may be carriers of alterations in BRCA1 • Breast tumors tend to be triple negative (ER, PR and Her2Neu negative), basal type, excess of medullary • Ovarian tumors: epithelial, high grade, mucinous and borderline tumors rare • Specific alterations observed in ~1% Ashkenazi Jewish individuals: 185delAG, 5382insC

  31. BRCA2 • Gene is twice the size of BRCA1 • Breast tumors tend to be ER +, and no specific histopathology observed • Ovarian tumors: epithelial, high grade, mucinous and borderline tumors rare • Wider spectrum of cancer types • Specific alteration in 1.5% of Ashkenazi Jewish individuals: 6174delT

  32. BRCA1 and BRCA2 in Ashkenazi Jewish Individuals • 1 in 40 will have mutation in BRCA1/2 regardless of family history • Founder effect: 3 mutations account for the majority of carriers • Ashkenazi Jewish heritage must be identified for proper risk assessment and mutation analysis

  33. The BRCA1 and 2 Genes

  34. BRCA1 & BRCA2-Associated Cancers: Lifetime Risk breast cancer (often < 50 yrs) 40%-85% Contralateral breast cancer 40-60% ovarian cancer 10%-40% male breast cancer elevated (6%) Pancreas & prostate cancers may also be elevated

  35. BRCA1/2 Mutations Increase Risk of Breast and Ovarian Cancer By age 30By age 50By age 70

  36. Identification of women at high risk for HBOC • Family History & Presentation • Two or more cases of breast and/or ovarian cancer on same side of the family • Consider both sides of the family, ethnicity • Ashkenazi Jewish heritage • Early age of onset, multiple primaries, TNBC • Breast cancer <45 yrs at diagnosis • Breast & ovarian cancer in the same woman, multiple breast primaries • TNBC: ER, PR and Her2 negative (BRCA1) • Autosomal dominant pattern of cancer

  37. Management of BRCA Mutation Positive Patient Positive BRCA1 or BRCA2 Mutation Offer test to relatives Increased Surveillance Chemo- prevention Lifestyle Changes Prophylactic Surgery Adapted from Myriad Genetics

  38. BRCA Carriers: Cancer Screening Breast cancer screening • Monthly BSE from age 18 • Clinical breast exam 2-4 times per year (beginning at age 25) • Annual mammography and MRI starting at age 25 or individualized based on earliest age of onset in family • MRI is most sensitive imaging modality for surveillance of BRCA carriers. 80% to 92% MRI vs 23% to 33% Mammo (based on 4 studies, N=714) Ovarian cancer screening • Concurrent TVU, Pelvic exam and CA125 q6 months starting at age 35 or 5-10 years earlier than earliest onset in family • No proven benefit

  39. Prophylactic Surgery in BRCA1/2 carriers • Prophylactic mastectomy • Reduces risk by ~90% • Total (simple) mastectomy recommended • Nipple sparing mastectomy may be good alternative • Risk-reducing salpingo-oopherectomy • Reduces risk by 85%-95% or more • Must remove ovaries and tubes; hysterectomy currently optional in most centers • Peritoneal washings recommended due to high incidence of occult malignancy • Breast cancer risk reduction • 55-70% if done pre-menopausally • Does not eliminate risk for primary peritoneal cancer • Residual risk reported as 1% to 4.3%

  40. Chemoprevention for BRCA1/2 Carriers Breast Cancer • Tamoxifen & Raloxifene: Very little data on carriers; few choose it • Tamoxifen may be less effective in BRCA1 carriers • One case control study reported ~50% contralateral cancer risk reduction from Tamoxifen use in BRCA1/2 carriers • No evidence that Tamoxifen post BSO reduces breast cancer risk Ovarian Cancer • Oral Contraceptives reduce risk by 50% to 70% with 5 yr use • Data unclear: two large studies reached opposite conclusions on effects of OCs in ovarian cancer risk for BRCA1/2 carriers • Use should be evaluated on case by case basis Narod et al, Lancet, 2000

  41. BRCA Carriers: Timing can influence decision making • How might a newly diagnosed breast cancer patient alter her treatment decisions? • Surgery? • Chemotherapy? • How might her future cancer risk for cancer influence these decisions? • Second breast cancer? • Ovarian cancer? d. 59 Breast CA dx. 54 73 Breast CA dx. 60 d. 53 Breast CA dx. 42 • 49 • Breast CA • 49 • BRCA2 + 52 50 29 27

  42. Could this be HBOC? Polish/Hungarian Jewish • How does Ashkenazi Jewish background affect probability of mutation in BRCA1 & 2? • Non Ash.: 1.1%-5.6% • Ash. Jewish: 8.2%-15.6% • How might cousin’s TAH/BSO affect family history of breast and ovarian cancer in this family? Unk CA d. 52 d.70s d. 53 Ovarian CA dx. 51 d. 68 70 53 43 41 34 TAH/BSO @ 45

  43. HBOC: Key Points • Clues in the personal or family history of cancer can help identify individuals who may have an inherited susceptibility to breast or ovarian cancer • Mutations in BRCA1/2: • Can be passed down from the mother or father • Are far more frequent in Ashkenazi Jewish families • Are inherited in autosomal dominant fashion • Genetic testing is offered only when personal and/or family history of cancer suggests inherited susceptibility • Genetic testing can identify mutations in BRCA1/2 and influence risk management, and save lives

  44. Cancer Genetics Resources • FORCE:Facing Our Risk of Cancer Empowered; support group for BRCA1/2 www.facingourrisk.org • Cancer Genetics Services Directory: http://cnetdb.nci.nih.gov/genesrch.shtml • Johns Hopkins Digestive Disease Library: www.hopkins-gi.org • CDC Colorectal Cancer: www.cdc.gov/cancer/colorctl/calltoaction/index.htm • Genetics of Cancer: www.cancergenetics.org

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