Assessment for hereditary colorectal cancer

1. Assessment for hereditary colorectal cancer Kalyani Maganti, M.D

2. Chromosomes, DNA, and Genes Gene Nucleus Cell Chromosomes Protein ASCO

3. Disease-Associated Mutations A “mutation” is a change in the normal coding sequence of a gene that alters the function of the corresponding protein ASCO

4. Disease-Associated Mutations Alter Protein Function Functional protein Nonfunctional or missing protein ASCO

5. “All cancer arises from gene mutations”

6. Genes Associated With Cancer Predisposition • Tumor suppressor genes • Control rates of cell division and growth • Cancer arises when both gene copies are mutated • DNA damage-repair genes • Repair errors in DNA replication • Cancer arises when both genes fail, leading to the accumulation of mutations inother critical genes • Oncogenes • Accelerate cell division • Cancer arises when stuck in “on” mode ASCO

8. Gene mutations – inherited or acquired? • All cancer is caused by gene mutations • Usually these mutations were notinherited, but were acquired over time in individual cells • In ~10% of cancers the mutation is inherited – the person has a “hereditary predisposition”to cancer

9. Gene mutations – inherited or acquired? Two normal genes (prevent cancer) 1st mutation (may be inherited (susceptible carrier), or acquired 2nd mutation or loss of gene function (leads to cancer) ASCO

10. Hereditary cancer “syndromes” • A mutation in a single gene increases cancer risk in multiple organs or parts of the body • Increased risk is inherited, not cancer – so the individual may develop cancer in a single, multiple, or no parts of the body

11. Sporadic or Hereditary? • ~75% of colon cancer is “sporadic” • ~15-20% of colon cancer is “familial” • ~5-8% of colon cancer is due to a single gene causing a “hereditary predisposition”

13. Characteristics of Hereditary Cancers • Cancer diagnosed at an early age (before age 50) • Close family members with same kind of cancer (or genetically related cancers, such as breast and ovarian) • Bilateral cancer, or multiple primary cancers • Unusual cancers (male breast cancer) • Two kinds of cancer in the same person (syndrome)

14. Hereditary Cancer Syndromes Syndrome Hereditary breast and ovarian cancer Lynch syndrome Familial adenomatouspolyposis Cowden syndrome Von Hippel-Lindau syndrome Li-Fraumeni syndrome Multiple Endocrine Neoplasia (1 or 2) Associated cancers Breast and Ovarian (etc.) Colon, Endometrial, ovarian, (etc.) Colon, duodenum (etc.) Breast, thyroid, endometrial (etc.) Renal cell, hemangioblastomas, (etc.) Sarcoma, breast, brain, adrenal, (etc.) Thyroid, parathyroid, other endocrine

15. Clues from the family history CRC 79 d.82 d. 58 MI BrCa 85 yrs d.87 84 56 55 58 60 Colon Ca 54 yrs Cerv.Ca 30 yr Cerv.Ca 32 yr Key: CRC 30 yrs Breast CA 34 yrs Cervical CA

16. 1st, 2nd-, and 3rd-Degree Relatives 2 2 2 2 Maternal grandfather Maternal grandmother Paternal grandmother Paternal grandfather 2 1 1 2 Aunt Father Mother Uncle 3 1 1 First cousin Brother Sister 1 Child ASCO

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

18. Noncarrier individual Non-affected carrier Affected individual Recessive Inheritance • Two germ-line mutations (one from each parent) necessary to develop disease • Equally transmitted by men and women ASCO

19. Genes aren’t the whole picture Normal Susceptible Carrier Carrier, affected with cancer Sporadic cancer • “Penetrance” is often incomplete • May appear to “skip” generations • Individuals inherit altered cancer susceptibilitygene, not cancer ASCO

20. “Familial” risk for colon cancer CRC 79 d.82 d. 58 MI BrCa 85 yrs d.87 84 56 55 58 60 Colon Ca 54 yrs Cerv.Ca 30 yr Cerv.Ca 32 yr Key: CRC 30 yrs Breast CA 34 yrs Cervical CA

21. Typical “hereditary” colon cancer family CRC dx 50s CRC dx 45 Gastric ca dx 52 CRC dx 61 + 63 CRC dx 75 OvarianCa, dx 64 CRC dx 48 CRC dx 50 EndometrialCa, dx 59 45 CRC dx 42 + 55

22. “Familial” versus “single gene inheritance” of risk

23. HNPCC: Colon cancer as part of a “syndrome” 88 yr Dx 50 61 yr 63 yr CRC Dx 48 4 polyps 50 yrs. Key: 38 yr 35 yr Endometrial CA Dx 38 Colorectal CA Adenomatous polyps 8 yr 10 yr

24. HNPCCor“HereditaryNon-polyposisColorectal Cancer syndrome” • 3-5% of all colorectal cancer cases • A cancer “syndrome” caused by a single gene mutation • Cancers outside the colon: endometrium (uterus), ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous glands

25. HNPCC:Clinical Diagnostic Criteria • 3 or more relatives with an HNPCC-related cancer, one of whom is a 1st degree relative of the other two • 2 or more generations affected • 1 or more cancers diagnosed before age 50 • Other syndromes excluded ( Failure to meet these criteria does not exclude HNPCC )

28. Cancer Risks in HNPCC 100 80 % with cancer Colorectal 78% 60 Endometrial 40-60% 40 Stomach 13-19% 20 Biliary tract 18% Urinary tract 10% Ovarian 9% 0 0 20 40 60 80 Age (years) Aarnio M et al. Int J Cancer 64:430, 1995 ASCO

29. The Family History Is Key to Diagnosing HNPCC CRC dx 50s CRCdx 45 Gastric ca dx 52 CRC dx 61+63 CRC dx 75 OvarianCa, dx 64 CRC dx 48 CRC dx 50 EndometrialCa, dx 59 45 CRC dx 42+ 55

30. NCCN Surveillance and Prevention Guidelinesfor Lynch syndrome • Colonoscopy at age 20-25, or 2-5 yrs prior to the earliest diagnosis; repeat every year • Prophylactic hysterectomy and bilateral salpingo-oophorectomy is a risk reducing option for women who have completed childbearing • Transvaginal U/S for ovarian and endometrial cancer may be considered at the clinicians’ discretion, but data do not support its efficacy • Consider upper endoscopy for gastric and small bowel cancers, beginning at age 30-35 • Consider annual urinalysis for urothelial cancer

31. 100 80 60 40 20 0 0 20 40 60 80 The value of surveillance in HNPCC Percentage of individuals with an altered disease gene who develop the disease Affected with colorectal cancer (%) HNPCC mutation carriers General population ASCO

32. Screening for HNPCC • Screening for HNPCC on basis of family history misses ~40% of cases • Screening with combined family history and tumor testing detects ~100% of cases • This combined approach to screening for HNPCC is recommended by current NCCN guidelines

33. Genetic Features of Lynch syndromeallow us to screen tumors – at the time of surgery(or years later) Four genes: can cause Lynch syndrome: (MLH1, MSH2, MSH6, PMS2) = “mismatch repair genes” Mutation in gene  absence of corresponding protein in tumor tissue  detected by IHC stains Mutation in gene  microsatellite instability in tumor DNA (caused by the loss of functional mismatch repair protein) These measurable differences in the tumor itself can be used to screen for Lynch syndrome and justify proceeding to genetic testing (of a blood sample)

34. Clues from the tumor – does this patient have a genetic mutation? • Microsatellite instability (MSI) testing if MSI- unstable  high probability of a MMR mutation  proceed to genetic testing • Immuno-histochemistry(IHC) for MMR proteins – are all four MMR proteins present? If no  proceed to genetic testing

35. Importance of the Pathology Report Colorectal cancer – polyp type and numberindicates which syndrome to test for: • Multiple adenomas  test APC gene – for FAP syndrome • Few or no adenomas, proximal location of tumor  test for HNPCC syndrome (several genes) • Hamartomas with freckling around mouth  test STK11 gene for Peutz-Jeghers syndrome with fam.hx. breast, thyroid, uterine cancer  test PTEN gene for Cowden syndrome

36. HNPCC1 PROTOCOL PRE-SURGERY 7/08 All Colorectal and Uterine Cancer Patients Pre-Admit Nurse __YES___NO Patient < 50 years old ___YES___NOParent, sibling or child has a CANCER history of: colorectal, uterine, ovarian, stomach, bile duct, urinary tract, small bowel, pancreatic, brain or sweat gland cancer ___YES___NOPatient’s has a previous CANCER history of: colorectal, uterine, ovarian, stomach, bile duct, urinary tract, small bowel, pancreatic, brain or sweat gland cancer No to all Yes to Any Questions = Follow the Protocol • Pre-op/Pre-Admit Nurse • Stamp pre-op form with HNPCC ALERT: Send Specimen for IHC • Notify OR scheduler – note on schedule made • Patient given information sheet on IHC2 and MSI3 testing • Circulating Nurse • Obtain verbal order from Surgeon • Request for IHC testing filled out on pathology slip • Place specimen in formalin – follow specimen handling protocol 1 – HNPCC=Hereditary Non-Polyposis Colorectal Cancer syndrome also called Lynch Syndrome 2 - IHC = immunohistochemistry 3 – MSI = microsatellite instability Specimen to Pathology

38. Clinical Features of FAP (Familial adenomatosispolyposis) • Early onset of colon polyps • in teens or childhood • Untreated polyposis leads to • 100% risk of colon cancer

39. FAP is associated with: Malignant tumors: periampullary carcinoma gastric carcinoma thyroid tumors brain tumors (medulloblastoma) Non-malignant features: CHRPEs osteomas of the jaw(>90%) duodenal polyps (70%) epidermoid cysts (67%) desmoid tumors

43. Noncarrier individual Non-affected carrier Affected individual MYH-associated Polyposis (MAP) • Multiple polyps (15-100) • Recessive inheritance • Two mutations (one from each parent) necessary to develop disease ASCO

44. MYH gene - normally functions to repair mistakes in DNA (mistakes can lead to cancer) • 1-2% of the population carries a single MYH mutation –> ~ 10,000 have two MYH mutations, and develop MYH-associated polyposis) • Multiple colorectal adenomas (~15-100 polyps) – with onset in 30-50’s • Progression of polyps to colon cancer usually by age 50

45. MYH-associated polyposismay be suspected if: • Individual has multiple colon polyps (and possibly colon cancer), and no family history of polyposis or colon cancer • Individual has multiple colon polyps (and possible colon cancer, and the only affected family members are siblings

47. Genetic Counseling for hereditary cancers Genetic counseling is an interactive process that allows people to: • Address their concerns about hereditary risk for cancer • Learn basic genetic principles • Look at their personal and family history in the context of these genetic principles • Learn if their perception of risk is realistic or not • Learn about the process and the implications of genetic testing • Find out what kinds of pro-active steps they could take to lower their cancer risks if they do carry a genetic mutation

48. Who should consider genetic counseling?(characteristics of hereditary cancers) • Cancer diagnosed at an early age (before age 50) • Close family members with same kind of cancer (or genetically related cancers, such as breast and ovarian) • Bilateral cancer, or multiple primary cancers • Ashkenazi Jewish ancestry and breast or ovary ca. • Unusual cancers (male breast cancer) in the family • Two kinds of cancer in the same person (syndrome)

49. Should everyone with a family history of colon cancer have genetic testing? CRC 79 d.82 d. 58 MI BrCa 85 yrs d.87 84 56 55 58 60 Colon Ca 54 yrs Cerv.Ca 30 yr Cerv.Ca 32 yr Key: CRC 30 yrs Breast CA 34 yrs Cervical CA

50. Using family history to screen for Lynch syndrome 88 yr Dx 50 61 yr 63 yr CRC Dx 48 4 polyps at 50 yrs. Key: 38 yr 35 yr Detects 60% Misses 40% Endometrial CA Dx 38 Colorectal CA Colon polyps 8 yr 10 yr