Genetics of Colorectal Cancer

1. Genetics of Colorectal Cancer

2. Cancer is a Disease of the Cell Cycle “Carcinoma is a genetic disease, it is not necessarily inherited”

3. Knudsen’s “two hit” hypothesis

4. Types of genes which may mutate to cause cancer: Oncogenes Suppressor genes DNA repair genes p53

5. Adenoma-Carcinoma SequenceAccumulation of MutationsDCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.

6. Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000

7. Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996

8. Prevalence of Adenomas and Incidence of Colon Cancer Age >50 years with any adenomas: 25-40% Lifetime risk of cancer at age 50 years 5% for females 6% for males Persons with advanced adenomas are at greatest risk

9. Risk Factors for Colorectal Cancer (CRC) Aging Personal history of CRC or adenomas High-fat, low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

10. Risk of Colorectal Cancer (CRC) 5% General Population Personal History of Colorectal Neoplasia 15-20% 15-40% Inflammatory Bowel Disease 70-80% HNPCC Mutation >95% Familial Adenomatous Polyposis (FAP) Lifetime Risk (%)

11. Colorectal CancerStatistics in the US Second overall leading cause of cancer-related deaths in the U.S. Estimated 149,000 new cases and 50,000 deaths in the year 2008 Declining trends between 1990 and 1996 Incidence rate: ~2.1% per year Mortality rates: ~1.7% per year

12. Family History: Empiric Risks

13. Outline Hereditary colorectal cancer syndromes Cancer family history – a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary colorectal cancer How, when, where to refer patients for genetic services

14. Colorectal Cancer ~5-8% of all cases of CRC are hereditary ~15-20% are “familial”/multifactorial ~75% of cases are sporadic

15. Characteristics of Average Risk No well-defined threshold between sporadic and familial CRC at this time Probably safe to include individuals with: No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC >60 years with no other family history of CRC

16. Characteristics of “Familial” CRC “Clustering” of colon cancer cases in the family (>50 at diagnosis) without clear dominant pattern, or One close relative with CRC <60 years and family history does not meet criteria for known hereditary CRC syndromes Likely to be multiple low penetrant genes plus environmental factors at play Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis of the youngest affected relative

17. Characteristics of Hereditary CRC Multiple relatives with colorectal cancer One or more diagnosed at an early age (<50) Sequential generations affected Except in autosomal recessive syndromes Other cancers in the family known to be associated with CRC (uterine, ovarian, GI) Multiple primary tumors or polyps

18. Hereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Variants: Muir-Torre, Turcot Familial Adenomatous Polyposis (FAP) Variants: Gardner, Turcot Attenuated FAP APC mutation in Ashkenazi Jews Others: Multiple adenomatous polyposis syndrome/MYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

19. HNPCC: AKA “Lynch Syndrome” 2-3% of all colorectal cancer cases Autosomal dominant; high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70% right-sided/proximal CRC tumors Polyps may be present, multiple primaries common. Can overlap with AFAP.

20. HNPCC Lifetime cancer risks: Colorectal 80% Endometrial 20-60% Gastric 13-19% Ovarian 9-12% Biliary Tract 2% Urinary Tract 4% Small Bowel 1-4% Brain/CNS 1-3%

21. HNPCC:Clinical Diagnostic Criteria Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer, one of whom is a 1st degree relative of the other two 2 or more successive generations affected 1 or more cancers diagnosed before age 50

22. HNPCC Caused by mutations or deletions in mismatched repair (MMR) genes MSH2, MLH1, MSH6, (PMS2) 50% of families meeting Amsterdam II Criteria have detectable mutations Testing/Screening options: Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSI/IHC

23. MSI/IHC Screening Microsatellite Instability (MSI) on tumor tissue can be used to screen for HNPCC in select cases Immunohistochemistry (IHC) on tumor tissue can be used to detect the presence or absence of the mismatch repair proteins (MSH2, MLH1, etc.) “Screen positive” individuals can be offered cancer genetic counseling/assessment and targeted genetic testing

24. FAP 1 in 10,000 incidence 100’s to 1000’s of colonic adenomas by teens Cancer risk: colon, gastric, duodenum (periampulla), small bowel, pancreas, papillary thyroid, childhood hepatoblastoma 7% risk of CRC by 21 yrs; 93% by 50 yrs Autosomal dominant: APC gene mutations Variants: Gardner, Turcot

25. FAP - Surveillance Colon Annual sigmoidoscopy, age 10-12 yrs Prophylactic colectomy following polyp detection with continued surveillance of rectum, ileal pouch Duodenal/gastric EGD age 25, repeat 1-3 yrs Thyroid Annual PE, age 10 Hepatoblastoma Annual screen by abd U/S & AFP from birth to 5 yrs.

26. Attenuated FAP 20 to 100 polyps, usually more proximal Onset later than FAP, average AOO = 50 Lifetime risk of CRC = 80% Extracolonic tumors occur at same rate as FAP Variant of FAP, mutations in same APC gene Surveillance: annual colonoscopy starting late teens or early 20’s Option of subtotal colectomy

27. Genetic Testing: FAP/AFAP Test an affected family member first! After genetic counseling and informed consent APC gene testing can confirm a suspected diagnosis Family members of a person with a known APC mutation can have mutation-specific testing Genetic testing for children at risk for FAP can be considered before beginning colon screening

28. APC gene mutation inAshkenazi Jews Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ) Found in 6% of the general AJ population 12% of AJs with CRC 29% of AJs with CRC and a positive family history Lifetime risk of CRC in mutation carrier is 10-20% Screening: colonoscopy every 2-5 yrs starting at 35 yrs

29. MAP syndrome/MYH gene Multiple adenomatous polyposis (MAP) syndrome Autosomal recessive; mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas 30% of individuals with 15-100 polyps have homozygous mutations in the MYH gene Genetic testing should be offered if >15 polyps (and APC gene testing negative)

30. Peutz-Jeghers Syndrome <1% of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation lips, mouth, buccal mucosa, fingers Usually seen in children < 5 yrs Cancer risk: colon, small intestine, stomach, pancreas, breast, ovaries, uterus, testes, lungs, kidneys Mutations in STK11 gene found in 70% of familial cases and 30-70% of sporadic cases

31. Familial Juvenile Polyposis <1% of all CRC cases Autosomal dominant 5 or more juvenile polyps in colon or GI tract Appear in 1st or 2nd decade 50% lifetime risk of CRC; AOO in 30’s Increased risk gastric, GI, pancreatic CA ~50% of cases have mutations in eitherthe MADH4 or BMPR1A genes

33. Family Health History “The family tree has become the most important genetic test of all. The more you know, the more tools you have to practice preventive medicine” **Donna Russo, Certified Genetic Counselor, NY Presbyterian-Columbia Hospital

34. Goal: Classification Assessment Risk Classification Intervention Standard prevention recommendations Average Family History Moderate (“Familial”) Personalized prevention recommendations Referral for genetic evaluation with personalized prevention recommendations High/Genetic

35. Consider Genetics Referral for: Two or more family members with CRC* at least one <50 Three or more family members w/CRC*; any age Patient with colon cancer before 40 yrs Endometrial cancer and family history of CRC <50 Persons with more than one primary CRC <50 yrs or with both endometrial CA and CRC Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer, one diagnosed <50 yrs. *Same side of family

36. Consider Genetics Referral for: MSI and/or IHC tumor results suspicious for HNPCC Autosomal dominant pattern of cancers in the family Persons with 15 or more adenomatous colorectal polyps Persons with multiple hamartomatous or juvenile GI polyps Persons with a family history of a known hereditary cancer syndrome

37. CRC Risk Management Average Risk No family history CRCOR One 2nd or 3rd degree relative with CRC FOBT annually + flex sig every 5 years; OR Colonoscopy every 10 years; OR DCBE every 5 years Age to Begin 50 years

38. CRC Risk Management Moderate/Family history Two 1st degree relatives with CRC any age or one 1st degree relative with CRC < 60 - Colonoscopy every 5 yrs One 1st degree relative with CRC >60 or two 2nd degree relatives with CRC any age - Average risk screening * Or 5-10 yrs earlier than earliest case in family Age to begin 40 years* 40 years

39. CRC Risk Management Age toBegin HNPCC or suspected HNPCC20-25 years 1. Colonoscopy every 1-2 yrs 2. Genetic counseling; consider genetic testing FAP or suspected FAP10-12 years 1. Flex sig or colonoscopy every1-2 yrs 2. Genetic counseling; consider genetic testing

40. Case 1: Joan Joan, age 38, was recently diagnosed with endometrial cancer. Family history reveals: Paternal grandmother: endometrial cancer, age 50 Paternal uncle: colon cancer, age 48 Father: colonoscopy at age 50; four adenomatous polyps removed No other significant history Both sides of the family are Northern European Caucasian

41. Pedigree: Case 1 French, Irish, Scottish German, English 88 yr Dx 50 61 yr 63 yr CRC Dx 48 4 polyps 50 yrs 38 yr KEY: 35 yr Dx 38 Endometrial CA Colorectal CA Adenomatous Polyps 10 yr 8 yr

42. Case 1: Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC Testing options: Direct gene testing of MLH1 and MSH2 OR MSI/IHC screening of tumor tissue with gene sequencing if MSI positive

43. Case 2: Ted Ted is 30 and wants a colonoscopy because his mother was just diagnosed with colon cancer after routine screening at age 54. Family history reveals: Paternal grandfather: died of CRC at age 79. No hx of endometrial, ovarian, small bowel or ureter/kidney cancer on either side of family. Two maternal aunts: cervical cancer at ages 30 & 34 Maternal grandmother: breast cancer age 85

44. Pedigree: Case 2 Italian Irish German CRC 79 d.82 BrCa 85 yrs d.87 d. 58 MI 84 55 58 60 56 Cervical CA 30 yrs Cervical CA 32 yrs Colon CA 54 yrs KEY: CRC Breast CA Cervical CA 34 yrs 30 yrs

45. Case 2: Ted Verify Diagnoses! Obtain and review pathology reports on all reported cancers, whenever possible If diagnoses are correct: Ted has no family history indicative of a known colon cancer syndrome (HNPCC, FAP, other) Ted’s lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (>50) Moderate/familial risk: Screening by colonoscopy starting at age 40, or 10 yrs earlier than earliest case in family, is reasonable

46. Chemo Prevention Evidence that ASA, NSAIDs, Calcium, and COX-2 inhibitors may reduce incidence of CA by reducing # of adenomas 􀂃 40-50% risk reduction for developing colorectal CA regardless of location in colon, age, gender, and race Generally performed by RCT’s in patients with prior colorectal CA followed for recurrence of adenomas Diet, fiber, and antioxidant vitamins have not been shown by RCT’s to decrease risk of recurrent adenomas COX-2i’s and Sulindac have been shown to reduce the number of adenomas found in FAP alone 􀂃 Not effective for sporadic colon CA 􀂃 Actually can cause regression of adenomas