Genetics & Colorectal Cancer

1. Genetics & Colorectal Cancer Lisen Axell, MS, CGC University of Colorado Cancer Center

2. Overview • Cancer risk assessments • Family history of Colon cancer/ adenomatous (precancerous) polyps • Screening guidelines 3. Inherited Colon Cancer • Lynch syndrome (HNPCC) • Amsterdam criteria/Bethesda • Screening guidelines • Inheritance 4. Genetic discrimination protection

3. Genes and Cancer • All cancers are caused by gene mutations • The mutations can be either acquired or inherited. • Personal and family history are the indicators of when it may be inherited.

4. Cancer Risk Assessment Likelihood of developing cancer based on family history Likelihood of a inherited cancer syndrome Likelihood of a detectable mutation Medical management recommendations based on family history/mutation status Recommendations for at risk family members Discussion of genetic testing and if patient wants to pursue testing

5. Identifying the IMPORTANT family history • BOTH SIDES OF THE FAMILY • At least 3 generations • Establish age at diagnosis • Clarify the exact diagnosis (pathology reports can be invaluable) • Determine the number of family members without cancer

6. Cancer risk based on family history

7. Classification: Who Needs What? Standard screening recommendations Average (Sporadic) Personalized screening recommendations Moderate (“Familial”) FamilyHx genetic evaluation/testing with personalized screening and risk reduction recommendations High/Genetic

8. “Sporadic” Cancer

9. Dx 73 Dx 78 43 “Sporadic” Cancer • Later ages of onset >60 • No clear pattern on one side of family • Unilateral cancer • No inherited gene that is the cause of the cancer • Family members have a small if any increase in cancer risk

10. “Familial” Cancer

11. Dx 70 Dx 59 43 Dx 60 “Familial” Cancer • Clustering of cancer but no clear pattern • Typically later in life • May be due to: • inherited unknown genes (less penetrant) • or environment • or a combination of the two • At risk family members may have a small to moderate increased risk for cancer based on family history

12. Family History and CRC Risk Relative Risk Family History

14. All cancer is genetic but only a small portion is inherited

15. Inherited Breast Cancer

16. Inherited Cancer Cancer in young individuals (less than age 50) Many generations affected with the same type of cancer on the same side of the family Two primary cancers or two related cancers in same individual Related cancers in family Dx 55 Colon cancer uterine cancer Dx 65 Dx 35 43 Dx 45 Colon dx 50 Uterine dx 55

17. Colorectal Cancer Sporadic (average risk) (65%–85%) Family history(10%–30%) Rare syndromes (<0.1%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%)

18. Amsterdam Criteria • 3 first-degree relatives with CRC • 2 or more generations • 1 CRC by age 50 • Other cancers, especially endometrial may be substituted for colon cancer in making the diagnosis • >50% of families who meet criteria will have gene mutation • <8% of those who don’t will have mutation

19. Amsterdam II Criteria • HNPCC related cancers: • colorectal cancer • endometrial cancer • ovarian cancer • gastric cancer • hepatobiliary • small bowel • transitional cell ca of • renal pelvis or ureter Dx <50 Dx <50

20. T C G A C A G C T G T C A T C A G C T G T T C T A C C A T C A G AT G A G C T G HNPCC Results From Failure of Mismatch Repair (MMR) Genes Normal DNA repair Base pair mismatch Defective DNA repair (MMR+)

21. Bethesda Criteria (modified) do MSI and IHC screening first, if positive go to sequencing • HNPCC related cancers: • colorectal cancer • endometrial cancer • ovarian cancer • gastric cancer • hepatobiliary • small bowel • transitional cell ca of • renal pelvis or ureter 1. CRC Dx <50 Two HNPCC related cancers: (incl synchronous /metachronous colorectal ca) 2. 3. • Ind. with CRC and 1st degree with • Lynch related cancer dx<50 Dx <50 4. • Ind. with CRC with two or more 1st degree or 2nd degree relatives with Lynch related tumor regardless of age Ind. With CRC W/ infiltrating lymphocytes, Crohn’s like lymphocytic reaction, mucionous/signet-ring or medullary features on pathology dx<60 5.

22. Autosomal dominant Average age of CRC- 44 yrs Only few adenomas Proximal location Multiple- 20% synchronous 50% metachronous Mucinous, signet-ring, solid/cribiform, lymphocytic infiltration Clinical Features of Lynch syndrome

23. Cancer Risks in HNPCC 100 80 % with cancer Colorectal 78% 60 Endometrial 40-60% 40 Stomach 13% 20 Ovarian 12% Urinary tract 10% Biliary tract 2% 0 0 20 40 60 80 Age (years)

24. Management of HNPCC • Genetic testing (MSI and IHC, then mutation testing), start with index case • Colonoscopy, age 25 years, or 10 years younger than earliest diagnosis, repeat every 1-2 years • Appropriately timed colectomy • Other tumor screening • Endometrial, ovarian, gastric, biliary, small bowel, urinary tract

25. Inherited genetic abnormality • Individuals are born with an abnormal gene passed on by a parent and one normal gene from the other parent • This mutation is present in all cells though it only increases risk of some types of cancer • A blood test can often detect presence of mutation in families at very high risk

26. Carrier Not carrier Not carrier Carrier Carrier parent has a 50% or 1 in 2 chance to pass on the mutation with each pregnancy

27. Benefits Cancer prevention and early detection Information for the health care of family members. If mutation in family can determine who is at increased risk and who is a true negative and at general population risk Results can alleviate uncertainty and anxiety Limitations A negative result is not informative unless there is a known mutation in the family Some genetic variants are of unknown clinical significance Benefits and Limitations of Genetic Testing

28. Possible tests results and implications • If no known mutation in family • positive result • indeterminate negative result • variant of uncertain significance • If known mutation in family • positive result • true negative result

29. “Genetic Discrimination” in Health Insurance is Illegal • Health Insurance Portability and Accountability Act (HIPAA) • Prohibits group health insurance plans from discriminating on the basis of genetic information. • Most states have enacted additional protections • Family members do not have to disclose whether a relative has undergone genetic testing “Like so-called urban legends that are built on rumor rather than fact, the perception of insurance company bias against patients who undergo predictive genetic testing seems to be largely unsubstantiated.”- JAMA 1999;282:2197-8,

30. GINA (Genetic Information Non-discrimination Act) • Enacted May 2009. Federal protections against discrimination based on genetic information • Genetic information is defined as predictive genetic tests, family members’ genetic tests and family history information • Applies to group and individual health insurance as well as employment practices • Does not cover life, disability, long term care and other forms of insurance

31. Whom Do We Test? • Informed patients • Reasonable likelihood of positive test • Youngest affected individual • ?Minors • ?Prenatal