1. Familial Colorectal Cancers Francis M. Giardiello, M.D. The Johns Hopkins University

2. COLORECTAL CANCER Sporadic Familial

3. Familial Syndromes Hereditary nonpolyposis colorectal cancer Familial adenomatous polyposis Attenuated FAP I 1307K mutation of the APC gene

4. Hereditary Nonpolyposis Colorectal Cancer Autosomal dominant disease Due to mismatch repair gene mutation Proximal location of colorectal cancer Early age of onset Multiple primary malignancies Other family cancer

5. Hereditary Nonpolyposis Colorectal Cancer Warthin-Lynch syndrome Lynch I syndrome –hereditary site specific colorectal cancer Lynch II syndrome –cancer family syndrome

6. 3 or more with CRC 2 generations 1 diagnosed age < 50 yrs 65 49 70 Amsterdam Criteria

7. SITE OF COLORECTAL CANCER Sporadic HNPCC right sidedleft sided

8. Age of Diagnosis of Colorectal Cancer in HNPCC Age in Years No.

9. Cancer Risks in HNPCC Aarnio M et al. Int J Cancer 64:430, 1995 % with cancer 100 80 60 40 20 0 204060800 Age (years) Colorectal 78% Endometrial 43% Stomach 19% Biliary tract 18% Urinary tract 10% Ovarian 9%

10. Screening At-risk family members –colonoscopy 1-2 yr. starting age 20 to 25, and annually after age 40 –gyn exams in women annually with aspiration of endometrium and/or transvaginal ultrasound –screen for gastric or urologic cancer

11. Screening: Genetic Testing Mutation of the mismatch repair genes hMSH2, hMLH1, hPMS1, hPMS2, hMSH6

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

13. GermlineSomatic HNPCC GENETIC TESTING MSH2 MLH1 MSH6 Blood Cancer Microsatellite Instability/ Immunohistochemistry

14. Mismatch Repair Failure Leads to Microsatellite Instability (MSI) Normal Microsatellite instability Addition of nucleotide repeats

15. Immunohistochemistry Stain tumor for gene proteins Pursue absent proteins

16. Bethesda Criteria Adenoma < 40 or CRC < 45 yo –right-sided undifferentiated, cribiform; signet cell Endometrial Cancer < 45 yo 2 HNPCC cancers including met/syn CRC CRC and FDR with CRC or HNPCC extra colonic cancer (< 45, adenoma <40) ICG criteria

17. Familial Adenomatous Polyposis Autosomal dominant disease Mutation of APC gene Hundreds of adenomas in colorectum Presence/absence extracolonic lesions Colorectal cancer inevitable

19. Cause of FAP Mutation of APC gene (Adenomatous Polyposis Coli) Located chromosome 5q 21 Discovered 1991

20. Clinical Course Puberty - polyps appear 15 y.o. - average age onset of polyps 33 y.o. - symptoms appear 36 y.o. - average age of diagnosis 39 y.o. - average age of colorectal cancer dx 42 y.o. - death from colorectal cancer

23. Treatment Proctocolectomy with ileostomy Proctocolectomy with ileoanal pull through Colectomy with ileorectal anastomosis

24. Cause of FAP APC gene mutation Located chromosome 5q21 Tumor suppressor gene 300 different mutations identified APC protein - cell adhesion, signal transduction, and transcription activation

25. APC GENE 5’3’ CLASSIC FAP 28430codons RNA PROTEIN 1581596

26. APC GENE 5’3’ CLASSIC FAP 28430codons RNA PROTEIN 1581596

27. Attenuated FAP 5’ and 3’ APC gene mutations 6% of FAP pedigrees Oligopolyposis (<100 adenomas), R-sided Heterogeneous phenotype Later development of CRC (51 vs 39 y.o.)

28. Screening At-risk persons (1st degree relatives) Sigmoidoscopy q yr. starting age 12, then q 2 yrs after age 25, then q 3 yrs after age 35, then average risk guidelines after age 50

29. Screening: APC Gene Testing Gene test for mutation of APC gene by PTT Start at-risk persons age 10-12 Pretest genetic counseling/informed consent Test affected pedigree member first

30. APC Gene Testing - At Risk APC mutation

31. APC Gene Test Result Positive - FAP- sigmoidoscopy yearly Negative - No FAP- sigmoidoscopy age 25

32. Multiple Adenomas Mutation of MYH gene Base excision gene Phenotype: multiple adenomas or polyposis Autosomal recessive

33. Familial Colorectal Cancer I1307K APC gene mutation –Mutation in codon 1307 of the APC gene –T to A mutation

34. AGAAA[TAA]AA AGAAA[AAA]A APC I1307K Mutation 5’3’ * * isoleucine lysine mutations predisposing CRC * *

35. APC I1307K Mutation

36. Lifetime Risk of Colorectal Cancer Ashkenazi Jew 10-15% Gene Pos20-30% Gene Pos + FH> 50%

37. I1307K Genetic Testing Allele-Specific Oligonucleotide Analysis NormalMutant X

38. Screening Consideration of genetic counseling and genetic testing in Ashkenazi Jewish person with family history of colorectal cancer Colonoscopy q 2 yrs starting age 35 in gene positive patients

39. Summary

40. Hereditary Nonpolyposis Colorectal Cancer –colonoscopic screening –MSI testing, MMR gene testing

41. Summary Hereditary Nonpolyposis Colorectal Cancer –colonoscopic screening –MSI testing, MMR gene testing Familial adenomatous polyposis –APC gene testing/ MYH gene testing –sigmoid/colonoscopy screening

42. Summary Hereditary Nonpolyposis Colorectal Cancer –colonoscopic screening –MSI testing, MMR gene testing Familial adenomatous polyposis –APC gene testing/ MYH gene testing –sigmoid/colonoscopy screening Familial Colorectal Cancer –family history/ I1307K