Hereditary Colon Cancer

1. Hereditary Colon Cancer ACP, October 2013 Steve Lanspa MD, FACP

2. Magnitude of the Problem • Annual worldwide incidence of CRC is 1,023,152*: • • Lynch syndrome (LS) accounts for  2-5% • (20,460-51,160 cases). • • < 1% (10,230 cases) constitute FAP. • •  20% (204,630 cases) are familial (2 or more first- • degree relatives with CRC. • • Each family is a cancer prevention target! • *International Agency for Research on Cancer. Globocan 2002. Available at: http://www-dep.iarc.fr/.

3. Magnitude All CRC worldwide – Approx 1 million per year LS associated CRC – 21,000 – 50,000 per year

4. JAMA294:2465-2473, 2005.

7. Maintenance of DNA integrity Illustration by Jerry Schoendorf, MAMS. Pages 577-587 (February 2006) GE

8. Molecular Classification of CRC • Step-wise accumulations of multiple mutations • Chromosomal Instability (CIN) 85% • Microsatellite Instability (MSI) 5% • CpG island methylator phenotype (CIMP) 10%

9. Chromosomal Instability Pathway (CIN) • Chromosomal gains and losses (aneuploidy; copy number change) • Allele losses (LOH) • Is the molecular basis of progression in CRC in Familial Adenomatous Polyposis

10. Microsatellite Instability Pathway (MSI) • Mononucleotide mutations of tumor suppressor genes • Arises from defective DNA mismatch repair • Is the molecular basis of progression in CRC in Lynch Syndrome

11. Microsatellite Instability (MSI) • Microsatellites (short nucleotide repeats) are prone to replication errors, but corrected by MMR genes in normal cells • In tumor DNA, there are altered lengths (instability) of microsatellites • MSI is a phenotype that can be used as a surrogate for MMR mutation/inactivation (now also IHC for absence of protein expression) • Inactivation of one copy of MMR = 1st hit • Subsequent somatic lesion (2nd hit) leads to mutation rates 1000 times normal

12. CpG Island Methylation (CIMP) • Short stretch of DNA with high CG sequences (phosphodiester bond) • Located at gene promoter • Methylation leads to inactivation of many tumor suppressor genes • ~200 CpG islands that are methylated have been identified in tumor DNA • Epigenetic, biallelic silencing of MLH1 • Tumors highly correlated with a mutation of the BRAF-kinase encoding gene (Chr 7) • May be the molecular basis of progression of CRC in the serrated pathway

14. Familial Adenomatous Polyposis FAP

19. FAP • Germline mutation of APC • Autosomal dominant • Polyps in teens, cancers in 20’s • >100 polyps • Gene testing, colectomy • Surveillance of UGIT • nccn.org

20. Attenuated FAP aFAP

21. Attenuated FAP • Later onset (CRC ~age 50) • Few colonic adenomas • Not associated with CHRPE • UGI lesions • Associated with mutations at extreme 5’, 3' ends of APC gene, & exon 9A

22. Multiple Adenomatous Polyposis • MAP • Biallelic MUTYH mutation • Autosomal recessive • 10 polyps • CRCS > age 50 years

23. Lynch Syndrome(HNPCC) • H.T. Lynch • Jane Lynch • Patrick Lynch • Creighton University

25. JAMA 2011

26. Lynch Syndrome associated tumors Colorectal Endometrial Ovarian Genitourinary Brain Small bowel Hepatobiliary

27. Diagnosing Lynch Syndrome • Amsterdam criteria • 3 relatives with cancer • 2 generations involved • 1 patient under age 50 Yeats • Bethesda criteria • Test familial and synchronous tumors for MSI • MSI+ tumor in a patient under age 60 years • Test all tumors for MSI+

28. Unique Pathology • Carcinoma of Colon • mucinous carcinomas • signet cell carcinomas • diploid tumors (on flow cytometry) • TILs (tumor infiltrating lymphocytes) • Adenoma • Found in 20% of colons with CRC • Jass and Stewart (Gut33:783-786, 1992): adenomas in LS were larger, more often villous, and had more high grade dysplasia • Consistent with our hypothesis that adenomas in LS have a greater proclivity for malignant degeneration than sporadic adenomas.

30. Colon Cancer Surveillance in LS • Adenoma removal is important • Surveillance must be at an earlier age and • more frequent than that for the general population • Colonoscopy to the cecum is important • Lesions under 1 cm are important • Would prophylactic subtotal colectomy be better?

31. Do New Technologies Help? • Narrow band imaging colonoscopy • Magnifying colonoscopy • Chromoendoscopy • Autoflorescence • CT colography (computer-assisted) • MRI colography • Chemoprevention

32. Metachronous CRC in LS • Overall incidence 22-41% • Parry al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut. 2011;60:950–957. • Cumulative incidence after varying type of resection • Segmental colectomy: 16% • Subtotal colectomy: 2 % • de Vos tot Nederveen Cappel et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum. 2002;45:1588–1594.

33. DisColRec 2010

35. National Comprehensive Cancer Network (http://nccn.org) • Colonoscopy at age 20-25 or 10 years younger than youngest age of cancer Dx • Repeat every 1-2 years • Annual urinalysis with cytology • Endometrial and ovarian cancer screening age 30-35; every 6-12 months; TAH-BSO

36. Serrated Polyposis Syndrome • “Hyperplastic polyposis” • ? gene, but there is a familial syndrome • Associated with pancreatic cancer • May have rapid adenoma-carcinoma sequence, similar to LS

41. Peutz-Jeghers Syndrome PJS

43. Peutz-Jeghers Syndrome • Inactivating mutations of tumor suppressor STK gene on chromosome 19p13 • Hyperpigmented macules on buccal mucosa and lips, gastrointestinal (respiratory tract, genitourinary tract) hamartomatous polyps • Increased risk of Gastrointestinal, breast, thyroid lung, pancreatic, uterine cancer, Ovarian sex cord tumors Sertoli cell testicular tumors • Lifelong endoscopic, radiologic (SBS), ultrasound incl. testicular surveillance • ? Role of capsule endoscopy surveillance

45. Summary • Complete family history • High index of suspicion • Expert colonoscopy • Hereditary Cancer Institute • nccn.org