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 Available at:

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

4 JAMA 294: , 2005.

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

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

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

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

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 = 1 st hit Subsequent somatic lesion (2 nd hit) leads to mutation rates 1000 times normal

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

Familial Adenomatous Polyposis FAP

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

Attenuated FAP aFAP

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

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

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

JAMA 2011

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

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+

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 (Gut 33: , 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.

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?

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

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.

DisColRec 2010

National Comprehensive Cancer Network ( Colonoscopy at age 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 ; every 6-12 months; TAH-BSO

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

Peutz-Jeghers Syndrome PJS

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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

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