Colon Cancer Syndromes Robin B. Mendelsohn MD Memorial Sloan Kettering Cancer Center Department of Medicine Gastroenterology and Nutrition Service
Background: Etiology of Colorectal Cancer (CRC) Sporadic: 65-85% Familial 10-30% Rare CRC syndromes <0.1% Lynch syndrome 4-5% Familial adenomatous Polyposis (FAP) 1% Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996
Genetics of Hereditary CRC Gene Syndrome Mode of Inheritance MLH1/MSH2/MSH6/PMS2 Lynch Syndrome (LS) Autosomal Dominant APC (chr 5q21-22) MYH (MutYH) (chr 1p32-34) STK 11 (chr 19p) PTEN (chr 10) SMAD 4 (chr 18q) BMPR1A (chr 10q) Familial Adenomatous Polyposis (FAP)/Attenuated FAP MutYH-Associated Polyposis (MAP) Peutz-Jeghers Syndrome (PJS) Cowden Syndrome Bannayan-Riley- Ruvalcaba Syndrome (BRRS) Juvenile Polyposis Syndrome (JPS) Autosomal Dominant Autosomal Recessive Autosomal Dominant Autosomal Dominant Autosomal Dominant Autosomal Dominant
Lynch Syndrome (LS): Clinical Features Early onset CRC (~45 years) Proximal colon predominates (~70%) Synchronous primaries (~10%) Metachronous CRC: 25-30% (by 10 yrs) Extracolonic cancers (Endometrium, Ovary, Urinary tract, Stomach, Small Bowel) Lynch, Clin Genet 2009;76:1
LS: Interval Cancers Accelerated adenoma-carcinoma sequence Cancer dwell times ~35 months Edelstein Clin Gastroenterol Hepatol 2011;9;340
LS: Lifetime Cancer Risks 100 80 % with 60 cancer 40 20 0 0 20 40 60 80 Age (years) Colorectal 70% Endometrial 50% Stomach 4-13% Ovarian 4-12% Urinary tract 2-12% Biliary tract 2% Adapted from Aarnio M et al. 1995, 1999
LS: Lifetime Cancer Risks Cancer Site General Population LS Colon 5-6% 70% Endometrium 2-3% 50% Stomach 1% 13% Ovaries 1-2% 12% Colon Endometrial MLH1/MSH2 30-74% MLH1/MSH2 14-54% MSH6 10-22% MSH6 17-71% PMS2 15-20% PMS2 15% Bonadana et al, JAMA, 2011;30:2304; Alarcon et al. Eur J Human Genet 2007;15:831; Dunlap et al. Hum Mol Genet 1997;6:105;Baglietto et al. J Natl Cancer Inst 2010;102:193.Quehenberger et al. J Med Genet 2005;42:491; Choi et al. Hered Cancer Clin Pract 2009;7:14 Jenkins et al. Clin Gastroenterol Hepatol 2006;4:489; Setnter et al. Gastroenterology 2008;135:419
LS: Genetic Features Autosomal Dominant Germline mutation in DNA mismatch repair (MMR) genes or loss of expression of MSH2 due to deletion in EPCAM gene High Penetrance (80-85%) Among Individuals with an IDENTIFIABLE Germline Mutation PMS2 14% MSH6 MSH6 15% 15% MSH2 39% MLH1 32% MLH1 MSH2 MSH6 PMS2 Palomaki, Genet Med 2009;11:42
LS: Genetic Heterogeneity MSH6 MSH2 EPCAM MLH1 PMS2 Chr 2 Chr 3 Chr 7
LS:MMR Gene Failure Leads To Microsatellite Instability (MSI) Normal Microsatellite Instability (MSI+) Phenotype Due to errors of insertion or deletion of dinucleotide repeats or other short repeated sequences during DNA replication Addition of nucleotide repeats Boland, Cancer Res 1998;58:4248
LS: Clinical Criteria Amsterdam I Amsterdam II 3 relatives with CRC 3 relatives with CRC, endometrial, small bowel, or renal-pelvis/ureter Up to 50% of LS families One is first degree do not relative meet these (FDR) of other two criteria! At least 2 successive generations At least one individual diagnosed before age 50 FAP excluded as cause of colorectal cancers Pathology verification if possible Vasen (ICG-HNPCC 1990), Dis Colon Rectum 1991;34:424; Vasen (ICG-HNPCC 1998) Gastro 1999;116:1453
LS: Revised Bethesda Guidelines for tumor testing: CRC under age 50 Synchronous or metachronous Lynchassociated Up to cancer, 30% of LS families regardless do not meet of Bethesda age criteria CRC with 10-15% 1 of FDR sporadic with cancers Lynch-associated have abnormal IHC/MSI cancer, one less than age 50 IHC and MSI are each false negative in ~5-10% of CRC with with 2 FDR/SDR LS cases with with Lynchassociated cancer, regardless of age CRC with high MSI or suggestive histology in a patient under age 60 Umar (NCI Workshop on HNPCC 2002) JNCI 2004;96:261
LS: Universal testing? Evaluation of Genomic Application in Practice and Prevention Sufficient evidence: offer genetic testing to all patients with CRC Insufficient evidence: offer a specific genetic testing strategy Healthy People 2020 National Comprehensive Cancer Network (NCCN) Evaluation of Genomic Application in Practice and Prevention (EGAPP Working Group). Genet Med 2009;11:35
General Testing Strategy for LS (No known mutation in family) Tumor available Tumor not available Test tumor for IHC/MSI Formal Genetic Counseling For consideration of germline testing Normal Loss of MLH1 BRAF Testing Loss of other MMR proteins Absence of BRAF Mutation Mutation Negative Mutation Positive Presence of BRAF Mutation Tailored surveillance based on individual/family risk assessment LS surveillance guidelines Targeted genetic testing for at-risk family members
Risk Reduction Strategies in LS Procedure Age to begin Interval Colon 1 Colonoscopy 20-25 Q1-2 years Endometrium/ Ovary 2 Pelvic Exam, Endometrial Bx and/or Transvaginal Ultrasound 30-35 Q1-2 years Stomach 3 EGD 30-35 Q2-4 years Urinary Tract 3 Urinalysis 30-35 Q1-2 years 1 Sub-total colectomy could be considered (not standard of care) 2 Could also consider prophylactic hysterectomy and BSO 3 Some advocate only if there is a positive family hx of these types of cancers
LS: Colonoscopy Improves Survival Survival 100 80 60 Surveillance No surveillance 92.2% 92.2% 73.9% 73.9% 40 0 5 10 15 Follow-up time (years) Jarvinen HJ et al. Gastroenterology. 2000; 118:829
LS: Chemoprevention Burn et al. Lancet 2011;378:2081
Familial Colorectal Cancer Syndrome Type X Families with multi-generational, early onset CRC without MSI have different cancer risks than families with LS Lower overall risk for CRC Higher age at diagnosis Distal (left sided) Less likely synchronous/metachronous Less likely MSH-H histology Lindor et al., JAMA. 2005;293:1979 Lynch, NEJM 2003;348:919;Lindor, JAMA 2005;293:1979; Schiemann, Digestion 2004;69:166; Woods, Clin Cancer Res 2005;11:6853
Familial Adenomatous Polyposis (FAP): Clinical Features 100 s-1000 s of adenomas Early onset adenomas: 15 yrs (75% by 20 yrs) Early onset CRC: 35 yrs If untreated, cancer inevitable by 4 th -5 th decade Extraintestinal manifestations Gardner Variant: FAP + Extraintestinal Manifestations Turcot Variant: FAP + CNS malignancy (medulloblastoma)
FAP: Extracolonic Manifestations Mandibular Osteoma Epidermoid Cyst Stomach Polyps CHRPE Duodenal Polyps Desmoid
FAP: Extracolonic Malignancies Malignancy Duodenal/Ampullary carcinoma Thyroid cancer (follicular or papillary) Childhood hepatoblastoma (usually age 5 yrs) Lifetime Risk 4-12% < 2% 1-2% Gastric cancer < 1%
Attenuated FAP (AFAP) Fewer adenomas (~20-100) Later onset CRC: age 50 UGI polyps APC mutation located at 5' and 3' ends of gene
FAP: Genotype-Phenotype Correlations APC gene >20 to <100 100 to 1000s 1000s Nieuwenhuis, Crit Rev Oncol Hematol 2007;61:153
FAP: Screening Guidelines Cancer Site Procedure Age to begin Interval Colon Flexible Sigmoidoscopy or Colonoscopy 10-12 1 year Until 35-40 if negative Upper GI Cancers EGD + side viewing duodenoscope 25-30 (Earlier if Fam Hx, symptoms) 1-3 years (depending on Spigelman classification) Thyroid Thyroid Exam Thyroid US Late teens 1 year Hepatoblastoma (Controversial: at risk children) AFP and US Infancy 1 year (until age 7)
MutYH-Associated Polyposis (MAP) Phenotype: resembles attenuated FAP Mode of inheritance: autosomal recessive Genetic defect: biallelic germline mutation in MutY homologue (MYH) MMR gene (chr 1p32-34) MYH mutation: Mechanism: increases frequency of somatic APC gene mutations Accounts for: ~1.4% all adenomatous polyposis ~20% adenomatous polyposis w/o an identifiable APC gene mutation Lefevre, Ann Surg 2006;244:874
Hamartomatous Polyposis Syndromes Gene Dx/Sx Cancer Risk Peutz-Jeghers STK 11 (LKB1) (chr 19p) Polyps, mucocutaneous pigmentation Intussusception, SBO, GIB Breast, colon, stomach, SB, pancreas, ovary, cervix, uterus, sex cord tumor, sertoli cell tumor Juvenile Polyposis SMAD 4 (chr 18q): 15% BMPR1A (chr 10q): 25% 5-10 GI juvenile polyps Anemia, GIB Colon, stomach (rare - SB, pancreas) Cowden PTEN (chr 10): 20-34% Polyps,facial trichilemmomas verrucous skin lesions; cobblestone-like papules of oral mucosa, gingiva, tongue, macrocephaly; dysplastic gangliocytoma of cerebellum Breast, thyroid, endometrial, kidney, CRC Bannayan- Riley- Ruvalcaba Syndrome (BRRS) PTEN (chr 10): 55-60% GI hamartomatous polyps; subcutaneous/visceral lipomas; macrocephaly; penile lentigines; hemangiomas/other vascular anomalies Thyroid
Serrated Polyposis Syndrome (SPS) World Health Organization Classification (any one of the following ) 5 serrated polyps, of which 2 are > 1cm, proximal to sigmoid colon 1 serrated polyp proximal to sigmoid colon, plus first degree relative with SPS > 20 serrated polyps of any size distributed throughout colon Prevalence of CRC after SPS diagnosed: 2%-6.5% Jasperson, DCR 2013;56:1211; Huang, Am J Gastro 2011;106:229; Boparai, Gut 2010;59:1094
A Note on Next Generation Sequencing (NGS) Multigene panel testing Includes high penetrance genes and genes associated with moderate cancer risk Unknown level of risk for many genes Unknown implications **Ordered in consultation with cancer genetics professional **Careful interpretation **Exact role remains unclear Laduca Genet Med. 2014 Nov;16(11):830-7
General Strategy for Hereditary CRC Syndromes: STEPWISE APPROACH Affected family member Pedigree and Clinical Criteria +/- tumor testing for IHC/MSI (LS Suspicion) Suspicion for Hereditary CRC Formal Genetic Testing Mutation Positive Mutation Negative Surveillance guidelines Targeted genetic testing for at-risk family members Tailored surveillance based on individual/family risk assessment
Colon Cancer Syndromes: Conclusions Comprises ~5% of all CRC Requires physicians to take a good family history and to recognize the syndromes Genetic counseling is important NGS will likely change our traditional approach to genetic testing. More to come