title: Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer.
abstract: The extracolonic tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC) includes cancer of the endometrium, ovaries, stomach, biliary tract, and urinary tract. This study was designed to determine the penetrance of colorectal and extracolonic tumors in HNPCC mutation carriers. Forty-nine patients (22 females and 27 males) were identified with an MSH2 germline mutation, and 56 patients (28 females and 28 males) were identified with an MLH1 I mutation. Cumulative incidence by age 60 (lifetime risk) and mean age of cancer diagnosis were compared. The lifetime risk of extracolonic cancers in MSH2 and MLH1 carriers was 48% and 11%, respectively (P = 0.016). Extracolonic cancer risk in MSH2 females and males was 69% and 34%, respectively (P = 0.042). Mean age of extracolonic cancer diagnosis was significantly older for MSH2 males than females (55.4 vs. 39.0, P = 0.013). No difference was observed in colorectal cancer risk between MLH1 and MSH2 carriers (84% vs. 71%). Colorectal cancer risk was 96% in MSH2 males compared to 39% in MSH2 females (P = 0.034). No differences in colorectal and extracolonic cancer risks between MLH1 females and males were identified. The risk of extracolonic cancer by age 60 was greater in MSH2 mutation carriers than in MLH1 carriers. Gender differences in colorectal and extracolonic cancer risk were observed for MSH2 carriers only. These phenotypic features of HNPCC genotypes may have clinical significance in the design of genotype-specific screening, surveillance, and follow-up for affected individuals.
authors.affiliation: Section of Colon and Rectal Surgery, Department of Surgery, Creighton Universiy School of Medicine, Omaha, NE, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Shashidharan
authors.forename: A G
authors.initials: AG
authors.lastname: Thorson
authors.forename: C A
authors.initials: CA
authors.lastname: Ternent
authors.forename: G J
authors.initials: GJ
authors.lastname: Blatchford
authors.forename: M A
authors.initials: MA
authors.lastname: Christensen
authors.forename: P
authors.initials: P
authors.lastname: Watson
authors.forename: S J
authors.initials: SJ
authors.lastname: Lemon
authors.forename: B
authors.initials: B
authors.lastname: Franklin
authors.forename: B
authors.initials: B
authors.lastname: Karr
authors.forename: J
authors.initials: J
authors.lastname: Lynch
authors.forename: H T
authors.initials: HT
authors.lastname: Lynch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D001661:Biliary Tract Neoplasms / Q000235:genetics; D002352:Carrier Proteins; D003110:Colonic Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000235:genetics; D010641:Phenotype; D011159:Population Surveillance; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics*; D012307:Risk Factors; D012737:Sex Factors; D013274:Stomach Neoplasms / Q000235:genetics; D014571:Urologic Neoplasms / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein