title: CHEK2 mutations and HNPCC-related colorectal cancer.
abstract: Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty-five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR-positive families). A positive association between the CHEK2 I157T mutation and HNPCC-related cancer was observed only for MMR-negative cases (OR = 2.1; p = 0.0004), but not for MMR-positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR-negative cases with familial colorectal cancer (2 or more first-degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR-negative, HNPCC/HNPCC-related families in Poland.
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, il. Połabska 4, Szczecin, Poland. jsuchy@sci.pam.szczecin.pl
authors.forename: Janina
authors.initials: J
authors.lastname: Suchy
authors.forename: Cezary
authors.initials: C
authors.lastname: Cybulski
authors.forename: Dominika
authors.initials: D
authors.lastname: Wokołorczyk
authors.forename: Oleg
authors.initials: O
authors.lastname: Oszurek
authors.forename: Bohdan
authors.initials: B
authors.lastname: Górski
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Debniak
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.forename: Jacek
authors.initials: J
authors.lastname: Gronwald
authors.forename: Tomasz
authors.initials: T
authors.lastname: Huzarski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Byrski
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Dziuba
authors.forename: Marek
authors.initials: M
authors.lastname: Gogacz
authors.forename: Rafał
authors.initials: R
authors.lastname: Wiśniowski
authors.forename: Piotr
authors.initials: P
authors.lastname: Wandzel
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Banaszkiewicz
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kurzawski
authors.forename: Józef
authors.initials: J
authors.lastname: Kładny
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: Jan
authors.initials: J
authors.lastname: Lubiński
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D005190:Family; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015996:Survival Rate
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein