title: Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?
abstract: Germline mutations in cell cycle checkpoint kinase 2 (CHEK2) have been associated with a range of cancer types, in particular of the breast and prostate. Protein-truncating mutations in CHEK2 have been reported to confer higher risks of cancer of the breast and the prostate than the missense I157T variant. In order to estimate the risks of colorectal cancer associated with truncating and missense CHEK2 mutations, we genotyped 1085 unselected colorectal cancer cases and 5496 controls for four CHEK2 founder mutations present in Poland. We observed an increased risk of colorectal cancer in association with the missense I157T mutation (odds ratios (OR) = 1.5; 95% CI 1.2-2.0; P = 0.002) but not with truncating mutations (OR = 1.0; 95% CI 0.5-1.8; P = 0.9); however the difference in the two OR was not statistically significant (P = 0.2). We conclude that the I157T mutation increases the risk of colorectal cancer in the population, but that truncating mutations may confer a lower risk or no increase in risk. It is important that other studies of CHEK2 mutation carriers be conducted to confirm this hypothesis.
authors.affiliation: Pomeranian Medical University, Szczecin, Poland. cezarycy@sci.pam.szczecin.pl
authors.forename: Cezary
authors.initials: C
authors.lastname: Cybulski
authors.forename: Dominika
authors.initials: D
authors.lastname: Wokołorczyk
authors.forename: Józef
authors.initials: J
authors.lastname: Kładny
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kurzawski
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kurzwaski
authors.forename: Joanna
authors.initials: J
authors.lastname: Suchy
authors.forename: Ewa
authors.initials: E
authors.lastname: Grabowska
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: Bohdan
authors.initials: B
authors.lastname: Górski
authors.forename: Tadeusz
authors.initials: T
authors.lastname: D Ecedil Bniak
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: Jan
authors.initials: J
authors.lastname: Lubiński
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D064447:Checkpoint Kinase 2; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007532:Isoleucine / Q000737:chemistry / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012306:Risk; D017384:Sequence Deletion; D013912:Threonine / Q000737:chemistry / Q000235:genetics
chemical_list: D007532:Isoleucine; D013912:Threonine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases