title: Mutations in CHEK2 associated with prostate cancer risk.
abstract: The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.
authors.affiliation: Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic/Mayo Medical School, Rochester, MN 55905, USA.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Dong
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.forename: Chiping
authors.initials: C
authors.lastname: Qian
authors.forename: Angela F
authors.initials: AF
authors.lastname: Marks
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Peterson
authors.forename: David I
authors.initials: DI
authors.lastname: Smith
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.forename: Michael L
authors.initials: ML
authors.lastname: Blute
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Jacobsen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Wanguo
authors.initials: W
authors.lastname: Liu
mesh_terms: D017668:Age of Onset; D000368:Aged; D002461:Cell Line, Transformed; D064447:Checkpoint Kinase 2; D004273:DNA, Neoplasm / Q000032:analysis; D016368:Frameshift Mutation; D015870:Gene Expression; D005809:Genes, Regulator; D016158:Genes, p53; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D012307:Risk Factors
chemical_list: D004273:DNA, Neoplasm; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases