Mutations in CHEK2 associated with prostate cancer risk.
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.
Dong
Xiangyang
X
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic/Mayo Medical School, Rochester, MN 55905, USA.
Wang
Liang
L
Taniguchi
Ken
K
Wang
Xianshu
X
Cunningham
Julie M
JM
McDonnell
Shannon K
SK
Qian
Chiping
C
Marks
Angela F
AF
Slager
Susan L
SL
Peterson
Brett J
BJ
Smith
David I
DI
Cheville
John C
JC
Blute
Michael L
ML
Jacobsen
Steve J
SJ
Schaid
Daniel J
DJ
Tindall
Donald J
DJ
Thibodeau
Stephen N
SN
Liu
Wanguo
W
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
D004273:DNA, Neoplasm; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases