Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines.
Genetic defects in CHEK2 and TP53 have been implicated in prostate cancer development. However, the interaction of these two genes in prostate cancer tumorigenesis has not been investigated. We previously described 11 CHEK2 mutations in a group of 84 primary prostate tumors. In this report, we screened the same group of tumors for TP53 mutations and revealed nine somatic and two germline mutations. One germline TP53 mutation (c.408A > T/p.Gln136His) and two somatic mutations (c.1022T > G/p.Phe341Cys and c.108-109ins22/p.His37fsX13) are novel to human cancer. More interestingly, CHEK2 and TP53 mutations were observed to be mutually substituted in these tumors. Analysis of five commonly used prostate cancer cell lines revealed that four cell lines harboring TP53 mutations carry no CHEK2 mutation while the only cell line (LNCaP) carrying wild-type TP53 harbors a CHEK2 mutation. The novel CHEK2 mutation (c.1160C>T/p.Thr387Asn) identified in LNCaP cells changes amino acid Thr387 to Asn which has been shown to impair CHEK2 autophosphorylation and activation. Our data suggest that the CHEK2 and TP53 mutations can substitute each other in at least 25% (21/84) of prostate cancers and that DNA damage-signaling pathway plays an important role in prostate cancer tumorigenesis.
Zheng
Li
L
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic/Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Wang
Fengwei
F
Qian
Chiping
C
Neumann
Roxann M
RM
Cheville
John C
JC
Tindall
Donald J
DJ
Liu
Wanguo
W
D000368:Aged; D001483:Base Sequence; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D020440:Gene Duplication; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53