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Promoter polymorphisms in the gene encoding checkpoint kinase 1 are associated with survival in cancer
Author(s) -
Riemann Kathrin,
Hasenbein Constanze,
Siffert Winfried
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a418-d
Subject(s) - single nucleotide polymorphism , genotype , allele , biology , snp , gene , cancer , promoter , cancer research , genetics , colorectal cancer , chek1 , oncology , microbiology and biotechnology , cell cycle , gene expression , medicine , cell cycle checkpoint
Objectives: The aim of this study was to investigate whether polymorphisms in the promoter of CHK1, which is an essential gene involved in cell cycle checkpoint control, regulate gene expression and, thereby, influence course of cancer diseases. Methods and Results: Single nucleotide polymorphisms (SNP) in the promoter region of CHK1 were identified by systematic sequencing. One of the detected SNPs, ‐1143G>T, revealed genotype‐dependent differences in functional analyses. Binding of transcription factors as shown by EMSA was significantly stronger for the G allele compared to the T allele. Furthermore, CHK1 expression in tissues of patients with GG genotype was significantly increased. Association studies were performed with different collectives of cancer patients. Overall survival of patients with bladder cancer was significantly dependent on the ‐1143G>T genotype. CHK1 ‐1143T homozygous patients displayed a higher risk for death than ‐1143G allele carriers (HR: 2.6; p=0.01). In patients with colorectal cancer, however, GG genotype was associated with a higher risk for death (HR: 3.0; p=0.03). Multivariate analysis revealed that the ‐1143G>T SNP was an independent risk factor for death. Conclusion: The identified promoter SNP in CHK1 might serve as molecular marker for survival of cancer patients. This observation may also be of interest in regard to CHK1 inhibitors which are currently investigated in phase II and III trials.