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Mutations in the ataxia telangiectasia and rad3‐related–checkpoint kinase 1 DNA damage response axis in colon cancers
Author(s) -
Lewis Kriste A.,
BakkumGamez Jamie,
Loewen Ralitsa,
French Amy J.,
Thibodeau Stephen N.,
Cliby William A.
Publication year - 2007
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20486
Subject(s) - chek1 , microsatellite instability , dna damage , cancer research , mutation , ataxia telangiectasia , dna repair , dna mismatch repair , biology , colorectal cancer , cell cycle checkpoint , genetics , cancer , cell cycle , dna , microsatellite , gene , allele
Abstract In response to certain types of DNA damage, ataxia telangiectasia and rad3‐related (ATR) phosphorylates checkpoint kinase 1 (CHEK1) resulting in cell cycle arrest and subsequent DNA repair. ATR and CHEK1 contain mononucleotide microsatellite repeat regions, which are mutational targets in tumors with defective mismatch repair (MMR). This study examined the frequency of such mutations in colon cancers and their impact on biologic behavior. Screening for ATR mutations in 48 tumors was performed using denaturing high‐performance liquid chromatography (DHPLC) and confirmed with sequencing analysis. The CHEK1 exon 7 A(9) region was sequenced in 20 of the 27 (74%) tumors with high frequency of microsatellite instability (MSI‐H). Univariate and multivariate analyses were used to examine associations with clinical outcomes. Frequent mutations in MSI‐H colon cancers were identified within the ATR (37%)/ CHEK1 (5%) damage response pathway. Stage and MSI status both independently predicted overall survival (OS) and disease‐free survival (DFS). ATR status was not associated with stage, but was associated with a trend toward improved DFS: 0/9 cancers recurred in MSI‐H cases harboring ATR mutations vs. 4/18 recurrences in MSI‐H cases without ATR mutations. This suggests that ATR mutations may affect clinical behavior and response to therapy in MSI‐H colon cancers. © 2007 Wiley‐Liss, Inc.