Mutations in the ataxia telangiectasia and rad3-related-checkpoint kinase I DNA damage response axis in colon cancers

Kriste A. Lewis, Jamie N Bakkum-Gamez, Ralitsa Loewen, Amy J. French, Stephen N Thibodeau, William Arthur Cliby

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase I (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.

Original languageEnglish (US)
Pages (from-to)1061-1068
Number of pages8
JournalGenes Chromosomes and Cancer
Volume46
Issue number12
DOIs
StatePublished - Dec 2007

Fingerprint

Ataxia Telangiectasia
Colonic Neoplasms
DNA Damage
Phosphotransferases
Mutation
Disease-Free Survival
Neoplasms
Microsatellite Instability
DNA Mismatch Repair
Mutation Rate
Cell Cycle Checkpoints
DNA Repair
Microsatellite Repeats
N-methylsuccinimide
Exons
Multivariate Analysis
High Pressure Liquid Chromatography
Recurrence

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Mutations in the ataxia telangiectasia and rad3-related-checkpoint kinase I DNA damage response axis in colon cancers. / Lewis, Kriste A.; Bakkum-Gamez, Jamie N; Loewen, Ralitsa; French, Amy J.; Thibodeau, Stephen N; Cliby, William Arthur.

In: Genes Chromosomes and Cancer, Vol. 46, No. 12, 12.2007, p. 1061-1068.

Research output: Contribution to journalArticle

@article{10e8783119cb485282595934943f43f2,
title = "Mutations in the ataxia telangiectasia and rad3-related-checkpoint kinase I DNA damage response axis in colon cancers",
abstract = "In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase I (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.",
author = "Lewis, {Kriste A.} and Bakkum-Gamez, {Jamie N} and Ralitsa Loewen and French, {Amy J.} and Thibodeau, {Stephen N} and Cliby, {William Arthur}",
year = "2007",
month = "12",
doi = "10.1002/gcc.20486",
language = "English (US)",
volume = "46",
pages = "1061--1068",
journal = "Genes Chromosomes and Cancer",
issn = "1045-2257",
publisher = "Wiley-Liss Inc.",
number = "12",

}

TY - JOUR

T1 - Mutations in the ataxia telangiectasia and rad3-related-checkpoint kinase I DNA damage response axis in colon cancers

AU - Lewis, Kriste A.

AU - Bakkum-Gamez, Jamie N

AU - Loewen, Ralitsa

AU - French, Amy J.

AU - Thibodeau, Stephen N

AU - Cliby, William Arthur

PY - 2007/12

Y1 - 2007/12

N2 - In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase I (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.

AB - In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase I (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.

UR - http://www.scopus.com/inward/record.url?scp=35348970340&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35348970340&partnerID=8YFLogxK

U2 - 10.1002/gcc.20486

DO - 10.1002/gcc.20486

M3 - Article

C2 - 17879369

AN - SCOPUS:35348970340

VL - 46

SP - 1061

EP - 1068

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

IS - 12

ER -