Response to DNA damage of CHEK2 missense mutations in familial breast cancer
Open Access
- 13 March 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 21 (12) , 2738-2744
Abstract
Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case–control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences.Keywords
This publication has 32 references indexed in Scilit:
- Contribution of Inherited Mutations in the BRCA2-Interacting Protein PALB2 to Familial Breast CancerCancer Research, 2011
- Rare, evolutionarily unlikely missense substitutions in CHEK2contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening studyBreast Cancer Research, 2011
- Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencingProceedings of the National Academy of Sciences, 2010
- A method and server for predicting damaging missense mutationsNature Methods, 2010
- In silico analysis of missense substitutions using sequence-alignment based methodsHuman Mutation, 2008
- Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applicationsHuman Mutation, 2008
- CHEK2 Mutations Affecting Kinase Activity Together With Mutations in TP53 Indicate a Functional Pathway Associated with Resistance to Epirubicin in Primary Breast CancerPLOS ONE, 2008
- Trans‐activation of the DNA‐damage signalling protein kinase Chk2 by T‐loop exchangeThe EMBO Journal, 2006
- CHEK2*1100delC and Susceptibility to Breast Cancer: A Collaborative Analysis Involving 10,860 Breast Cancer Cases and 9,065 Controls from 10 StudiesThe American Journal of Human Genetics, 2004
- Mutations in CHEK2 Associated with Prostate Cancer RiskThe American Journal of Human Genetics, 2003