Mutation analysis of the ATR gene in breast and ovarian cancer families.
BACKGROUND
Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for only 20-30% of the familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. The ATR (ataxia-telangiectasia- and Rad3-related) kinase is essential for the maintenance of genomic integrity. It functions both in parallel and cooperatively with ATM, but whereas ATM is primarily activated by DNA double-strand breaks induced by ionizing radiation, ATR has been shown to respond to a much broader range of DNA damage. Upon activation, ATR phosphorylates several important tumor suppressors, including p53, BRCA1 and CHK1. Based on its central function in the DNA damage response, ATR is a plausible candidate gene for susceptibility to cancer.


METHODS
We screened the entire coding region of the ATR gene for mutations in affected index cases from 126 Finnish families with breast and/or ovarian cancer, 75 of which were classified as high-risk and 51 as moderate-risk families, by using conformation sensitive gel electrophoresis and direct sequencing.


RESULTS
A large number of novel sequence variants were identified, four of which -- Glu254Gly, Ser1142Gly, IVS24-48G>A and IVS26+15C>T -- were absent from the tested control individuals (n = 300). However, the segregation of these mutations with the cancer phenotype could not be confirmed, partly because of the lack of suitable DNA samples.


CONCLUSIONS
The present study does not support a major role for ATR mutations in hereditary susceptibility to breast and ovarian cancer.
Heikkinen
Katri
K
Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland. kheikkin@paju.oulu.fi
Mansikka
Virpi
V
Karppinen
Sanna-Maria
SM
Rapakko
Katrin
K
Winqvist
Robert
R
D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors
D018797:Cell Cycle Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases