Population‐based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066–6T>G (IVS10–6T>G) from the Breast Cancer Family Registry

The ATM gene variants segregating in ataxia‐telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066–6T>G (IVS10–6T>G), are associated with increased risk. Using population‐based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2–25.5; P=0.04) and delayed child‐bearing (OR=5.1; 95% CI=1.0–25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28–80%; hazard ratio [HR]=8.6; 95% CI=3.9–18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066–6T>G allele (OR=0.4; 95% CI=0.2–1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066–6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population. Hum Mutat 27(11), 1122–1128, 2006. Published 2006 Wiley‐Liss, Inc.

[1]  Lesley McGuffog,et al.  Cancer risks and mortality in heterozygous ATM mutation carriers. , 2005, Journal of the National Cancer Institute.

[2]  P. Oefner,et al.  Two ATM variants and breast cancer risk , 2005, Human mutation.

[3]  D. Stoppa-Lyonnet,et al.  Cancer risk according to type and location of ATM mutation in ataxia‐telangiectasia families , 2005, Genes, chromosomes & cancer.

[4]  S. Lees-Miller,et al.  DNA damage-induced activation of ATM and ATM-dependent signaling pathways. , 2004, DNA repair.

[5]  Christopher J Bakkenist,et al.  Initiating Cellular Stress Responses , 2004, Cell.

[6]  G. Colditz,et al.  Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case–control study , 2004, Breast Cancer Research.

[7]  T. Dörk,et al.  Functional consequences of ATM sequence variants for chromosomal radiosensitivity , 2004, Genes, chromosomes & cancer.

[8]  Norman Boyd,et al.  The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer , 2004, Breast Cancer Research.

[9]  T. Buchholz,et al.  A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls , 2004, Cancer.

[10]  J. Houwing-Duistermaat,et al.  Are ATM Mutations 7271T→G and IVS10-6T→G Really High-Risk Breast Cancer-Susceptibility Alleles? , 2004, Cancer Research.

[11]  A. Børresen-Dale,et al.  ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer , 2003, British Journal of Cancer.

[12]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.

[13]  A. Børresen-Dale,et al.  Designing and implementing quality control for multi‐center screening of mutations in the ATM gene among women with breast cancer , 2003, Human mutation.

[14]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[15]  W. Bennett,et al.  Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls. , 2002, Cancer genetics and cytogenetics.

[16]  S. Henikoff,et al.  Accounting for human polymorphisms predicted to affect protein function. , 2002, Genome research.

[17]  J. Sambrook,et al.  Dominant negative ATM mutations in breast cancer families. , 2002, Journal of the National Cancer Institute.

[18]  T. Dörk,et al.  Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  T. Dörk,et al.  Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. , 2001, Cancer research.

[20]  E. Ostrander,et al.  Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history , 2001, Cancer.

[21]  A. Aurias,et al.  Cancer risk in heterozygotes for ataxia‐telangiectasia , 2001, International journal of cancer.

[22]  Warren C. Lathe,et al.  Prediction of deleterious human alleles. , 2001, Human molecular genetics.

[23]  A. Børresen-Dale,et al.  Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. , 2001, Journal of the National Cancer Institute.

[24]  J. Klijn,et al.  ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. , 2000, American journal of human genetics.

[25]  C. Mathew,et al.  Identification of germline missense mutations and rare allelic variants in the ATM gene in early‐onset breast cancer , 1999, Genes, chromosomes & cancer.

[26]  A. Tward,et al.  Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. , 1999, Molecular genetics and metabolism.

[27]  G. Giles,et al.  Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[28]  K. Gelmon,et al.  Absence of mutations in the ATM gene in forty-seven cases of sporadic breast cancer , 1999, British Journal of Cancer.

[29]  A. Aurias,et al.  Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families , 1999, British Journal of Cancer.

[30]  H. Inskip,et al.  Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia , 1999, British Journal of Cancer.

[31]  D. Easton,et al.  ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. , 1998, American journal of human genetics.

[32]  J. Hopper,et al.  AT-tributable risks? , 1997, Nature Genetics.

[33]  K. Isselbacher,et al.  Heterozygous ATM mutations do not contribute to early onset of breast cancer , 1997, Nature Genetics.

[34]  M. Swift,et al.  Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. , 1996, Cancer genetics and cytogenetics.

[35]  M. Lovett,et al.  A single ataxia telangiectasia gene with a product similar to PI-3 kinase. , 1995, Science.

[36]  Jack A. Taylor,et al.  Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies. , 1994, Statistics in medicine.

[37]  D Morrell,et al.  Incidence of cancer in 161 families affected by ataxia-telangiectasia. , 1991, The New England journal of medicine.

[38]  P. Møller,et al.  Breast cancer and other cancers in Norwegian families with ataxia‐telangiectasia , 1990, Genes, chromosomes & cancer.

[39]  M. Swift,et al.  Breast and other cancers in families with ataxia-telangiectasia. , 1987, The New England journal of medicine.

[40]  H. White.  A Heteroskedasticity-Consistent Covariance Matrix Estimator and a Direct Test for Heteroskedasticity , 1980 .

[41]  K. Lange,et al.  Programs for pedigree analysis: Mendel, Fisher, and dGene , 1988, Genetic epidemiology.