Skip to content

Advertisement

Breast Cancer Research

Open Access

ATM mutations associated with breast cancer

  • RA Gatti1 and
  • P Concannon2
Breast Cancer Research20057(Suppl 2):S.05

https://doi.org/10.1186/bcr1048

Published: 17 June 2005

Keywords

Breast CancerBreast Cancer RiskMissense MutationBreast Cancer SusceptibilityIncrease Breast Cancer Risk

Despite over a decade of scrutiny and over 20 published reports from various countries, the degree to which ATM mutations lead to breast cancer in the general population remains unclear. Furthermore, the methodology of ATM mutation detection is still laborious and costly. Because the ATM protein kinase phosphorylates such a wide array of downstream targets, many pathways to oncogenesis are possible and largely unexplored. What seems clear is that: A-T heterozygotes are at a fourfold to fivefold increased risk of breast cancer, although confidence intervals are large; and the spectrum of ATM mutations is distinct for A-T families versus breast cancer cohorts. Only a handful of mutations have been identified in both A-T families and breast cancer cohorts. Missense mutations represent <10% of mutations in A-T patients and >80% in breast cancer cohorts. ATM missense mutations are also more common in some leukemias and lymphomas. Experimental data suggest that some missense mutations represent dominant interfering mutations [15]; however, clinical support for a dominant interfering model is minimal in family studies, suggesting either that the model is flawed or that penetrance of these mutations is very low. Histological classifications of breast cancer are largely grouped as genetically homogeneous models, although expression microarray data suggest otherwise. Other studies have associated ATM-SNPs with increased breast cancer risk; however, just three SNP haplotypes across the ATM locus include ~95% of a global population, and this must be factored into such association models. Without the benefit of mRNA analyses, of minigene experiments, of Maximum Entropy Scores, of site-directed mutagenesis or of functional assays of ATM activity, most 'missense' mutations cannot be reliably distinguished from polymorphisms or from other types of mutations, such as splicing variants that lead to secondary stop codons. Our recent analyses have focused on two ATM missense mutations, 7271T>G and IVS10-6T>G. For each of these mutations, there are published functional data suggesting that they act as dominant interfering mutations, and epidemiological data suggesting a role in breast cancer. Some family studies of the 7271T>G mutation suggest that it is a highly penetrant breast cancer susceptibility allele. However, its infrequency in the population means that its contribution to breast cancer risk is slight and it is possible that 7271T>G represents only one of a diverse array of uncommon ATM mutations leading to increased cancer risk. We found that the frequency of the IVS10-6T>G mutation was not increased in breast cancer cases as compared with controls. Furthermore, the evidence that IVS10-6T>G is an A-T mutation is called into question by our recent evidence that, in the one known example of a homozygous IVS10-6T>G individual with A-T, a homozygous mutation at 5644C>T was also present (Purayidom and colleagues, submitted). Taken together, these studies suggest that whereas no single ATM mutation impacts significantly upon breast cancer risk, it may be possible to group mutations that do modulate risk for breast cancer based on their phenotypic effects. This group of patients might benefit substantially from a therapeutic approach to correct missense mutations.

Declarations

Acknowledgements

These efforts were partially funded by NIH grant NS35322 and the A-T Medical Research Foundation, Los Angeles, California, USA.

Authors’ Affiliations

(1)
Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, USA
(2)
Benaroya Research Institute at Virginia Mason, Seattle, USA

References

  1. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Biol Metab. 1999, 68: 419-426. 10.1006/mgme.1999.2942.Google Scholar
  2. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, et al: Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet. 2002, 32: 185-190. 10.1038/ng958.View ArticlePubMedGoogle Scholar
  3. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA. 2002, 99: 925-930. 10.1073/pnas.012329699.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Concannon P: ATM heterozygosity and cancer risk. Nat Genet. 2002, 32: 89-90. 10.1038/ng0902-89.View ArticlePubMedGoogle Scholar
  5. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, et al: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst. 2002, 94: 205-215.View ArticlePubMedGoogle Scholar

Copyright

© BioMed Central 2005

Advertisement