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Cited by 240BRCA gene mutations in cancerDNA Repair MechanismsBreast Lesions and Carcinomas

ATM-Heterozygous Germline Mutations Contribute to Breast Cancer–Susceptibility

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Broeks, Annegien, Urbanus, Jos H.M., Floore, Arno N., Dahler, Ellen C., Klijn, Jan G.M., Rutgers, Emiel J. Th., Devilee, Peter, Russell, Nicola S. +2 more·2000·The American Journal of Human Genetics
DOI 10.1086/302746PMC PMC1288102
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Abstract

Approximately 0.5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived >/=5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-->G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.

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  • CHEK2, ATM, NBS1, RAD50, TOPBP1, and RAD51C are mutated in breast cancer patients.

    “Correspondingly, these and other genes functioning in the DNA damage response, such as CHEK2, ATM, NBS1, RAD50, TOPBP1 and RAD51C, are mutated in breast cancer patients [12–21].”

    From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [16]

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Authors
Broeks, A., Urbanus, J. H. M., Floore, A. N., Dahler, E. C., Klijn, J. G. M., Rutgers, E. J. T., Devilee, P., Russell, N. S., van Leeuwen, F. E., & van't Veer, L. J.
Affiliations
  • The Netherlands Cancer Institute (NL)
  • Daniel den Hoed Kliniek (NL)
  • Leiden University Medical Center (NL)
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2000-02
Volume
66
Issue
2
Pages
494-500
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/302746
PMC
PMC1288102
OpenAlex
W2050668424
Cited by
240
References
24
Citations by year
2026: 1 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 7
FWCI
13.02
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Funders
KWF Kankerbestrijding
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
Keywords
ATM gene, germline mutations, breast cancer susceptibility, ataxia telangiectasia, heterozygous carriers, bilateral breast cancer, early-onset breast cancer, splice site mutation, protein truncation test, Dutch patients
MeSH terms
Adult, Alleles, Breast Neoplasms, DNA-Binding Proteins, Exons, Female, Gene Frequency, Haplotypes, Heterozygote, Humans, Male, Middle Aged, Netherlands, Regulatory Sequences, Nucleic Acid, Protein Serine-Threonine Kinases, Alternative Splicing, Age of Onset, Germ-Line Mutation, Carcinoma, Ductal, Breast, Cell Cycle Proteins, Microsatellite Repeats, Loss of Heterozygosity, Genetic Predisposition to Disease, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins

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