The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.
The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers
Open accessAbstract
Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.
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“Despite the role of TP53, ATM and CHEK2 in DNA-damage signalling and double-strand breaks detection, these tumours do not show evidence of BRCA-deficient signatures, as previously described [9, 13, 19], but instead they harbour highly complex clustered chromosomal rearrangements.”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [19]
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Cites
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Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
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Self-citationMolecular and genetic properties of tumors associated with local immune cytolytic activity
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G., & Hacohen, N. (2015) · Cell · doi:10.1016/j.cell.2014.12.033 · Cited by 3,825
Genomic instability — an evolving hallmark of cancer
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L. B., Martin, S., Wedge, D. C., et al. (2016) · Nature · doi:10.1038/nature17676 · Cited by 2,218
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Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
Cheng, D. T., Mitchell, T. N., Zehir, A., Shah, R. H., Benayed, R., Syed, A., Chandramohan, R., Liu, Z. Y., Won, H. H., Scott, S. N., et al. (2015) · The Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2014.12.006 · Cited by 2,119
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Pathogenesis of Triple-Negative Breast Cancer
Derakhshan, F., & Reis-Filho, J. S. (2022) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-042420-093238 · Cited by 714
Self-citationAbida, W. M., Campbell, D. C., Patnaik, A., Shapiro, J. D., Sautois, B. R., Vogelzang, N. J., Voog, É., Bryce, A. H., McDermott, R., Ricci, F., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-0394 · Cited by 388
“The apparent lower sensitivity to PARP inhibitors of tumors harboring an ATM alteration may be due to ATM's role as a sensor of DNA damage rather than a mediator of homologous recombination repair (15).”
BackgroundTung, N., Boughey, J. C., Pierce, L. J., Robson, M. E., Bedrosian, I., Dietz, J. R., Dragun, A. J., Balmañà, J., Hofstatter, E. W., Isaacs, C. J., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.00299 · Cited by 335
Self-citationSynthetic Lethality in Cancer Therapeutics: The Next Generation
Setton, J. S., Zinda, M. J., Riaz, N., Durocher, D., Zimmermann, M., Koehler, M. T., Reis-Filho, J. S., & Powell, S. N. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1503 · Cited by 214
“In addition to its role in DNA damage signaling, ATM has a key gatekeeper role via regulation of p53 stabilization in response to cellular stress (104); inactivation of ATM appears to suppress p53 signaling to a degree that is sufficient for tumorigenesis, evidenced by the observation that LOF alterations in ATM and T…”
BackgroundSelf-citationSuwinski, P., Ong, C. K., Ling, M. H., Poh, Y. M., Khan, A. M., & Ong, H. S. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00049 · Cited by 218
“…actionable areas of the genome to determine the variations in the exon regions and identify causal variants of a disease or disease-causing mutations (Gorski et al., 2016; LaHaye et al., 2016; Gambin et al., 2017; Gupta et al., 2017; Hixson et al., 2017; Mueller et al., 2018; Weigelt et al., 2018).”
Background
Metadata
- Authors
- Weigelt, B., Bi, R., Kumar, R., Blecua, P., Mandelker, D. L., Geyer, F. C., Pareja, F., James, P. A., kConFab Investigators, Couch, F. J., Eccles, D. M., Blows, F., Pharoah, P., Li, A., Selenica, P., Lim, R. S., Jayakumaran, G., Waddell, N., Shen, R., Norton, L., Wen, H. Y., Powell, S. N., Riaz, N., Robson, M. E., Reis-Filho, J. S., & Chenevix-Trench, G.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Peter MacCallum Cancer Centre (AU)
- Mayo Clinic (US)
- University of Cambridge (GB)
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia (NW, GCT)
- Corresponding author
- Reis-Filho, Jorge S
- ORCID
- Weigelt, Britta
- Bi, Rui
- Kumar, Rahul
- Blecua, Pedro
- Mandelker, Diana L
- Geyer, Felipe C
- Pareja, Fresia
- James, Paul A
- Couch, Fergus J
- Eccles, Diana M
- Pharoah, Paul
- Li, Anqi
- Selenica, Pier
- Lim, Raymond S
- Jayakumaran, Gowtham
- Shen, Ronglai
- Norton, Larry
- Wen, Hannah Y
- Powell, Simon N
- Riaz, Nadeem
- Robson, Mark E
- Reis-Filho, Jorge S
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-02-28
- Volume
- 110
- Issue
- 9
- Pages
- 1030-1034
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC6136925
- OpenAlex
- W2792571019
- Cited by
- 128
- References
- 22
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 19 · 2020: 21 · 2019: 18 · 2018: 4
- FWCI
- 9.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Meredith Israel Thomas Fund
- Breast Cancer Research Foundation
- National Institutes of Health
- National Cancer Institute (P30CA008748)
- NIH (CA192393, CA176785)
- National Health and Medical Research Council of Australia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- breast cancer, somatic alterations, loss of heterozygosity, TP53 mutation, epistasis, hormone receptor-positive breast cancer, tumor immune infiltrate, DNA damage response
- MeSH terms
- Exome Sequencing, Adult, Aged, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Mutation, Biomarkers, Tumor, Germ-Line Mutation, Genetic Predisposition to Disease, Genomics, Genetic Association Studies, Ataxia Telangiectasia Mutated Proteins
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