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Cancers with Biallelic ATM Mutations

The ataxia-telangiectasia mutated (ATM) gene is essential in the detection and signaling to repair DNA double-strand breaks.1 Carriers of germline mutations in ATM are predisposed to cancer2,3 and ATM is also often mutated somatically. In light of new cancer therapies targeting cells with ATM loss, we hypothesized that ATM loss would result in a mutational signature apparent in cancer genomes.

In order to evaluate the evidence, we prepared a Chromoscope configuration containing 21 cancers with pathogenic mutations in ATM, as annotated by the PCAWG consortium4. In this data, cancer genomes with ATM loss display a subtle but non-characteristic pattern of chromosomal instability in this tumor group. Larger cohort sizes and stricter annotation of pathogenic mutations leading to complete ATM loss might be needed.

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You can see visualization of 21 cancer genomes with putative ATM loss at:

https://chromoscope.bio/app/?showSamples=true&external=https://somatic-browser-test.s3.amazonaws.com/atm_bi/configs/atm_bi.all.config.json

  1. Pitter, Kenneth L et al. “Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy.” Journal of the National Cancer Institute vol. 113,3 (2021):↩
  2. Swift, M et al. “Incidence of cancer in 161 families affected by ataxia-telangiectasia.” The New England journal of medicine vol. 325,26 (1991): 1831-6. ↩
  3. Weigelt, Britta et al. “The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers.” Journal of the National Cancer Institute vol. 110,9 (2018): 1030-1034.↩
  4. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. “Pan-cancer analysis of whole genomes.” Nature vol. 578,7793 (2020): 82-93. doi:10.1038/s41586-020-1969-6↩