ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM to TP53 Synthetic Essentiality.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Ataxia-Telangiectasia, DNA Repair Deficits, Immune Dysfunction, and Cancer: A Review of Mechanisms, Clinical Presentations, and Emerging Therapies.Clinical reviews in allergy & immunology · 2026Review
- Article
- Landscape of somatic genetic alterations and PAM50 intrinsic subtypes in breast cancer associated with germline pathogenic variants in DNA-repair genes.Journal of the National Cancer Institute · 2026Article
- DNA copy number patterns reveal prognostic markers and elucidate mechanisms of evolution in IDH-mutant astrocytoma.Neuro-oncology · 2026Article
- Germline DNA Repair Gene Mutations and Clonal Hematopoiesis (CH) in 24,849 Patients with BRCA-Associated Cancers.Cancers · 2025Article
- Case Report: Deep and durable response to talazoparib in germlineFrontiers in oncology · 2025Article
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Abstract
purposeGermline alterations in homologous recombination repair (gHRR) genes affect the pathogenesis, treatment options, and survival of patients with cancer. However, distinct gHRR gene alterations may differentially affect treatment response and oncogenic signaling. In this study, we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities. EXPERIMENTAL
designWe assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants [germline BRCA1, germline BRCA2, germline PALB2, germline ATM (gATM), and germline CHEK2] were analyzed. HRs were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis were used to compare transcriptomic profiles.
resultsSomatic TP53 mutations were depleted in gATM carriers (P < 0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with germline BRCA1/2 mutations were associated with improved survival in patients with ovarian cancer and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (P < 0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (P < 0.001). Finally, using gene dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function.
conclusionsgATM-associated cancers seem to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.
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