Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM to TP53 Synthetic Essentiality

Abstract Background: Germline alterations in homologous recombination repair (gHRR) genes impact the pathogenesis, treatment options, and survival of cancer patients. However, distinct gHRR gene alterations may differentially impact treatment response and oncogenic signaling. Here 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. Methods: We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants (gBRCA1, gBRCA2, gPALB2, gATM, gCHEK2) were analyzed. Hazard ratios 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 was used to compare transcriptomic profiles. Results: Somatic TP53 mutations were depleted in gATM carriers (p<0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with gBRCA1/2 mutations were associated with improved survival in ovarian cancer patients, 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. Conclusion: gATM-associated cancers appear to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.