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Updated: May 24, 2025
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM
Ali T Arafa1,2, Siddhartha Yadav3, Catherine H Marshall4
1Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Purpose:
Germline 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 Design:
We 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.
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 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.
Conclusions:
gATM-associated cancers seem to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.
Insights
Germline ATM mutations in cancers suggest a dependency on p53 activity. This synthetic essentiality offers potential for targeted therapies affecting TP53 function in BRCA-associated cancers.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Germline homologous recombination repair (gHRR) gene alterations influence cancer development and treatment.
- Distinct gHRR alterations may differentially impact treatment response and oncogenic signaling pathways.
Purpose of the Study:
- To investigate the impact of gHRR gene mutations on cancer pathogenesis, treatment, and survival.
- To identify therapeutic vulnerabilities by analyzing genomic and transcriptomic data in BRCA-associated cancers.
Main Methods:
- Analysis of genomic and transcriptomic data from 24,309 patients with matched tumor/normal sequencing.
- Assessment of germline variants in BRCA1, BRCA2, PALB2, ATM (gATM), and CHEK2.
- Comparison of survival outcomes, somatic alterations, gene expression, and pathway enrichment across gHRR-altered groups.
Main Results:
- Somatic TP53 mutations were depleted in gATM carriers across four BRCA-associated cancers.
- gATM mutations correlated with elevated p53 transcriptional activity and increased inflammatory pathways in breast, ovarian, and prostate cancers.
- Cell lines dependent on ATM showed co-dependency on canonical p53 function.
Conclusions:
- Cancers with germline ATM mutations appear to require intact p53 activity.
- This synthetic essentiality presents a potential therapeutic strategy targeting TP53 function in gATM-associated cancers.
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