The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations
| Autor: | Adam M. Bailis, Yuan Chun Ding, Jeremy M. Stark, Aaron Adamson, Carlos Mendez-Dorantes, Susan L. Neuhausen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases DNA repair RAD52 genetic processes Biology lcsh:RC254-282 Germline 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer breast cancer Mutant protein Genetics medicine Allele skin and connective tissue diseases fungi General Medicine medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens BRCA2 Double Strand Break Repair enzymes and coenzymes (carbohydrates) 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis double‐strand break repair Cancer research Molecular Medicine DNA |
| Zdroj: | Molecular Oncology, Vol 14, Iss 6, Pp 1124-1133 (2020) |
| ISSN: | 1574-7891 1878-0261 |
| Popis: | Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer of up to 80%. However, risk estimates vary in part due to genetic modifiers. We investigated the association of the RAD52 S346X variant as a modifier of the risk of developing breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. The RAD52 S346X allele was associated with a reduced risk of developing breast cancer in BRCA2 carriers [per-allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56-0.86; P = 0.0008] and to a lesser extent in BRCA1 carriers (per-allele HR = 0.78, 95% CI 0.64-0.97, P = 0.02). We examined how this variant affected DNA repair. Using a reporter system that measures repair of DNA double-strand breaks (DSBs) by single-strand annealing (SSA), expression of hRAD52 suppressed the loss of this repair in Rad52-/- mouse embryonic stem cells. When hRAD52 S346X was expressed in these cells, there was a significantly reduced frequency of SSA. Interestingly, expression of hRAD52 S346X also reduced the stimulation of SSA observed upon depletion of BRCA2, demonstrating the reciprocal roles for RAD52 and BRCA2 in the control of DSB repair by SSA. From an immunofluorescence analysis, we observed little nuclear localization of the mutant protein as compared to the wild-type; it is likely that the reduced nuclear levels of RAD52 S346X explain the diminished DSB repair by SSA. Altogether, we identified a genetic modifier that protects against breast cancer in women who carry pathogenic mutations in BRCA2 (P = 0.0008) and to a lesser extent BRCA1 (P = 0.02). This RAD52 mutation causes a reduction in DSB repair by SSA, suggesting that defects in RAD52-dependent DSB repair are linked to reduced tumor risk in BRCA2-mutation carriers. |
| Databáze: | OpenAIRE |
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