RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Abstract

RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p = 0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.

The spectrum of mutations predisposing to familial breast cancer in Poland

“…The evidence that mutations in XRCC2 , BLM , BARD1 and RAD50 genes confer breast cancer risk is mixed . In our study, we identified rare recurrent mutations in XRCC2 , BLM and BARD1 , which were not associated with elevated breast cancer risk.…”

“…The evidence that mutations in XRCC2, BLM, BARD1 and RAD50 genes confer breast cancer risk is mixed. 6,8,9,33,[44][45][46] In our study, we identified rare recurrent mutations in XRCC2, BLM and BARD1, which were not associated with elevated breast cancer risk. Our data provide further evidence that including these genes in testing panels is controversial.…”

Identification of driver genes and somatic mutations in cell‐free DNA of patients with pulmonary lymphangioleiomyomatosis

“…35 RAD50 mutations were reported to increase the risk of BC. 36 The functional consequence in RAD50 exhibited a significant lower expression in LAM cohorts in comparison to controls indicating several inactivation mutations of RAD50 occurred in LAM patients. These observations may provide plausible candidates for potential molecular markers to guide targeted therapy.…”

“…It is also critical to regulate cell cycle checkpoints in the DDR, taking a stand for genome integrity and sustaining tumor suppression . RAD50 mutations were reported to increase the risk of BC . The functional consequence in RAD50 exhibited a significant lower expression in LAM cohorts in comparison to controls indicating several inactivation mutations of RAD50 occurred in LAM patients.…”

Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes

“…Heterozygotní no sičství mutací v genu RAD50 bylo v litera tuře spojováno s mírně zvýšeným rizikem rozvoje nádorových onemocnění, pře devším karcinomu prsu a vaječníků, ale podle posledních studií jsou mutace spíše prediktorem horšího přežití pa cientek s karcinomem prsu než zvýšeného rizika. Nosičství mutací v genu RAD50 je v naší populaci vzácné, v čínské populaci je frek vence tří nejčastějších mutací zastoupena v 0,18 % [37]. Jedná se o vzácné mutace a vzhledem k zatím ne zcela jasné asociaci se zvýšeným rizikem rozvoje nádorů není nutné v případě nálezu mutace provádět další prediktivní vyšetření v rodině.…”