New Perspectives on the Recurrent BRCA Mutations and Clinical Variability

Familial cancer syndromes include about 5% to 10% of all tumors and are attributable to genetic defects. Hereditary breast and ovarian cancer syndrome (HBOC) is distinguished by an elevated risk for male and female breast cancer, ovarian cancer (Fallopian tube and primary peritoneal cancers), and to a smaller degree, other cancers such as prostate cancer, pancreatic cancer, and melanoma. In this study, we performed next-generation sequencing or a comprehensive cancer panel on 335 patients to explain the importance of recurrent germline mutations of BRCA1-2 and their clinical results and determine how often BRCA gene mutations were seen in people suspected of Lynch syndrome. BRCA2 mutations were more predominant (n= 212, 63.3%) than BRCA1 mutations (123, 36.7%) in all groups except for the ovarian and breast-ovarian groups. The most common recurrent mutations were BRCA2:c.3318C>G, BRCA2:c.632-2A > C, BRCA1:c.5266dupC, BRCA2:c.9317G > A, BRCA2:c.8452G > A, BRCA1:c.2800C > T, respectively. BRCA1 variants were associated with ovarian cancers, and BRCA2 variants show a higher incidence of extra-ovarian malignancy. The principal finding of our study is that BRCA2 mutations were more predominant not just in the breast group but also in the colorectal group. This is the first study mentioning the importance of BRCA2 variants in patients with Lynch Syndrome (LS) phenotype to the best of our knowledge. Our data broadens the spectrum of BRCA gene mutations and provides insights for genotype-phenotype correlations for familial cancer syndromes.

Automated summary

This study highlights the importance of recurrent germline mutations of BRCA1-2 in breast and ovarian cancer syndromes, and introduces the occurrence of these mutations in patients with Lynch syndrome for the first time.