e13684 Background: Pathogenic variants in cancer predisposition genes BRCA1/2 confer susceptibility to breast and ovarian cancer and well-studied. But the characteristics of BRCA in other cancers is unknown, we identified and characterized BRCA germline variants in a large pan-cancer in China. Methods: NGS was performed on genomic DNA from 29,676 pan-cancer patients. Large fragment deletions were all verified by QPCR. We integrated guidelines of ACMG/AMP, ENIGMA and China expert consensus. Based on the in-house system, variants were interpreted one-by-one and classified into 5 grades: Benign (B), Likely Benign(LB), Variant of Uncertain significance(VUS), Likely pathogenic (LP), Pathogenic (P). Results: Among 29,676 patients, 300 BRCA1 mutations and 440 BRCA2 mutations were detected in our study. The proportion among P/LP/VUS/LB/B were 36.1%, 11.6%, 36.6%, 11.1% and 4.6%. Consistent with previous reports, the mutations spread around the whole genes. Missense and frameshift were most common types in BRCA1 (40%, 25.3%) and BRCA2 (42.3%, 29.3%). 192(25.9%) mutations were not reported in any of the databases. Among these newly reported mutations, 32 (16.7%) were classified as P, 62 (32.3%) LP and 98 (51%) VUS. Totally, 522 (1.8%) patients were identified with P/LP BRCA1/2 mutations. No founder mutations in Chinese population were defined, but BRCA1 5470_5477delATTGGGCA (I1824Dfs*3) and BRCA2 3109C > T (Q1037*) had the highest prevalence indicating the common P/LP mutations in Chinese. On the whole, BRCA-associated hereditary cancer harbored higher P/LP percent than other cancer types (11.1% vs 0.7%). Different distribution and percent were observed in BRCA1 and BRCA2, the P/LP mutations were found in double primary cancers of breast and ovary (76.9% vs 38.5%), followed by ovarian cancer (15.5% vs 6.3%), breast cancer(3.8% vs 4.0%), endometrial cancer(1.6% vs 2.4%), prostatic cancer(1.3% vs 1.9%), pancreatic cancer (0.3% vs 1.8%), biliary tract tumor (0% vs 1%), thyroid cancer (0% vs 0.9%), NSCLC(0.2% vs 0.5%) and colorectal cancer(0.08% vs 0.4%). Except for SNV/Indels, large range heterozygous deletions were found in 9 patients, including 4 (0.6%) OC, 4 (0.2%) BC and 1 NSCLC, almost all interfering with BRCA1. Conclusions: This analysis depicted a comprehensive landscape of germline BRCA1/2 variants in Chinese pan-cancer. Besides breast and ovarian cancer, lots of other cancers also harbor BRCA germline mutation, retrospective family history and hereditary cancer risk assessment needs further study.
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