Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants
Yukiko Inagaki‐Kawata, Kenichi Yoshida, Nobuko Kawaguchi‐Sakita, Masahiro Kawashima, T Nishimura, Noriko Senda, Yusuke Shiozawa, Yasuhide Takeuchi, Yoshikage Inoue, Aiko Sato‐Otsubo, Yoichi Fujii, Yasuhito Nannya, Eiji Suzuki, Masahiro Takada, Hiroko Tanaka, Yuichi Shiraishi, Kenichi Chiba, Yuki Kataoka, Masae Torii, Hiroshi Yoshibayashi, Kazuhiko Yamagami, Ryuji Okamura, Yoshio Moriguchi, Hironori Kato, Shigeru Tsuyuki, Akira Yamauchi, Hirofumi Suwa, Takashi Inamoto, Satoru Miyano, Seishi Ogawa, Masakazu Toi
Abstract
The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.