講演情報
[OE6-5]BRCA関連重複癌と生殖細胞の全エクソン解析により同定された新規候補遺伝子
○谷岡 真樹1, 吉田 正行2, 平岡 伸介2, 吉野 友美6, 岡田 千尋3, 野原 祥夫3, 須藤 一起4, 三井 純5 (1.岡山大学医歯薬学域医療AI人材育成プログラム, 2.国立がん研究センター中央病院病理診断科, 3.三菱電機ソフトウエア株式会社, 4.国立がん研究センター中央病院腫瘍内科, 5.東京大学大学院医学系研究科 分子神経学講座, 6.国立がん研究センター研究所 分子薬理学)
Backgrounds: Breast (BR), ovarian (OV), and pancreatic (PA) cancers were defined as BRCA-associated cancers in this study. The incidence of double primary BRCA-associated cancers (DPBRCA) is less than 1% among breast cancer patients (pts), so their genetic backgrounds and optimal treatments remain unclear. Methods: We performed whole exome sequencing of 50 normal and 50 tumor tissues from 50 DPBRCA pts diagnosed between 2008-20. Loss of heterogeneity (LOH) scores which reflect homologous recombination (HR) deficiency was calculated in tumors. Results: DPBRCA derived from BR & OV, BR & PA, and OV & PA in 37, 11 and 2 pts, respectively. The median age was 61 (26-79). Twenty-four pts (48%) had germline, pathogenic mutations in BRCA1 (n=13), BRCA2 (n=9), ATM（n=1), TP53 (n=1), MRE11 (n=1), BLM (n=1), and TET2 (n=1), and 3 pts (6%) had two of these mutations. Among the other 26 pts, a germline variant of LMO2 was found as a sole candidate in a pt with BR & PA cancers. In addition, she experienced diffuse large B-cell lymphoma (DLBCL) twice in breast and stomach. LMO2 is known as a prognostic factor in DLBCL, also interacts with 53BP1 to inhibit HR and confers synthetic lethality to PARP inhibition in DLBCL (Parvin, 2019, Cancer Cell). The variant allele frequency (VAF) was higher in breast tumor (68%) than that in blood (52%) and the LOH score was as high as 24% in the breast tumor. Conclusions: The pts with DPBRCA had germline mutations in a high frequency. A novel variant in LMO2 might cause DLBCL and BRCA-associated cancers which are responsive to PARP inhibitors.