Abstract P5-03-20: Mutations of TP53 and genes related to homologous recombination repair in breast cancer with germline BRCA1/2 mutations
Authors: Kim Jinyong , Jeong Kyeonghun , Jun Hyeji , Kim Kwangsoo , Kim Tae-Yong , Lee Dae-Won , Woo Go-un , Park Songyi , Yi Hanbaek , Lee Kyung-Hun , Im Seock-Ah 
Published: March 2023

Background Germline mutations of breast cancer susceptibility gene BRCA1 and BRCA2 (gBRCA1/2) are associated with elevated risk of breast cancer in young women in Asia. BRCA1 and BRCA2 proteins contribute to genomic stability through homologous recombination (HR)-mediated double strand DNA break repair (DDR) in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of the breast cancer patients with gBRCA1/2 mutations to investigate the landscape of HR-related gene mutations and their clinical implications. Materials and Methods Data of the breast cancer patients with pathogenic gBRCA1/2 mutations and qualified targeted next generation sequencing, SNUH FiRST cancer panel, were analyzed. Single nucleotide polymorphisms, small insertions and deletions were analyzed with functional annotations using ANNOVAR. HR-related genes were defined as ABL1, ATM, ATR, BARD1, BRCA1, BRCA2, CDKN1A, CDKN2A, CHEK1, CHEK2, FANCA, FANCD2, FANCG, FANCI, FANCL, KDR, MUTYH, PALB2, POLE, POLQ, RAD50, RAD51, RAD51D, RAD54L, and TP53. Mismatch-repair genes were MLH1, MSH2, and MSH6. Clinical data were analyzed with cox proportional hazard models and survival analyses. Results Fifty five Korean breast cancer patients with known gBRCA1/2 mutations and qualified targeted NGS data were analyzed. Ethnically distinct mutations in gBRCA1/2 genes were noted, with higher frequencies of Val1833Ser (14.8%), Glu1210Arg (11.1%), and Tyr130Ter (11.1%) in gBRCA1 and Arg2494Ter (25.0%) and Lys467Ter (14.3%) in gBRCA2. Considering subtypes, gBRCA1 mutations were associated with triple-negative breast cancers (TNBC), while gBRCA2 mutations were more likely hormone receptor-positive breast cancers. At least one missense mutation of homologous recombination (HR)-related genes were observed in 44 cases (80.0%). The most frequently co-mutated gene was TP53 (38.1%). In patients with gBRCA1/2 mutations, however, genetic variations of TP53 occurred in locations different from the known hotspots of those with sporadic breast cancers. The patients with both gBRCA1/2 and TP53 mutations were more likely to have TNBC, high Ki-67 values, and increased genetic mutations, especially of HR-related genes. Survival benefit was observed in the TP53 mutants of patients with gBRCA2 mutations, compared to those with TP53 wildtypes. Conclusion Our study showed distinct genetic landscape of breast cancer patients with gBRCA1 and gBRCA2 mutations in the Asian populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.

Citation Format: Jinyong Kim, Kyeonghun Jeong, Hyeji Jun, Kwangsoo Kim, Tae-Yong Kim, Dae-Won Lee, Go-un Woo, Songyi Park, Hanbaek Yi, Kyung-Hun Lee, Seock-Ah Im. Mutations of TP53 and genes related to homologous recombination repair in breast cancer with germline BRCA1/2 mutations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-20.