Mutations of TP53 and genes related to homologous recombination repair in breast cancer with germline BRCA1/2 mutations

Abstract

AbstractBackgroundGermline mutations of breast cancer susceptibility geneBRCA1andBRCA2(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 in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of Korean breast cancer patients withgBRCA1/2mutations to investigate the alterations in HR-related genes and their clinical implications.Materials and methodsData of the breast cancer patients with pathogenicgBRCA1/2mutations 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 asABL1, ATM, ATR, BARD1, BRCA1, BRCA2, CDKN1A, CDKN2A, CHEK1, CHEK2, FANCA, FANCD2, FANCG, FANCI, FANCL, KDR, MUTYH, PALB2, POLE, POLQ, RAD50, RAD51, RAD51D, RAD54L,andTP53. Mismatch-repair genes wereMLH1, MSH2, andMSH6. Clinical data were analyzed with cox proportional hazard models and survival analyses.ResultsFifty-five Korean breast cancer patients with knowngBRCA1/2mutations and qualified targeted NGS data were analyzed. Ethnically distinct mutations ingBRCA1/2genes were noted, with higher frequencies of Val1833Ser (14.8%), Glu1210Arg (11.1%), and Tyr130Ter (11.1%) ingBRCA1and Arg2494Ter (25.0%) and Lys467Ter (14.3%) ingBRCA2.Considering subtypes,gBRCA1mutations were associated with triple-negative breast cancers (TNBC), whilegBRCA2mutations were more likely hormone receptor-positive breast cancers. At least one missense mutation of HR-related genes was observed in 44 cases (80.0%). The most frequently co-mutated gene wasTP53(38.1%). In patients withgBRCA1/2mutations, however, genetic variations ofTP53occurred in locations different from the known hotspots of those with sporadic breast cancers. The patients with bothgBRCA1/2andTP53mutations were more likely to have TNBC, high Ki-67 values, and increased genetic mutations, especially of HR-related genes. Survival benefit was observed in theTP53mutants of patients withgBRCA2mutations, compared to those withTP53wild types.ConclusionOur study showed genetic heterogeneity of breast cancer patients withgBRCA1andgBRCA2mutations in the Korean populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.