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

Abstract

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 in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of Korean breast cancer patients with gBRCA1/2 mutations to investigate the alterations in HR-related genes 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 HR-related genes was 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 wild types. Conclusion Our study showed genetic heterogeneity of breast cancer patients with gBRCA1 and gBRCA2 mutations in the Korean populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.

Distinct genomic and immunologic tumor evolution in germlineTP53-driven breast cancers

“…Therefore, it is possible that p53 dysfunction leads to a different program of genome instability in estrogen responsive tissues compared to other tissues. Other groups have shown that homologous recombination deficiency (HRD) occurs in TP53 mutated samples irrespective of HR gene alterations 49 ; however, we did not observe higher HRD in LFS-BC compared to nonLFS-BC and DNA damage response pathway were not dysregulated. This again shows that tumorigenesis follows distinct, likely tissue-specific, pathways when p53 dysfunction is the initiating event versus a later event in tumor evolution.…”

DNA Damage Responses in Tumors Are Not Proliferative Stimuli, but Rather They Are DNA Repair Actions Requiring Supportive Medical Care

“…Patients with both BRCA1/2 and TP53 gene mutations were more likely to have hormone receptor negative cancers, high Ki-67 values, and increased genetic mutations, especially of hormone receptor-related genes. Survival benefits were observed in the BRCA2 mutation carrier patients with TP53 co-mutation, compared to those with TP53 wild types [63]. This valuable observation supports the increased genome stabilizer impact of mutated TP53, providing compensatory genome stabilization in tumors with BRCA2 gene mutation.…”

Pan-cancer analysis of the interplay between mutational signatures and cellular signaling

“…Notably, this result agrees with a recent study reporting that TP53 mutation in the background of germline BRCA2 mutation has a beneficial effect on survival. 57 …”