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

Human Genomics

Research

Myung Geun Song¹  Tae-Yong Kim²  Go-un Woo²  Dae-Won Lee²  Jinyong Kim²  Hanbaek Yi²  Seock-Ah Im³  Kyung-Hun Lee³  Jeong Mo Bae⁴  Songyi Park⁵  Kyeonghun Jeong⁶  Hyeji Jun⁷  Kwangsoo Kim⁷ 

[1] Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, 03080, Seoul, Republic of Korea;Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, 03080, Seoul, Republic of Korea;Cancer Research Institute, Seoul National University, Seoul, Republic of Korea;Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea;Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Republic of Korea;Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea;Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea;

关键词: BRCA;    P53;    Breast cancer;    NGS;    Signature 3;   

DOI  :  10.1186/s40246-022-00447-3

 received in 2022-09-25, accepted in 2022-12-19,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundGermline 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 methodsData 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.ResultsFifty-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.ConclusionOur 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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