Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions

Background:Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients recommends that BRCA1/2 testing should be performed in those with clinical risk factors, such as an early onset, triple-negative breast cancer (TNBC) or family history of cancer. With th...

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Autores principales:	Yifan Su, Qianlan Yao, Yuyin Xu, Chengli Yu, Jing Zhang, Qian Wang, Jiwei Li, Di Shi, Baohua Yu, Yupeng Zeng, Xiaoli Zhu, Qianming Bai, Xiaoyan Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	breast cancer high risk non-BRCA genes germline mutation Chinese Genetics QH426-470
Acceso en línea:	https://doaj.org/article/eab916b4e8a84a7e8b8efaa8d1c1a3b6
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spelling	oai:doaj.org-article:eab916b4e8a84a7e8b8efaa8d1c1a3b62021-12-01T19:44:34ZCharacteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions1664-802110.3389/fgene.2021.674094https://doaj.org/article/eab916b4e8a84a7e8b8efaa8d1c1a3b62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.674094/fullhttps://doaj.org/toc/1664-8021Background:Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients recommends that BRCA1/2 testing should be performed in those with clinical risk factors, such as an early onset, triple-negative breast cancer (TNBC) or family history of cancer. With the increasing application of multigene panels, testing for genes beyond BRCA1/2 has become more prevalent. However, the non-BRCA mutation status of Chinese high-risk breast cancer patients has not been fully explored.Methods: A total of 230 high-risk breast cancer patients from Fudan University Shanghai Cancer Center who had undergone peripheral blood germline 72 genes next-generation sequencing (NGS) from June 2018 to June 2020 were enrolled for retrospective analysis. The 72 genes include common hereditary breast cancer genes, such as homologous recombination repair (HRR) genes and other DNA damage repair genes. High-risk factors included: 1) TNBC; 2) male breast cancer; 3) primary bilateral breast cancer; 4) diagnosed with breast cancer at age less than or equal to 40 years; or 5) at least one first- and/or second-degree relative with BRCA-related cancer (breast or ovarian or prostate or pancreatic cancer).Results: The germline pathogenic or likely pathogenic mutation rate was 29.6% (68/230) in high-risk breast cancer patients. Among them, 44 (19.1%, 44/230) were identified as harboring BRCA1/2 mutation, and 28 (12.2%, 28/230) patients carried non-BRCA germline variants. Variants were detected in 16 non-BRCA genes, including PALB2 (5, 2.2%), ATM (4, 1.7%), RAD51D (3, 1.3%), TP53 (3, 1.3%), CHEK2 (2, 0.9%), FANCA (2, 0.9%) and ATR, BARD1, BRIP1, ERCC3, HOXB13, MLH1, MRE11, PMS2, RAD51C, RAD54L (1, 0.4%). Besides, 22 (9.6%, 22/230) patients were non-BRCA HRR gene mutation (including ATM, ATR, BARD1, BRIP1, CHEK2, FANCA, MRE11, PALB2, RAD51C RAD51D and RAD54L) carriers. Among high-risk factors, family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036). In addition, TNBC showed a correlation with BRCA1 gene mutation status (p = 0.038). However, other high-risk factors have not shown significantly related to BRCA1/2, non-BRCA genes and non-BRCA HRR gene mutations (p > 0.05). In addition, 312 unique variants of uncertain significance (VUS) were identified among 175 (76.1%, 175/230) patients and 65 different genes.Conclusions: Non-BRCA gene mutations are frequently identified in breast cancer patients with high risk factors. Family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036), so we strongly suggest that breast cancer patients with a BRCA-related family history receive comprehensive gene mutation testing in China, especially HRR genes, which are not only related to high risk of breast cancer, but also potentially related to poly ADP ribose polymerase inhibitor (PARPi) targeted therapy. The exact relationship of rare gene mutations to breast cancer predisposition and the pathogenicity of VUS need to be further investigated.Yifan SuYifan SuYifan SuQianlan YaoQianlan YaoQianlan YaoYuyin XuYuyin XuYuyin XuChengli YuChengli YuChengli YuJing ZhangJing ZhangJing ZhangQian WangQian WangQian WangJiwei LiJiwei LiJiwei LiDi ShiDi ShiDi ShiBaohua YuBaohua YuBaohua YuYupeng ZengYupeng ZengYupeng ZengXiaoli ZhuXiaoli ZhuXiaoli ZhuQianming BaiQianming BaiQianming BaiXiaoyan ZhouXiaoyan ZhouXiaoyan ZhouFrontiers Media S.A.articlebreast cancerhigh risknon-BRCA genesgermline mutationChineseGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer high risk non-BRCA genes germline mutation Chinese Genetics QH426-470
spellingShingle	breast cancer high risk non-BRCA genes germline mutation Chinese Genetics QH426-470 Yifan Su Yifan Su Yifan Su Qianlan Yao Qianlan Yao Qianlan Yao Yuyin Xu Yuyin Xu Yuyin Xu Chengli Yu Chengli Yu Chengli Yu Jing Zhang Jing Zhang Jing Zhang Qian Wang Qian Wang Qian Wang Jiwei Li Jiwei Li Jiwei Li Di Shi Di Shi Di Shi Baohua Yu Baohua Yu Baohua Yu Yupeng Zeng Yupeng Zeng Yupeng Zeng Xiaoli Zhu Xiaoli Zhu Xiaoli Zhu Qianming Bai Qianming Bai Qianming Bai Xiaoyan Zhou Xiaoyan Zhou Xiaoyan Zhou Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions
description	Background:Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients recommends that BRCA1/2 testing should be performed in those with clinical risk factors, such as an early onset, triple-negative breast cancer (TNBC) or family history of cancer. With the increasing application of multigene panels, testing for genes beyond BRCA1/2 has become more prevalent. However, the non-BRCA mutation status of Chinese high-risk breast cancer patients has not been fully explored.Methods: A total of 230 high-risk breast cancer patients from Fudan University Shanghai Cancer Center who had undergone peripheral blood germline 72 genes next-generation sequencing (NGS) from June 2018 to June 2020 were enrolled for retrospective analysis. The 72 genes include common hereditary breast cancer genes, such as homologous recombination repair (HRR) genes and other DNA damage repair genes. High-risk factors included: 1) TNBC; 2) male breast cancer; 3) primary bilateral breast cancer; 4) diagnosed with breast cancer at age less than or equal to 40 years; or 5) at least one first- and/or second-degree relative with BRCA-related cancer (breast or ovarian or prostate or pancreatic cancer).Results: The germline pathogenic or likely pathogenic mutation rate was 29.6% (68/230) in high-risk breast cancer patients. Among them, 44 (19.1%, 44/230) were identified as harboring BRCA1/2 mutation, and 28 (12.2%, 28/230) patients carried non-BRCA germline variants. Variants were detected in 16 non-BRCA genes, including PALB2 (5, 2.2%), ATM (4, 1.7%), RAD51D (3, 1.3%), TP53 (3, 1.3%), CHEK2 (2, 0.9%), FANCA (2, 0.9%) and ATR, BARD1, BRIP1, ERCC3, HOXB13, MLH1, MRE11, PMS2, RAD51C, RAD54L (1, 0.4%). Besides, 22 (9.6%, 22/230) patients were non-BRCA HRR gene mutation (including ATM, ATR, BARD1, BRIP1, CHEK2, FANCA, MRE11, PALB2, RAD51C RAD51D and RAD54L) carriers. Among high-risk factors, family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036). In addition, TNBC showed a correlation with BRCA1 gene mutation status (p = 0.038). However, other high-risk factors have not shown significantly related to BRCA1/2, non-BRCA genes and non-BRCA HRR gene mutations (p > 0.05). In addition, 312 unique variants of uncertain significance (VUS) were identified among 175 (76.1%, 175/230) patients and 65 different genes.Conclusions: Non-BRCA gene mutations are frequently identified in breast cancer patients with high risk factors. Family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036), so we strongly suggest that breast cancer patients with a BRCA-related family history receive comprehensive gene mutation testing in China, especially HRR genes, which are not only related to high risk of breast cancer, but also potentially related to poly ADP ribose polymerase inhibitor (PARPi) targeted therapy. The exact relationship of rare gene mutations to breast cancer predisposition and the pathogenicity of VUS need to be further investigated.
format	article
author	Yifan Su Yifan Su Yifan Su Qianlan Yao Qianlan Yao Qianlan Yao Yuyin Xu Yuyin Xu Yuyin Xu Chengli Yu Chengli Yu Chengli Yu Jing Zhang Jing Zhang Jing Zhang Qian Wang Qian Wang Qian Wang Jiwei Li Jiwei Li Jiwei Li Di Shi Di Shi Di Shi Baohua Yu Baohua Yu Baohua Yu Yupeng Zeng Yupeng Zeng Yupeng Zeng Xiaoli Zhu Xiaoli Zhu Xiaoli Zhu Qianming Bai Qianming Bai Qianming Bai Xiaoyan Zhou Xiaoyan Zhou Xiaoyan Zhou
author_facet	Yifan Su Yifan Su Yifan Su Qianlan Yao Qianlan Yao Qianlan Yao Yuyin Xu Yuyin Xu Yuyin Xu Chengli Yu Chengli Yu Chengli Yu Jing Zhang Jing Zhang Jing Zhang Qian Wang Qian Wang Qian Wang Jiwei Li Jiwei Li Jiwei Li Di Shi Di Shi Di Shi Baohua Yu Baohua Yu Baohua Yu Yupeng Zeng Yupeng Zeng Yupeng Zeng Xiaoli Zhu Xiaoli Zhu Xiaoli Zhu Qianming Bai Qianming Bai Qianming Bai Xiaoyan Zhou Xiaoyan Zhou Xiaoyan Zhou
author_sort	Yifan Su
title	Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions
title_short	Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions
title_full	Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions
title_fullStr	Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions
title_full_unstemmed	Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions
title_sort	characteristics of germline non-brca mutation status of high-risk breast cancer patients in china and correlation with high-risk factors and multigene testing suggestions
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/eab916b4e8a84a7e8b8efaa8d1c1a3b6
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Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions

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