AUTHOR=Su Yifan , Yao Qianlan , Xu Yuyin , Yu Chengli , Zhang Jing , Wang Qian , Li Jiwei , Shi Di , Yu Baohua , Zeng Yupeng , Zhu Xiaoli , Bai Qianming , Zhou Xiaoyan 

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

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.674094

DOI=10.3389/fgene.2021.674094

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold><italic>Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients</italic> recommends that <italic>BRCA1/2</italic> 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 <italic>BRCA1/2</italic> has become more prevalent. However, the non-<italic>BRCA</italic> mutation status of Chinese high-risk breast cancer patients has not been fully explored.</p><p><bold>Methods:</bold> 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 <italic>BRCA</italic>-related cancer (breast or ovarian or prostate or pancreatic cancer).</p><p><bold>Results:</bold> 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 <italic>BRCA1/2</italic> mutation, and 28 (12.2%, 28/230) patients carried non-<italic>BRCA</italic> germline variants. Variants were detected in 16 non-<italic>BRCA</italic> genes, including <italic>PALB2</italic> (5, 2.2%), <italic>ATM</italic> (4, 1.7%), <italic>RAD51D</italic> (3, 1.3%), <italic>TP53</italic> (3, 1.3%), <italic>CHEK2</italic> (2, 0.9%), <italic>FANCA</italic> (2, 0.9%) and <italic>ATR</italic>, <italic>BARD1</italic>, <italic>BRIP1</italic>, <italic>ERCC3</italic>, <italic>HOXB13</italic>, <italic>MLH1</italic>, <italic>MRE11</italic>, <italic>PMS2</italic>, <italic>RAD51C</italic>, <italic>RAD54L</italic> (1, 0.4%). Besides, 22 (9.6%, 22/230) patients were non-<italic>BRCA</italic> HRR gene mutation (including <italic>ATM</italic>, <italic>ATR</italic>, <italic>BARD1</italic>, <italic>BRIP1</italic>, <italic>CHEK2</italic>, <italic>FANCA</italic>, <italic>MRE11</italic>, <italic>PALB2</italic>, <italic>RAD51C RAD51D</italic> and <italic>RAD54L</italic>) carriers. Among high-risk factors, family history showed a correlation with both <italic>BRCA</italic> (<italic>p</italic> = 0.005) and non-<italic>BRCA</italic> HRR gene mutation status (<italic>p</italic> = 0.036). In addition, TNBC showed a correlation with <italic>BRCA1</italic> gene mutation status (<italic>p</italic> = 0.038). However, other high-risk factors have not shown significantly related to <italic>BRCA1/2</italic>, non-<italic>BRCA</italic> genes and non-<italic>BRCA</italic> HRR gene mutations (<italic>p</italic> &gt; 0.05). In addition, 312 unique variants of uncertain significance (VUS) were identified among 175 (76.1%, 175/230) patients and 65 different genes.</p><p><bold>Conclusions:</bold> Non-<italic>BRCA</italic> gene mutations are frequently identified in breast cancer patients with high risk factors. Family history showed a correlation with both <italic>BRCA</italic> (<italic>p</italic> = 0.005) and non-<italic>BRCA</italic> HRR gene mutation status (<italic>p</italic> = 0.036), so we strongly suggest that breast cancer patients with a <italic>BRCA</italic>-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.</p>