Abstract
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.
Highlights
Breast cancer is considered the most common cancer among females worldwide
A total of 5.7% patients were diagnosed with primary bilateral breast cancer
In terms of each risk factor, our results suggest that the frequencies of BRCA mutations in early-onset breast cancer, familial breast cancer, triple-negative breast cancer (TNBC) and bilateral breast cancer (19.4–38.5%) are higher than those observed in other Chinese population studies (2.3–12.5%) (Gavande et al, 2016; Li et al, 2019; Sherill-Rofe et al, 2019; Abida et al, 2020; Hirsch et al, 2020; Foo et al, 2021) and the frequencies of non-BRCA mutations are at a high level (7.7–17.5%)
Summary
Breast cancer is considered the most common cancer among females worldwide. According to the epidemiologic analysis report of International Agency for Research on Cancer (IARC), breast cancer had the highest incidence among Chinese female malignant tumors in 2020, with 416,000 patients, accounting for 19.9% of all malignant tumors in women (World Health Organization, 2021). The Breast Cancer Precision Treatment Committee of the Chinese Medical Doctor Association has issued expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients referring to the international guidelines issued by the National Comprehensive Cancer Network (NCCN) and proposed characteristics of breast cancer patients who should be recommended for BRCA1/2 testing based on clinical risk factors such as age of onset, hormone receptor status and personal or family history of cancer (Wang et al, 2018). 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. The non-BRCA mutation status of Chinese high-risk breast cancer patients has not been fully explored
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