State Key Laboratory of Oncogenes and Related Genes, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Hematol Oncol. 2021 Jan 18;14(1):18. doi: 10.1186/s13045-020-01010-0.
Accurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2-5 and 15-23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.
准确解读 BRCA1/2 变异对于乳腺癌（BC）的风险评估和精准治疗至关重要。因此，建立基于种族的中国人群 BRCA1/2 变异数据库至关重要。本研究采用基于panel 的测序方法，对中国多中心 21216 例 BC 患者和 6434 例健康对照者的 BRCA1/2 变异进行检测。总体而言，BC 患者携带致病性变异的比例为 5.5%（1174/21216），健康对照者为 1.1%（71/6434）。我们发现 13 种致病性变异为高频变异，在 BC 患者中的频率>0.45‰（≥21216 例患者中的 10 例），这些变异在高加索人群中均未见报道。BRCA1/2 致病性变异与发病年龄较轻、双侧和三阴性乳腺癌（TNBC）、浸润性癌、高组织学分级以及乳腺癌和其他癌症家族史相关。此外，BC 患者携带意义未明的变异（VUS）的比例为 9.8%（2071/21216），健康对照者为 6.9%（446/6434）。基于本队列研究，我们明确重新分类了 858 个 VUS 中的 7 个，使患者（从 9.8%降至 7.9%）和健康对照者（从 6.9%降至 5.3%）中的 VUS 比例降低。我们还使用功能检测（饱和基因组编辑；SGE）对 BRCA1 基因的 13 个外显子（2-5 和 15-23）中的 100 个变异进行了重新分析。SGE 研究中 59 个 VUS 中有 55 个具有明确状态：24 个（43.6%）为致病性，31 个（56.4%）为良性。在中国人群中发现了强烈的种族特异性致病性 BRCA1/2 变异。因此，这些发现为在中国人群中实施针对 BRCA1/2 变异的临床风险评估提供了依据和测序信息。
