Genome Institute of Singapore, Human Genetics, Singapore, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
Genome Med. 2021 Dec 2;13(1):185. doi: 10.1186/s13073-021-00978-9.
Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent.
Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease.
PTV carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV carriership, but not PTV carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]).
PTV carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.
已知某些基因的突变会增加乳腺癌风险。我们研究了在 8852 名亚洲裔乳腺癌患者中，可能导致乳腺癌易感性基因功能丧失的罕见蛋白截断变异（PTV）与肿瘤特征和生存的相关性。
对 34 个已知或疑似乳腺癌易感性基因进行基因panel 测序，其中 9 个基因（ATM、BRCA1、BRCA2、CHEK2、PALB2、BARD1、RAD51C、RAD51D 和 TP53）与乳腺癌风险相关。使用多项逻辑回归检查一个或多个基因中 PTV 携带者与肿瘤特征之间的关系。在排除年龄较大（≥75 岁）和 0 期和 IV 期疾病的 6477 名乳腺癌患者中，使用 Cox 回归模型估计 10 年总生存率。
PTV 携带者（n=690）与更具侵袭性的肿瘤特征显著相关（p<0.001），包括高分级（差 vs 高分化，比值比[95%置信区间]3.48[2.35-5.17]，中 vs 高分化 2.33[1.56-3.49]），以及管腔 B[HER-]和三阴性亚型（与管腔 A 相比分别为 2.15[1.58-2.92]和 2.85[2.17-3.73]），调整诊断时年龄、研究和种族。在排除 BRCA1/2 携带者后，与分级和管腔 B[HER2-]亚型的关联仍然显著。PTV 携带者（n=289，不包括与乳腺癌相关的九个基因的携带者）与肿瘤特征无关。然而，PTV 携带者与较差的 10 年总生存率相关（风险比[CI]1.63[1.16-2.28]），但 PTV 携带者与较差的 10 年总生存率相关。
PTV 携带者与更具侵袭性的肿瘤相关。其他基因的变异可能与乳腺癌患者的生存相关。PTV 携带者不仅与更高的乳腺癌风险相关，而且与更严重和致命的疾病形式相关的发现表明，基因检测有可能提供额外的健康信息，并帮助健康个体做出筛查决策。
