Association of Gene Variant Type and Location with Breast Cancer Risk in the General Population.

IF 56.7 1区医学 Q1 ONCOLOGY

Annals of Oncology Pub Date : 2025-04-25 DOI:10.1016/j.annonc.2025.04.010

M P Akamandisa, N J Boddicker, S Yadav, C Hu, S N Hart, C Ambrosone, H Anton-Culver, P L Auer, C Bodelon, E S Burnside, F Chen, A H Eliassen, D E Goldgar, C Haiman, J M Hodge, H Huang, E M John, R Karam, J V Lacey, S Lindstroem, E Martinez, J Na, S L Neuhausen, K M O'Brien, J E Olson, T Pal, J R Palmer, A V Patel, T Pesaran, E C Polley, M E Richardson, K Ruddy, D P Sandler, L R Teras, A Trentham-Dietz, C M Vachon, C Weinberg, S J Winham, S Yao, G Zirpoli, P Kraft, J N Weitzel, S M Domchek, F J Couch, K L Nathanson

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引用次数: 0

Abstract

Background: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk. However, it is unknown whether this risk differs by PV type or location in carriers ascertained from the general population.

Patients and methods: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2, and PALB2, we performed age adjusted case-control association analysis in 32,247 women with and 32,544 age-matched women without breast cancer from the CARRIERS Consortium. PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and P-values) using logistic regression.

Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex1-10 PTVs (OR=13.5, 95%CI 6.0-38.7, P<0.001) and ex13-27 PTVs (OR=9.0, 95%CI 4.9-18.5, P<0.001) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9, P=0.035; ex1-10 OR=0.5, 95%CI 0.1-1.0, P=0.065), and earlier age at breast cancer diagnosis (ex13-27 5.5 years, P<0.001; ex1-10 2.4 years, P=0.169). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort from Ambry Genetics and the population-based UK Biobank cohort. No differences in risk by gene region were observed for PTVs in other predisposition genes.

Conclusion: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced breast cancer risk, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs.

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普通人群中基因变异类型和位置与乳腺癌风险的关系

背景：ATM、BRCA1、BRCA2、CHEK2和PALB2的致病变异（pv）与乳腺癌风险增加有关。然而，目前尚不清楚这种风险是否因从一般人群中确定的携带者的PV类型或位置而不同。患者和方法：为了评估与ATM、BRCA1、BRCA2、CHEK2和PALB2中PV类型和位置相关的乳腺癌风险，我们对来自携带者协会的32247名患有乳腺癌的女性和32544名年龄匹配的无乳腺癌的女性进行了年龄调整的病例对照关联分析。将pv按基因类型和位置分组，并使用逻辑回归评估乳腺癌风险（优势比（OR）、95%置信区间（CI）和p值）。结果：在基于携带者人群的研究中，与携带BRCA2外显子11蛋白截断变异体（PTVs）的女性相比，携带BRCA2外显子1-10 PTVs的女性（OR=13.5, 95%CI 6.0-38.7, p）结论：基于人群和临床高风险队列建立了BRCA2外显子11 PTVs与乳腺癌风险降低、诊断年龄推迟和er阴性疾病风险增加相关。这些差异风险可能改善携带BRCA2 PTVs的女性的个体化风险预测和临床管理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Oncology 医学-肿瘤学

CiteScore

63.90

自引率

1.00%

发文量

3712

审稿时长

2-3 weeks

期刊介绍： Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.