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DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations

التفاصيل البيبلوغرافية
العنوان: DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations
المؤلفون: Mei Yang, Yanhui Fan, Zhi-Yong Wu, Jin Gu, Zhendong Feng, Qiangzu Zhang, Shunhua Han, Zhonghai Zhang, Xu Li, Yi-Ching Hsueh, Yanxiang Ni, Xiaoling Li, Jieqing Li, Meixia Hu, Weiping Li, Hongfei Gao, Ciqiu Yang, Chunming Zhang, Liulu Zhang, Teng Zhu, Minyi Cheng, Fei Ji, Juntao Xu, Hening Cui, Guangming Tan, Michael Q. Zhang, Changhong Liang, Zaiyi Liu, You-Qiang Song, Gang Niu, Kun Wang
المصدر: EBioMedicine, Vol 69, Iss , Pp 103446- (2021)
بيانات النشر: Elsevier, 2021.
سنة النشر: 2021
المجموعة: LCC:Medicine
LCC:Medicine (General)
مصطلحات موضوعية: HER2-negative breast cancer, Germline rare coding mutations, Damage assessment of genomic mutations (DAGM), Risk assessment, Activity profiles of signalling pathways (APSP), HER2 signalling pathway, Medicine, Medicine (General), R5-920
الوصف: Background: Breast cancers can be divided into HER2-negative and HER2-positive subtypes according to different status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to obtain accurate risk assessment and to understand the potential underlying mechanisms. Methods: We developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs). Findings: We characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed that HER2 signalling pathway was up-regulated in germline of HER2-negative patients, and those with high APSP risk scores had exhibited immune suppression. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk for HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations. Interpretation: The DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer. Funding: This work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); Shenzhen Science and Technology Planning Project (grant no. JCYJ20170817095211560 574 to YN); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW and S2013010012048 to MY); Hefei National Laboratory for Physical Sciences at the Microscale (grant no. KF2020009 to GN); and RGC General Research Fund (grant no. 17114519 to YQS).
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2352-3964
Relation: http://www.sciencedirect.com/science/article/pii/S2352396421002395; https://doaj.org/toc/2352-3964
DOI: 10.1016/j.ebiom.2021.103446
URL الوصول: https://doaj.org/article/e0a93f66f07e4e4c8bc8d205d5087231
رقم الأكسشن: edsdoj.0a93f66f07e4e4c8bc8d205d5087231
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:23523964
DOI:10.1016/j.ebiom.2021.103446