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

doi:10.1016/j.ebiom.2021.103446

	DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations
	Yang, Mei 2; Fan, Yanhui 3,4; Wu, Zhi-Yong 5; Gu, Jin 14; Feng, Zhendong 3; Zhang, Qiangzu 3; Han, Shunhua 3,7; Zhang, Zhonghai 8; Li, Xu 8; Hsueh, Yi-Ching 3
刊名	EBIOMEDICINE
	2021-07-01
卷号	69 页码:11
关键词	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 Immune suppression
ISSN号	2352-3964
DOI	10.1016/j.ebiom.2021.103446
英文摘要	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 codingmutations 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. (C) 2021 The Authors. Published by Elsevier B.V.
资助项目	National Key Research and Development Program of China[2018YFC0910406] ; National Key Research and Development Program of China[2018AAA0103302] ; National Natural Science Foundation of China[81202076] ; National Natural Science Foundation of China[82072939] ; National Natural Science Foundation of China[81871513] ; Guangzhou Science and Technology Program key projects[2014J2200007] ; Guangzhou Science and Technology Program key projects[202002030236] ; National Key R&D Program of China[2017YFC1309100] ; Shenzhen Science and Technology Planning Project[JCYJ20170817095211560] ; Natural Science Foundation of Guangdong Province[2017A030313882] ; Natural Science Foundation of Guangdong Province[S2013010012048] ; Natural Science Foundation of Guangdong Province[KF2020009] ; RGC General Research Fund[17114519]
WOS研究方向	General & Internal Medicine ; Research & Experimental Medicine
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000684979000017
内容类型	期刊论文
源URL	[http://119.78.100.204/handle/2XEOYT63/17261]
专题	中国科学院计算技术研究所
通讯作者	Niu, Gang; Wang, Kun
作者单位	1.Shenzhen Univ, Inst Microscale Optoelect, Shenzhen, Peoples R China 2.Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Canc Ctr, Dept Breast Canc, Guangzhou, Guangdong, Peoples R China 3.Phil Rivers Technol, Beijing 100095, Peoples R China 4.Phil Rivers Technol, Shenzhen, Peoples R China 5.Shantou Cent Hosp, Diag & Treatment Ctr Breast Dis, Shantou, Guangdong, Peoples R China 6.Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China 7.Univ Georgia, Inst Bioinformat, Athens, GA 30602 USA 8.Chinese Acad Sci, Inst Comp Technol, State Key Lab Comp Architecture, Beijing, Peoples R China 9.Tsinghua Univ, MOE Key Lab Bioinformat, TNLIST, Beijing, Peoples R China 10.Tsinghua Univ, Bioinformat Div, TNLIST, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Yang, Mei,Fan, Yanhui,Wu, Zhi-Yong,et al. DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations[J]. EBIOMEDICINE,2021,69:11.
APA	Yang, Mei.,Fan, Yanhui.,Wu, Zhi-Yong.,Gu, Jin.,Feng, Zhendong.,...&Wang, Kun.(2021).DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations.EBIOMEDICINE,69,11.
MLA	Yang, Mei,et al."DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations".EBIOMEDICINE 69(2021):11.