DAGM: a novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations
Authors: Yang Mei , Fan Yanhui , Wu Zhi-Yong , Gu Jin , Feng Zhendong , Zhang Qiangzu , Han Shunhua , Zhang Zhonghai , Li Xu , Hsueh Yi-Ching , Li Xiaoling , Li Jieqing , Hu Meixia , Li Weiping , Gao Hongfei , Yang Ciqiu , Zhang Chunming , Zhang Liulu , Zhu Teng , Cheng Minyi , Ji Fei , Xu Juntao , Cui Hening , Tan Guangming , Zhang Michael Q. , Liang Changhong , Liu Zaiyi , Song You-Qiang , Niu Gang , Wang Kun 
Published: January 2021

AbstractBackgroundBreast cancers can be divided into HER2-negative and HER2-positive subtypes according to the 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 accurately assess its potential risk and to understand the potential mechanisms.MethodsWe 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).FindingsWe 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 the HER2 signalling pathway was up-regulated in the germline of HER2-negative patients, and those with high APSP risk scores had suppressed immunity. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk of developing HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations.InterpretationThe 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.FundingThis 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); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW)Research in contextEvidence before this studyThe majority of hereditary breast cancers are caused by BRCA1/2 mutations, and the presence of these mutations is strongly associated with an increased risk of breast cancer. Meanwhile, BRCA1/2 gene mutations are rarely found in sporadic breast cancers and only account for a modest percentage of all breast cancer patients. Polygenic risk score (PRS), a widely-used approach for stratifying individuals according to their risk of a certain kind of complex disease, has been used to predict subjects at high risk for breast cancer. However, relying on SNPs from genome-wide association studies (GWAS) without including gene expressions or pathway activities, PRS is not very suitable for cross-population prediction and describes disease risk in terms of genomic mutations without alluding to the underlying pathogenic mechanism(s). Therefore, there is still an urgent need for a population-independent comprehensive method to accurately assess the risk of breast cancer and to gain insights on potential mechanism(s).Added value of this studyWhen subjecting germline rare coding mutations (gRCMs) to DAGM framework, which results in the corresponding APSP and APSP risk score. Both APSP and APSP risk score can identify HER2-negative from HER2-positive breast cancers. These findings suggest HER2-negative breast cancer does not develop accidentally, but rather is defined by a genomic evolutionary strategy. Furthermore, this study also revealed the up-regulation of HER2 signalling pathway in germlines of HER2-negative breast cancers and the immune suppression in subjects with high APSP risk score, shedding new light on the potential mechanisms of developing HER2-negative breast cancer. Moreover, our APSP risk score was able to relatively accurately evaluate the risk of developing HER2-negative breast cancer for each female, including not only BRCA1/2 carriers, but also non-carriers.Implications of all the available evidenceThe present study suggests that HER2 signalling pathway activity, as an aggressive factor, contribute to the development of different types of breast cancers, either via the combined effects of multiple germline mutations in HER2-negative germlines or via amplifying the gene itself in HER2-positive tumour cells. This provides a theoretical basis for the prevention, diagnosis, and treatment of breast cancers. At the same time, the study provides preliminary methods for assessing the relative risk of HER2-negative breast cancer for females with or without BRCA1/2 mutations. Finally, our findings provide a new perspective and theoretical basis for identifying high-risk female subjects, based on the high APSP risk score, for early screening and prevention of HER2-negative breast cancer.