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Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer

  • Preclinical study
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Abstract

Purpose

Genomic studies have revealed that genomic aberrations play important roles in the progression of this disease. The aim of this study was to evaluate the associations between clinical survival outcomes of the clonality and subclonality status of driver genes in breast cancer.

Methods

We performed an integrated analysis to infer the clonal status of 55 driver genes in breast cancer data from TCGA. We used the chi-squared test to assess the relations between clonality of driver gene mutations and clinicopathological factors. The Kaplan–Meier method was performed for the visualization and the differences between survival curves were calculated by log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors.

Results

We identified a high proportion of clonal mutations in these driver genes. Among them, there were 17 genes showing significant associations between their clonality and multiple clinicopathologic factors. Performing survival analysis on BRCA patients with clonal or subclonal driver gene mutations, we found that clonal ERBB2, FOXA1, and KMT2C mutations and subclonal GATA3 and RB1 mutations predicted shorter overall survival compared with those with wild type. Furthermore, clonal ERBB2 and FOXA1 mutations and subclonal GATA3 and RB1 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. By longitudinal analysis, the clonality of ERBB2, FOXA1, GATA3, and RB1 significantly predicted patients’ outcome within some specific BRCA tumor stages and histological subtypes.

Conclusions

In summary, these clonal or subclonal mutations of driver genes have implications for diagnosis, prognosis, and treatment with BRCA patients.

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Funding

This study was funded in part by the National Program on Key Basic Research Project [973 Program, Grant No. 2014CB910504], the National Natural Science Foundation of China [Grant Nos. 61473106, 61573122], the China Postdoctoral Science Foundation (2016M600260), Wu lien-teh youth science fund project of Harbin medical university [Grant No. WLD-QN1407], Special funds for the construction of higher education in Heilongjiang Province [Grant No. UNPYSCT-2016049], the Heilongjiang Postdoctoral Foundation (LBH-Z16098).

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Author notes

  1. Yujia Lan and Erjie Zhao are Contributed equally to this work.

Authors and Affiliations

  1. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, Heilongjiang, China

    Yujia Lan, Erjie Zhao, Shangyi Luo, Yun Xiao, Xia Li & Shujun Cheng

  2. State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, China

    Shujun Cheng

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  1. Yujia Lan
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Contributions

SJC, XL, and YX conceived and designed the project. YJL, EJZ, and SYL acquired the data. YJL and EJZ performed the statistical analysis and analyzed and interpreted all the data. YJL, EJZ, and SYL prepared the figures and tables. YX and YJL wrote the paper. EJZ and SYL reviewed and revised the manuscript. All authors approved the final manuscript.

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Correspondence to Yun Xiao, Xia Li or Shujun Cheng.

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Lan, Y., Zhao, E., Luo, S. et al. Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer. Breast Cancer Res Treat 175, 91–104 (2019). https://doi.org/10.1007/s10549-019-05153-8

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