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Clinical and molecular relevance of mutant-allele tumor heterogeneity in breast cancer

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data.

Methods

We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment.

Results

The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P < 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P < 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P < 0.05), including Chr8q24 with only the MYC gene in the “peak” region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation.

Conclusion

Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation.

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Acknowledgements

We sincerely thank Edmund A. Mroz from Massachusetts General Hospital for the guidance on the generation of MATH value from TCGA publicly available data. This work was supported by grants from the Research Project of Fudan University Shanghai Cancer Center YJ201401 (Y. Z. Jiang), the National Natural Science Foundation of China 81572583 (Z. M. Shao), 81502278 (Y. Z. Jiang), and 81372848 (Z. M. Shao); the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals SHDC12010116 (Z. M. Shao); the Cooperation Project of Conquering Major Diseases in Shanghai Municipality Health System 2013ZYJB0302 (Z. M. Shao); the Innovation Team of Ministry of Education IRT1223 (Z. M. Shao); and the Shanghai Key Laboratory of Breast Cancer 12DZ2260100 (Z. M. Shao).The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

YZJ and ZMS designed the experiments. DM, YZJ, and XYL carried out most experiments and analyzed data. YRL provided technical support. DM and YZJ wrote and revised the manuscript.

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    Authors and Affiliations

    1. Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People’s Republic of China

      Ding Ma, Yi-Zhou Jiang, Xi-Yu Liu, Yi-Rong Liu & Zhi-Ming Shao

    2. Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People’s Republic of China

      Ding Ma, Yi-Zhou Jiang, Xi-Yu Liu, Yi-Rong Liu & Zhi-Ming Shao

    3. Institutes of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China

      Zhi-Ming Shao

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    Correspondence to Zhi-Ming Shao.

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    Since the TCGA database is publicly available, ethics committee approval was not needed. Neither patient informed consent nor permission to use this data was required to perform the current analysis.

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    Ding Ma, Yi-Zhou Jiang and Xi-Yu Liu have contributed equally to this work.

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    Ma, D., Jiang, YZ., Liu, XY. et al. Clinical and molecular relevance of mutant-allele tumor heterogeneity in breast cancer. Breast Cancer Res Treat 162, 39–48 (2017). https://doi.org/10.1007/s10549-017-4113-z

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