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Breast Cancer Research and Treatment

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01-02-2017 | Preclinical study

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

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

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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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Title: Clinical and molecular relevance of mutant-allele tumor heterogeneity in breast cancer
Authors: Ding Ma
Yi-Zhou Jiang
Xi-Yu Liu
Yi-Rong Liu
Zhi-Ming Shao
Publication date: 01-02-2017
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4113-z

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