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

• Published in: Breast cancer research and treatment Vol. 162; no. 1; pp. 39 - 48
• Main Authors: Ma, Ding, Jiang, Yi-Zhou, Liu, Xi-Yu, Liu, Yi-Rong, Shao, Zhi-Ming
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2017; Springer; Springer Nature B.V
• Subjects: Adult; African Americans; Aged; Aged, 80 and over; Algorithms; Alleles; Biomarkers, Tumor; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer genetics; Cancer research; Cancer therapies; Computational Biology - methods; Databases, Genetic; Development and progression; DNA Copy Number Variations; Female; Genes; Genetic aspects; Genetic Association Studies; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetics; Genomes; Genomics; Health aspects; Humans; Medical research; Medicine; Medicine & Public Health; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Oncology; Preclinical Study; Prognosis; Tumor proteins; Whole Exome Sequencing; Women's health; Young Adult; Intra-tumor genetic heterogeneity; Breast cancer; Mutant-allele tumor heterogeneity; MYC; The Cancer Genome Atlas
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4113-z

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.