Patterns of Mutation Enrichment in Metastatic Triple-Negative Breast Cancer

Abstract

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease with aggressive biology and complex tumor evolution. Our purpose was to identify enrichment patterns of genomic alterations in metastatic triple-negative breast cancer (mTNBC). Methods: Genomic data were retrieved (mutations and copy number variations) from 550 primary TNBC tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) data sets and 58 mTNBC tumors from “Mutational Profile of Metastatic Breast Cancers” and “The Metastatic Breast Cancer Project.” Statistical analysis of microarray data between primary and metastatic tumors was performed using a chi-square test, and the percentage of mutation enrichment in mTNBC cases was estimated. P-values were adjusted for multiple testing with Benjamini-Hochberg method with a false-discovery rate (FDR) <.05. In addition, we identified dominant hallmarks of cancer in mTNBC. Results: Seven genes with mutations were enriched in mTNBC after correcting for multiple testing. These included TTN, HMCN1, RELN, PKHD1L1, DMD, FRAS1, and RYR3. Only RPS6KB2 amplification was statistically significant in mTNBC; on the contrary, deletion of the genes TET1, RHOA, EPHA5, SET, KCNJ5, ABCG4, NKX3-1, SDHB, IGF2, and BRCA1 were the most frequent. The molecular alterations related to the hallmark of “genetic instability and mutation” were predominant in mTNBC. Interestingly, the hallmark of “activating immune destruction” was the least represented in mTNBC. Conclusion: Despite the study limitations, we identified recurrent patterns of genomic alterations with potential contribution to tumor evolution. Deletions were the aberrations more commonly found in mTNBC. Several molecular alterations are potentially targetable.