Integrative analysis of copy number and gene expression data identifies potential oncogenic drivers that promote mammary tumor recurrence.
Genes Chromosomes Cancer, 2019/06;58(6):381-391.
Jones RA[1], Moorehead RA[1]
Affiliations
PMID: 30597648DOI: 10.1002/gcc.22729
Impact factor: 4.263
Abstract
Tumor recurrence represents a significant clinical challenge in the treatment and management of breast cancer. To investigate whether copy number aberrations (CNAs) facilitate the re-emergence of tumor growth from residual disease, we performed array comparative genomic hybridization on primary and recurrent mammary tumors from an inducible mouse model of type-I insulin-like growth factor receptor driven breast cancer. This genome-wide analysis revealed primary and recurrent tumors harbored distinct CNAs with relapsed tumors containing an increased number of gene-level gains and losses. Remarkably, high-level CNAs detected in primary tumors were largely devoid of annotated cancer genes while the vast majority of recurrent tumors harbored at least one CNA containing a known oncogene or tumor suppressor. Specifically, 38% of recurrent tumors carried gains at 6qA2 and 9qA2 which encode the Met and Yap1 oncogenes, respectively. The most frequent CNA, occurring in 63% of recurrent tumors, was a focal deletion at 4qC5 involving the Cdkn2a/b tumor suppressor genes. Integrative analysis revealed positive correlations between gene copy number and mRNA expression suggesting Met, Yap1, and Cdkn2a/b may serve as potential drivers that promote tumor recurrence. Accordingly, cross-species analysis revealed gene-level murine CNAs were present in a subset of human breast cancers with high MET and YAP1 mRNA predictive of decreased relapse-free survival in basal-like breast cancers. Together, these findings indicate that tumor recurrence is facilitated by the acquisition of CNAs with oncogenic potential and provide a framework to dissect the molecular mechanisms that mediate tumor escape from dormancy.
Keywords: copy number aberration; epithelial-mesenchymal transition; gene expression; mouse model; tumor recurrence
MeSH terms
Adaptor Proteins, Signal Transducing; Animals; Carcinogenesis; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p16; DNA Copy Number Variations; Female; Gene Expression Regulation, Neoplastic; Mammary Neoplasms, Experimental; Mice; Neoplasm Recurrence, Local; Oncogene Proteins; Phosphoproteins; YAP-Signaling Proteins
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