Integrative analysis of copy number and gene expression data identifies potential oncogenic drivers that promote mammary tumor recurrence

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 (aCGH) on primary and recurrent mammary tumors from an inducible mouse model of type‐I insulin‐like growth factor receptor (IGF‐IR) driven breast cancer. This genome‐wide analysis revealed primary and recurrent tumors harbored distinct copy number aberrations (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.

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