An mRNA expression-based signature for oncogene-induced replication-stress.

Abstract

Oncogene-induced replication stress characterizes many aggressive cancers. Several treatments are being developed that target replication stress, however, identification of tumors with high levels of replication stress remains challenging.We describe a gene expression signature of oncogene-induced replication stress. A panel of triple-negative breast cancer (TNBC) and non-transformed cell lines were engineered to overexpress CDC25A, CCNE1 or MYC, which resulted in slower replication kinetics. RNA sequencing analysis revealed a set of 52 commonly upregulated genes. In parallel, mRNA expression analysis of patient-derived tumor samples (TCGA, n=10,592) also revealed differential gene expression in tumors with amplification of oncogenes that trigger replication stress (CDC25A, CCNE1, MYC, CCND1, MYB, MOS, KRAS, ERBB2, and E2F1). Upon integration, we identified a six-gene signature of oncogene-induced replication stress (NAT10, DDX27, ZNF48, C8ORF33, MOCS3, and MPP6). Immunohistochemical analysis of NAT10 in breast cancer samples (n=330) showed strong correlation with expression of phospho-RPA (R=0.451, p=1.82x10-20) and γH2AX (R=0.304, p=2.95x10-9). Finally, we applied our oncogene-induced replication stress signature to patient samples from TCGA (n=8,862) and GEO (n=13,912) to define the levels of replication stress across 27 tumor subtypes, identifying diffuse large B cell lymphoma, ovarian cancer, TNBC and colorectal carcinoma as cancer subtypes with high levels of oncogene-induced replication stress.