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

Sergi Guerrero Llobet, Arkajyoti Bhattacharya, Marieke Everts, Klaas Kok, Bert van der Vegt, Rudolf S N Fehrmann, Marcel A T M van Vugt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 = 1.82 x 10(-20)) and gamma H2AX (R = 0.304, p = 2.95 x 10(-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.

Original languageEnglish
Pages (from-to)1216-1224
Number of pages9
JournalONCOGENE
Volume41
Issue number8
Early online date29-Jan-2022
DOIs
Publication statusPublished - 18-Feb-2022

Keywords

  • DNA-DAMAGE RESPONSE
  • OVARIAN-CANCER
  • GENOMIC INSTABILITY
  • INDUCED SENESCENCE
  • NAT10
  • CELLS
  • ACETYLATION
  • ACTIVATION
  • RESISTANT
  • BARRIER

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