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

Oncogene volume 41, pages 1216–1224 (2022)Cite this article

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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 × 10−20) and γH2AX (R = 0.304, p = 2.95 × 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.

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Fig. 1: Overexpression of CDC25A, CCNE1 or MYC leads to replication stress.
Fig. 2: Overexpression of CDC25A, CCNE1, or MYC leads to upregulation of 52 genes.
Fig. 3: Common differential gene expression of 6 genes upon oncogene overexpression between in vitro models and patient samples.
Fig. 4: Immunohistochemical analysis of NAT10 in breast cancer patients and the landscape of oncogene-induced replication stress across cancer types.

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Acknowledgements

We thank members of the Medical Oncology laboratory for fruitful discussions. This work was financially supported by grant from the Netherlands Organization for Scientific Research (NWO-VIDI #917.13334 to M.A.T.M.v.V. and NWO-VENI #916-16025 to R.S.N.F.), the Dutch Cancer Society (RUG 2013-5960 to R.S.N.F and #11352 to M.A.T.M.v.V.) and from the European Research Council (ERC-Consolidator grant “TENSION” to M.A.T.M.v.V.).

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  1. These authors contributed equally: Sergi Guerrero Llobet, Arkajyoti Bhattacharya

Authors and Affiliations

  1. Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands

    Sergi Guerrero Llobet, Arkajyoti Bhattacharya, Marieke Everts, Rudolf S. N. Fehrmann & Marcel A. T. M. van Vugt

  2. Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands

    Klaas Kok

  3. Department of Pathology, University Medical Center Groningen, Groningen, the Netherlands

    Bert van der Vegt

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Contributions

R.S.N.F. and M.A.T.M.v.V. conceived and supervised the study. S.G.L. performed in vitro studies. S.G.L., A.B., K.K. and R.S.N.F. generated and analyzed RNAseq data. A.B. and R.S.N.F. conducted computational analyses. M.E. and B.v.d.V. conducted immunohistochemical analysis of patient samples. S.G.L., A.B., R.S.N.F. and M.A.T.M.v.V. wrote the manuscript. All authors provided feedback and approved the manuscript.

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Correspondence to Marcel A. T. M. van Vugt.

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M.A.T.M.v.V. has acted on the Scientific Advisory Board of Repare Therapeutics, which is unrelated to this work. The other authors declare no conflict of interest.

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shared senior authorship: Rudolf S.N. Fehrmann, Marcel A.T.M. van Vugt.

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Guerrero Llobet, S., Bhattacharya, A., Everts, M. et al. An mRNA expression-based signature for oncogene-induced replication-stress. Oncogene 41, 1216–1224 (2022). https://doi.org/10.1038/s41388-021-02162-0

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