MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma

Benjamin B. Morris, Nolan A. Wages, Patrick A. Grant, P. Todd Stukenberg, Ryan D. Gentzler, Richard D. Hall, Wallace L. Akerley, Thomas K. Varghese, Susanne M. Arnold, Terence M. Williams, Vincenzo Coppola, David R. Jones, David T. Auble, Marty W. Mayo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

Original languageEnglish
Article number585551
JournalFrontiers in Oncology
Volume10
DOIs
StatePublished - Jan 8 2021

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute (NCI R01 CA192399 to MM, NCI T32 CA009109-42 and NCI T32 CA009109-43 to BM, NCI R01 CA217169 and NCI R01 CA234617 to DJ, and P30 CA0044579-26 to NW) and the National Institutes of Health (NIH R01 GN118798 to PS and NIH R01 GM111911 to PG). Patient consent, specimen procurement, specimen processing, data abstraction, and access to molecular and clinical data were supported in part by the UVA Cancer Center Support Grant, P30CA044579. Funding sources listed were not involved in the design of this study, the analysis or interpretation of the data, the writing of this manuscript, or the decision to submit for publication.

Funding Information:
The authors would like to acknowledge the following ORIEN Member institutions for their commitment to data sharing and for contributing samples to this study: the University of Virginia Cancer Center, USC Norris Comprehensive Cancer Center, Roswell Park Comprehensive Cancer Center, Markey Cancer Center, Winship Cancer Institute, City of Hope Comprehensive Cancer Center, Rutgers Cancer Institute of New Jersey, University of Colorado Cancer Center, Huntsman Cancer Institute, and The Ohio State University Comprehensive Cancer Center. ORIEN molecular data analyzed in this study were managed by M2Gen under the Total Cancer Care (TCC) protocol at ORIEN member institutions. The authors also acknowledge the contributions of the UVA ORIEN Team and the UVA Biorepository and Tissue Research Facility (BTRF) in the consent of patients, specimen procurement, specimen processing, data abstraction, and providing access to molecular and clinical data (IRB HSR 18445). The authors thank Lisa Gray, Patrycja Lewandowska, and Jason P. Smith for insightful manuscript discussions.

Publisher Copyright:
© Copyright © 2021 Morris, Wages, Grant, Stukenberg, Gentzler, Hall, Akerley, Varghese, Arnold, Williams, Coppola, Jones, Auble and Mayo.

Keywords

  • MYBL2
  • error-prone DNA repair
  • homologous recombination (HR)
  • lung adenocarcinoma
  • microhomology mediated-end joining repair (MMEJ)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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