Replicative Instability Drives Cancer Progression

Benjamin B. Morris, Jason P. Smith, Qi Zhang, Zhijie Jiang, Oliver A. Hampton, Michelle L. Churchman, Susanne M. Arnold, Dwight H. Owen, Jhanelle E. Gray, Patrick M. Dillon, Hatem H. Soliman, Daniel G. Stover, Howard Colman, Arnab Chakravarti, Kenneth H. Shain, Ariosto S. Silva, John L. Villano, Michael A. Vogelbaum, Virginia F. Borges, Wallace L. AkerleyRyan D. Gentzler, Richard D. Hall, Cindy B. Matsen, C. M. Ulrich, Andrew R. Post, David A. Nix, Eric A. Singer, James M. Larner, Peter Todd Stukenberg, David R. Jones, Marty W. Mayo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Original languageEnglish
Article number1570
Issue number11
StatePublished - Nov 2022

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute (NCI Cancer Center Support Grant P30 CA44579 to B.B.M.; NCI R01 CA192399 to M.W.M.; NCI U54 CA193489 to K.H.S. and A.S.; NCI R01 CA234617 to D.R.J.; NCI R01 CA108633, NCI R01 CA169368, RC2 CA148190, and U10 CA180850 to A.C.), The Robert R. Wagner Fellowship Fund (to B.B.M.), the Pentecost Family Foundation (to K.H.S. and A.S.), the LUNGevity Career Development Award (to D.H.O.). Patient consent, specimen procurement, specimen processing, data abstraction, and access to molecular and clinical data were supported in part by the University of Virginia Comprehensive Cancer Center Support Grant (CCSG) P30CA044579, Moffitt CCSG P30-CA076292, Emory Winship CCSG P30CA138292, Ohio State CCSG P30CA016058, University of Southern California Norris CCSG P30CA014089, University of Iowa Holden CCSG P30CA086862, University of Colorado Comprehensive Cancer Center CCSG P30CA046934, Indiana University Melvin and Bren Simon Comprehensive Cancer Center CCSG P30CA082709, Roswell Park Comprehensive Cancer Center CCSG P30CA016056, Rutgers Cancer Institute of New Jersey CCSG P30CA072720, and University of Utah Huntsman Cancer Institute CCSG P30CA042014. 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.

Publisher Copyright:
© 2022 by the authors.


  • MYBL2
  • cancer progression
  • metastasis
  • replicative instability (RIN)
  • single-strand break repair
  • translesion synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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