Year: 2022
Type: article
Abstract: 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 have been shown to exhibit genomic instability and poor survival rates across tumor types. Here we utilize-omics data from two independent consortia to identify the genetic underpinnings of replication stress, therapy resistance, and primary carcinoma to brain metastasis in BRCA wildtype tumors. In doing so, we have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by genomic evolution secondary to replicative challenge. Our data supports a model whereby defective single-strand break repair, translesion synthesis, and non-homologous end joining effectors drive RIN. Collectively, we find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Statement of Significance Defining the genetic basis of genomic instability with wildtype BRCA repair effectors is a significant unmet need in cancer research. Here we identify and characterize a pan-cancer cohort of tumors driven by replicative instability (RIN). We find that RIN drives therapy resistance and distant metastases across multiple tumor types.
Source: Biomolecules
DOI: 10.3390/biom12111570
Authors: 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. Akerley, Ryan D. Gentzler, Richard D. Hall, Cindy B. Matsen, C. M. Ulrich, Andrew R. Post, David A. Nix, Eric A. Singer, James M. Larner, P. Todd Stukenberg, David R. Jones, Marty W. Mayo
Institutions: University of Virginia, Markey Cancer Center, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Moffitt Cancer Center, University of Virginia Medical Center, University of Virginia Cancer Center, University of Utah, Huntsman Cancer Institute, University of Colorado Cancer Center, Rutgers Cancer Institute, Memorial Sloan Kettering Cancer Center
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,199
Funders: Roswell Park Cancer Institute, LUNGevity Foundation, Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, University of Southern California, Celgene, Ohio State University, Emory University, Rutgers Cancer Institute of New Jersey, Helsinn, RTI International, University of Virginia, Moffitt Cancer Center, Huntsman Cancer Institute, Jazz Pharmaceuticals, Jounce Therapeutics, Mirati Therapeutics, USC Norris Comprehensive Cancer Center, G1 Therapeutics, Eisai, Ono Pharmaceutical, National Institutes of Health, Genentech, EMD Serono, Holden Comprehensive Cancer Center, University of Iowa, Winship Cancer Institute, Cancer Center, University of Colorado, Stephenson Cancer Center, Loxo Oncology, National Cancer Institute, National Institute of General Medical Sciences, Daiichi Sankyo Europe
Awards: G1010591873, G1045139486, G1565180698, G1628476732, G1801928695, G1823531124, G1858189645, Cancer as a Complex Adaptive System, G213385853, G215985982, G2215807464, G226324377, G267171126, G2814612780, G2937198776, G3359996489, G362094, G3658079094, G3670273158, G3687380347, G4103361985, Identifying tumor suppressor targets of SIRT6 in lung cancer, G4252746888, TOWARDS A REFINED MOLECULAR RECURSIVE PARTITIONING ANALYSIS MODEL FOR GLIOBLASTOM, G4545701882, G4551976579, G469290053, G4787186844, G5239122752, G5543716492, G6001075173, G630064964, G7941272330, G8135003176, G858682239, BRMS1-mediated suppression of metastases in p53 mutant lung adenocarcinoma, Cancer Center Support Grant, Cancer Center Support Grant, Moffitt Cancer Center Support Grant, Cancer Center Support Grant, University of Colorado Cancer Center Support Grant, University of Virginia Cancer Center Support Grant, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W4307350396