Replicative Instability Drives Cancer Progression.

Autor: Morris BB; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA., Smith JP; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.; Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA., Zhang Q; M2Gen, Tampa, FL 34667, USA., Jiang Z; M2Gen, Tampa, FL 34667, USA., Hampton OA; M2Gen, Tampa, FL 34667, USA., Churchman ML; M2Gen, Tampa, FL 34667, USA., Arnold SM; Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, Lexington, KY 40536, USA., Owen DH; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Gray JE; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Dillon PM; Division of Hematology/Oncology, Department of Internal Medicine, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22908, USA., Soliman HH; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Stover DG; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Colman H; Huntsman Cancer Institute and Department of Neurosurgery, University of Utah, Salt Lake City, UT 84112, USA., Chakravarti A; Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Shain KH; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Silva AS; Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Villano JL; Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, Lexington, KY 40536, USA., Vogelbaum MA; Department of NeuroOncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Borges VF; Division of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA., Akerley WL; Department of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA., Gentzler RD; Division of Hematology/Oncology, Department of Internal Medicine, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22908, USA., Hall RD; Division of Hematology/Oncology, Department of Internal Medicine, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22908, USA., Matsen CB; Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA., Ulrich CM; Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA., Post AR; Department of Biomedical Informatics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA., Nix DA; Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA., Singer EA; Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA., Larner JM; Department of Radiation Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22908, USA., Stukenberg PT; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA., Jones DR; Department of Thoracic Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA., Mayo MW; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2022 Oct 26; Vol. 12 (11). Date of Electronic Publication: 2022 Oct 26.
DOI: 10.3390/biom12111570
Abstrakt: 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.
Databáze: MEDLINE
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