Biomolecules · 2022
Replicative Instability Drives Cancer Progression.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Morris Benjamin B, Smith Jason P, Zhang Qi, Jiang Zhijie, Hampton Oliver A, Churchman Michelle L, Arnold Susanne M, Owen Dwight H, Gray Jhanelle E, Dillon Patrick M, Soliman Hatem H, Stover Daniel G, Colman Howard, Chakravarti Arnab, Shain Kenneth H, Silva Ariosto S, Villano John L, Vogelbaum Michael A, Borges Virginia F, Akerley Wallace L, Gentzler Ryan D, Hall Richard D, Matsen Cindy B, Ulrich C M, Post Andrew R, Nix David A, Singer Eric A, Larner James M, Stukenberg Peter Todd, Jones David R, Mayo Marty W
Аннотация
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.