Replicative Instability Drives Cancer Progression

被引：5

作者：

Morris, Benjamin B. ^{[1
,2
,25
]}

Smith, Jason P. ^{[1
,3
]}

Zhang, Qi ^{[4
]}

Jiang, Zhijie ^{[4
]}

Hampton, Oliver A. ^{[4
]}

Churchman, Michelle L. ^{[4
]}

Arnold, Susanne M. ^{[5
]}

Owen, Dwight H. ^{[6
]}

Gray, Jhanelle E. ^{[7
]}

Dillon, Patrick M. ^{[8
]}

Soliman, Hatem H. ^{[9
]}

Stover, Daniel G. ^{[6
]}

Colman, Howard ^{[10
,11
]}

Chakravarti, Arnab ^{[12
]}

Shain, Kenneth H. ^{[13
]}

Silva, Ariosto S. ^{[14
]}

Villano, John L. ^{[5
]}

Vogelbaum, Michael A. ^{[15
]}

Borges, Virginia F. ^{[16
]}

Akerley, Wallace L. ^{[17
]}

Gentzler, Ryan D. ^{[8
]}

Hall, Richard D. ^{[8
]}

Matsen, Cindy B. ^{[18
]}

Ulrich, C. M. ^{[10
,19
]}

Post, Andrew R. ^{[10
,20
]}

Nix, David A. ^{[21
]}

Singer, Eric A. ^{[22
]}

Larner, James M. ^{[23
]}

Stukenberg, Peter Todd ^{[1
]}

Jones, David R. ^{[24
]}

Mayo, Marty W. ^{[1
]}

机构：

[1] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA

[2] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA

[3] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA

[4] M2Gen, Tampa, FL 34667 USA

[5] Markey Canc Ctr, Dept Internal Med, Div Med Oncol, Lexington, KY 40536 USA

[6] Ohio State Univ, Dept Internal Med, Div Med Oncol, Comprehens Canc Ctr, Columbus, OH 43210 USA

[7] H Lee Moffitt Canc Ctr & Res Inst, Dept Thorac Oncol, Tampa, FL 33612 USA

[8] Univ Virginia, Dept Internal Med, Div Hematol Oncol, Comprehens Canc Ctr, Charlottesville, VA 22908 USA

[9] H Lee Moffitt Canc Ctr & Res Inst, Dept Breast Oncol, Tampa, FL 33612 USA

[10] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA

[11] Univ Utah, Dept Neurosurg, Salt Lake City, UT 84112 USA

[12] Ohio State Univ, Dept Radiat Oncol, Comprehens Canc Ctr, Columbus, OH 43210 USA

[13] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33612 USA

[14] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Physiol, Tampa, FL 33612 USA

[15] H Lee Moffitt Canc Ctr & Res Inst, Dept NeuroOncol, Tampa, FL 33612 USA

[16] Univ Colorado, Div Med Oncol, Comprehens Canc Ctr, Aurora, CO 80045 USA

[17] Huntsman Canc Inst, Dept Med Oncol, Dept Internal Med, Salt Lake City, UT 84112 USA

[18] Univ Utah, Huntsman Canc Inst, Dept Surg, Salt Lake City, UT 84112 USA

[19] Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT 84112 USA

[20] Univ Utah, Dept Biomed Informat, Salt Lake City, UT 84112 USA

[21] Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA

[22] Rutgers Canc Inst New Jersey, Sect Urol Oncol, New Brunswick, NJ 08901 USA

[23] Univ Virginia, Dept Radiat Oncol, Comprehens Canc Ctr, Charlottesville, VA 22908 USA

[24] Mem Sloan Kettering Canc Ctr, Dept Thorac Surg, New York, NY 10065 USA

[25] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

来源：

BIOMOLECULES | 2022年 / 12卷 / 11期

关键词：

replicative instability (RIN); cancer progression; metastasis; MYBL2; single-strand break repair; translesion synthesis; FRAGILE SITES; REPAIR; GENOME; HALLMARKS; LANDSCAPE;

D O I：

10.3390/biom12111570

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

BackgroundIn 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.

引用

页数：22

共 55 条

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