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. 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; Peter Todd Stukenberg; David R. Jones; Marty W. Mayo

doi:10.3390/biom12111570

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. 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, Peter Todd Stukenberg, David R. Jones, Marty W. Mayo

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 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 language	English
Article number	1570
Journal	Biomolecules
Volume	12
Issue number	11
DOIs	https://doi.org/10.3390/biom12111570
State	Published - Nov 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Funding

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.

Funders	Funder number
Pentecost Family Foundation
University of Colorado Comprehensive Cancer Center	CCSG P30CA046934
Huntsman Cancer Institute, University of Utah	CCSG P30CA042014
University of Virginia Comprehensive Cancer Center	CCSG P30-CA076292, P30CA086862, P30CA138292, P30CA014089, P30CA044579, P30CA016058
National Childhood Cancer Registry – National Cancer Institute	P30 CA44579, R01 CA169368, R01 CA192399, R01 CA234617, U10 CA180850, NCI U54 CA193489, R01 CA108633, RC2 CA148190
National Childhood Cancer Registry – National Cancer Institute
University of Southern Indiana	P30CA016056, P30CA082709
University of Southern Indiana
Rutgers Cancer Institute of New Jersey and Rutgers University	CCSG P30CA072720
Rutgers Cancer Institute of New Jersey and Rutgers University

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Biochemistry
Molecular Biology

Access to Document

10.3390/biom12111570

Cite this

Morris, B. B., Smith, J. P., Zhang, Q., Jiang, Z., Hampton, O. A., Churchman, M. L., Arnold, S. M., Owen, D. H., Gray, J. E., Dillon, P. M., Soliman, H. H., Stover, D. G., Colman, H., Chakravarti, A., Shain, K. H., Silva, A. S., Villano, J. L., Vogelbaum, M. A., Borges, V. F., ... Mayo, M. W. (2022). Replicative Instability Drives Cancer Progression. Biomolecules, 12(11), Article 1570. https://doi.org/10.3390/biom12111570

@article{c07dfc7c281544db921c3ca6c638e3e6,

title = "Replicative Instability Drives Cancer Progression",

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 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.",

keywords = "MYBL2, cancer progression, metastasis, replicative instability (RIN), single-strand break repair, translesion synthesis",

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

note = "Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = nov,

doi = "10.3390/biom12111570",

language = "English",

volume = "12",

number = "11",

}

Morris, BB, Smith, JP, Zhang, Q, Jiang, Z, Hampton, OA, Churchman, ML, Arnold, SM, Owen, DH, Gray, JE, Dillon, PM, Soliman, HH, Stover, DG, Colman, H, Chakravarti, A, Shain, KH, Silva, AS, Villano, JL, Vogelbaum, MA, Borges, VF, Akerley, WL, Gentzler, RD, Hall, RD, Matsen, CB, Ulrich, CM, Post, AR, Nix, DA, Singer, EA, Larner, JM, Stukenberg, PT, Jones, DR & Mayo, MW 2022, 'Replicative Instability Drives Cancer Progression', Biomolecules, vol. 12, no. 11, 1570. https://doi.org/10.3390/biom12111570

TY - JOUR

T1 - Replicative Instability Drives Cancer Progression

AU - Morris, Benjamin B.

AU - Smith, Jason P.

AU - Zhang, Qi

AU - Jiang, Zhijie

AU - Hampton, Oliver A.

AU - Churchman, Michelle L.

AU - Arnold, Susanne M.

AU - Owen, Dwight H.

AU - Gray, Jhanelle E.

AU - Dillon, Patrick M.

AU - Soliman, Hatem H.

AU - Stover, Daniel G.

AU - Colman, Howard

AU - Chakravarti, Arnab

AU - Shain, Kenneth H.

AU - Silva, Ariosto S.

AU - Villano, John L.

AU - Vogelbaum, Michael A.

AU - Borges, Virginia F.

AU - Akerley, Wallace L.

AU - Gentzler, Ryan D.

AU - Hall, Richard D.

AU - Matsen, Cindy B.

AU - Ulrich, C. M.

AU - Post, Andrew R.

AU - Nix, David A.

AU - Singer, Eric A.

AU - Larner, James M.

AU - Stukenberg, Peter Todd

AU - Jones, David R.

AU - Mayo, Marty W.

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

KW - MYBL2

KW - cancer progression

KW - metastasis

KW - replicative instability (RIN)

KW - single-strand break repair

KW - translesion synthesis

UR - https://www.scopus.com/pages/publications/85141751937

UR - https://www.scopus.com/pages/publications/85141751937#tab=citedBy

U2 - 10.3390/biom12111570

DO - 10.3390/biom12111570

M3 - Article

AN - SCOPUS:85141751937

VL - 12

JO - Biomolecules

JF - Biomolecules

IS - 11

M1 - 1570

ER -

Replicative Instability Drives Cancer Progression

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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