Comprehensive Analysis of Hypermutation in Human Cancer

Brittany B. Campbell, Nicholas Light, David Fabrizio, Matthew Zatzman, Fabio Fuligni, Richard de Borja, Scott Davidson, Melissa Edwards, Julia A. Elvin, Karl P. Hodel, Walter J. Zahurancik, Zucai Suo, Tatiana Lipman, Katharina Wimmer, Christian P. Kratz, Daniel C. Bowers, Theodore W. Laetsch, Gavin P. Dunn, Tanner M. Johanns, Matthew R. Grimmer & 42 others Ivan V. Smirnov, Valérie Larouche, David Samuel, Annika Bronsema, Michael Osborn, Duncan Stearns, Pichai Raman, Kristina A. Cole, Phillip B. Storm, Michal Yalon, Enrico Opocher, Gary Mason, Gregory A. Thomas, Magnus Sabel, Ben George, David S. Ziegler, Scott Lindhorst, Vanan Magimairajan Issai, Shlomi Constantini, Helen Toledano, Ronit Elhasid, Roula Farah, Rina Dvir, Peter Dirks, Annie Huang, Melissa A. Galati, Jiil Chung, Vijay Ramaswamy, Meredith S. Irwin, Melyssa Aronson, Carol Durno, Michael D. Taylor, Gideon Rechavi, John M. Maris, Eric Bouffet, Cynthia Hawkins, Joseph F. Costello, M. Stephen Meyn, Zachary F. Pursell, David Malkin, Uri Tabori, Adam Shlien

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

Original languageEnglish (US)
Pages (from-to)1042-1056.e10
JournalCell
Volume171
Issue number5
DOIs
StatePublished - Nov 16 2017

Fingerprint

Tumors
Repair
Neoplasms
Mutation
Pediatrics
Chemotherapy
Mutagens
DNA-Directed DNA Polymerase
Microsatellite Instability
Ultraviolet radiation
Carcinogens
Microsatellite Repeats
Genetic Testing
Ultraviolet Rays
Sarcoma
Tissue
Cluster Analysis
Clinical Trials
Testing
Drug Therapy

Keywords

  • cancer genomics
  • cancer predisposition
  • DNA repair
  • DNA replication
  • hypermutation
  • immune checkpoint inhibitors
  • mismatch repair
  • mutator

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Campbell, B. B., Light, N., Fabrizio, D., Zatzman, M., Fuligni, F., de Borja, R., ... Shlien, A. (2017). Comprehensive Analysis of Hypermutation in Human Cancer. Cell, 171(5), 1042-1056.e10. https://doi.org/10.1016/j.cell.2017.09.048

Comprehensive Analysis of Hypermutation in Human Cancer. / Campbell, Brittany B.; Light, Nicholas; Fabrizio, David; Zatzman, Matthew; Fuligni, Fabio; de Borja, Richard; Davidson, Scott; Edwards, Melissa; Elvin, Julia A.; Hodel, Karl P.; Zahurancik, Walter J.; Suo, Zucai; Lipman, Tatiana; Wimmer, Katharina; Kratz, Christian P.; Bowers, Daniel C.; Laetsch, Theodore W.; Dunn, Gavin P.; Johanns, Tanner M.; Grimmer, Matthew R.; Smirnov, Ivan V.; Larouche, Valérie; Samuel, David; Bronsema, Annika; Osborn, Michael; Stearns, Duncan; Raman, Pichai; Cole, Kristina A.; Storm, Phillip B.; Yalon, Michal; Opocher, Enrico; Mason, Gary; Thomas, Gregory A.; Sabel, Magnus; George, Ben; Ziegler, David S.; Lindhorst, Scott; Issai, Vanan Magimairajan; Constantini, Shlomi; Toledano, Helen; Elhasid, Ronit; Farah, Roula; Dvir, Rina; Dirks, Peter; Huang, Annie; Galati, Melissa A.; Chung, Jiil; Ramaswamy, Vijay; Irwin, Meredith S.; Aronson, Melyssa; Durno, Carol; Taylor, Michael D.; Rechavi, Gideon; Maris, John M.; Bouffet, Eric; Hawkins, Cynthia; Costello, Joseph F.; Meyn, M. Stephen; Pursell, Zachary F.; Malkin, David; Tabori, Uri; Shlien, Adam.

In: Cell, Vol. 171, No. 5, 16.11.2017, p. 1042-1056.e10.

Research output: Contribution to journalArticle

Campbell, BB, Light, N, Fabrizio, D, Zatzman, M, Fuligni, F, de Borja, R, Davidson, S, Edwards, M, Elvin, JA, Hodel, KP, Zahurancik, WJ, Suo, Z, Lipman, T, Wimmer, K, Kratz, CP, Bowers, DC, Laetsch, TW, Dunn, GP, Johanns, TM, Grimmer, MR, Smirnov, IV, Larouche, V, Samuel, D, Bronsema, A, Osborn, M, Stearns, D, Raman, P, Cole, KA, Storm, PB, Yalon, M, Opocher, E, Mason, G, Thomas, GA, Sabel, M, George, B, Ziegler, DS, Lindhorst, S, Issai, VM, Constantini, S, Toledano, H, Elhasid, R, Farah, R, Dvir, R, Dirks, P, Huang, A, Galati, MA, Chung, J, Ramaswamy, V, Irwin, MS, Aronson, M, Durno, C, Taylor, MD, Rechavi, G, Maris, JM, Bouffet, E, Hawkins, C, Costello, JF, Meyn, MS, Pursell, ZF, Malkin, D, Tabori, U & Shlien, A 2017, 'Comprehensive Analysis of Hypermutation in Human Cancer', Cell, vol. 171, no. 5, pp. 1042-1056.e10. https://doi.org/10.1016/j.cell.2017.09.048
Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R et al. Comprehensive Analysis of Hypermutation in Human Cancer. Cell. 2017 Nov 16;171(5):1042-1056.e10. https://doi.org/10.1016/j.cell.2017.09.048
Campbell, Brittany B. ; Light, Nicholas ; Fabrizio, David ; Zatzman, Matthew ; Fuligni, Fabio ; de Borja, Richard ; Davidson, Scott ; Edwards, Melissa ; Elvin, Julia A. ; Hodel, Karl P. ; Zahurancik, Walter J. ; Suo, Zucai ; Lipman, Tatiana ; Wimmer, Katharina ; Kratz, Christian P. ; Bowers, Daniel C. ; Laetsch, Theodore W. ; Dunn, Gavin P. ; Johanns, Tanner M. ; Grimmer, Matthew R. ; Smirnov, Ivan V. ; Larouche, Valérie ; Samuel, David ; Bronsema, Annika ; Osborn, Michael ; Stearns, Duncan ; Raman, Pichai ; Cole, Kristina A. ; Storm, Phillip B. ; Yalon, Michal ; Opocher, Enrico ; Mason, Gary ; Thomas, Gregory A. ; Sabel, Magnus ; George, Ben ; Ziegler, David S. ; Lindhorst, Scott ; Issai, Vanan Magimairajan ; Constantini, Shlomi ; Toledano, Helen ; Elhasid, Ronit ; Farah, Roula ; Dvir, Rina ; Dirks, Peter ; Huang, Annie ; Galati, Melissa A. ; Chung, Jiil ; Ramaswamy, Vijay ; Irwin, Meredith S. ; Aronson, Melyssa ; Durno, Carol ; Taylor, Michael D. ; Rechavi, Gideon ; Maris, John M. ; Bouffet, Eric ; Hawkins, Cynthia ; Costello, Joseph F. ; Meyn, M. Stephen ; Pursell, Zachary F. ; Malkin, David ; Tabori, Uri ; Shlien, Adam. / Comprehensive Analysis of Hypermutation in Human Cancer. In: Cell. 2017 ; Vol. 171, No. 5. pp. 1042-1056.e10.
@article{7ed41589aabd4c97bd82a9c5559e1c8a,
title = "Comprehensive Analysis of Hypermutation in Human Cancer",
abstract = "We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.",
keywords = "cancer genomics, cancer predisposition, DNA repair, DNA replication, hypermutation, immune checkpoint inhibitors, mismatch repair, mutator",
author = "Campbell, {Brittany B.} and Nicholas Light and David Fabrizio and Matthew Zatzman and Fabio Fuligni and {de Borja}, Richard and Scott Davidson and Melissa Edwards and Elvin, {Julia A.} and Hodel, {Karl P.} and Zahurancik, {Walter J.} and Zucai Suo and Tatiana Lipman and Katharina Wimmer and Kratz, {Christian P.} and Bowers, {Daniel C.} and Laetsch, {Theodore W.} and Dunn, {Gavin P.} and Johanns, {Tanner M.} and Grimmer, {Matthew R.} and Smirnov, {Ivan V.} and Val{\'e}rie Larouche and David Samuel and Annika Bronsema and Michael Osborn and Duncan Stearns and Pichai Raman and Cole, {Kristina A.} and Storm, {Phillip B.} and Michal Yalon and Enrico Opocher and Gary Mason and Thomas, {Gregory A.} and Magnus Sabel and Ben George and Ziegler, {David S.} and Scott Lindhorst and Issai, {Vanan Magimairajan} and Shlomi Constantini and Helen Toledano and Ronit Elhasid and Roula Farah and Rina Dvir and Peter Dirks and Annie Huang and Galati, {Melissa A.} and Jiil Chung and Vijay Ramaswamy and Irwin, {Meredith S.} and Melyssa Aronson and Carol Durno and Taylor, {Michael D.} and Gideon Rechavi and Maris, {John M.} and Eric Bouffet and Cynthia Hawkins and Costello, {Joseph F.} and Meyn, {M. Stephen} and Pursell, {Zachary F.} and David Malkin and Uri Tabori and Adam Shlien",
year = "2017",
month = "11",
day = "16",
doi = "10.1016/j.cell.2017.09.048",
language = "English (US)",
volume = "171",
pages = "1042--1056.e10",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Comprehensive Analysis of Hypermutation in Human Cancer

AU - Campbell, Brittany B.

AU - Light, Nicholas

AU - Fabrizio, David

AU - Zatzman, Matthew

AU - Fuligni, Fabio

AU - de Borja, Richard

AU - Davidson, Scott

AU - Edwards, Melissa

AU - Elvin, Julia A.

AU - Hodel, Karl P.

AU - Zahurancik, Walter J.

AU - Suo, Zucai

AU - Lipman, Tatiana

AU - Wimmer, Katharina

AU - Kratz, Christian P.

AU - Bowers, Daniel C.

AU - Laetsch, Theodore W.

AU - Dunn, Gavin P.

AU - Johanns, Tanner M.

AU - Grimmer, Matthew R.

AU - Smirnov, Ivan V.

AU - Larouche, Valérie

AU - Samuel, David

AU - Bronsema, Annika

AU - Osborn, Michael

AU - Stearns, Duncan

AU - Raman, Pichai

AU - Cole, Kristina A.

AU - Storm, Phillip B.

AU - Yalon, Michal

AU - Opocher, Enrico

AU - Mason, Gary

AU - Thomas, Gregory A.

AU - Sabel, Magnus

AU - George, Ben

AU - Ziegler, David S.

AU - Lindhorst, Scott

AU - Issai, Vanan Magimairajan

AU - Constantini, Shlomi

AU - Toledano, Helen

AU - Elhasid, Ronit

AU - Farah, Roula

AU - Dvir, Rina

AU - Dirks, Peter

AU - Huang, Annie

AU - Galati, Melissa A.

AU - Chung, Jiil

AU - Ramaswamy, Vijay

AU - Irwin, Meredith S.

AU - Aronson, Melyssa

AU - Durno, Carol

AU - Taylor, Michael D.

AU - Rechavi, Gideon

AU - Maris, John M.

AU - Bouffet, Eric

AU - Hawkins, Cynthia

AU - Costello, Joseph F.

AU - Meyn, M. Stephen

AU - Pursell, Zachary F.

AU - Malkin, David

AU - Tabori, Uri

AU - Shlien, Adam

PY - 2017/11/16

Y1 - 2017/11/16

N2 - We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

AB - We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

KW - cancer genomics

KW - cancer predisposition

KW - DNA repair

KW - DNA replication

KW - hypermutation

KW - immune checkpoint inhibitors

KW - mismatch repair

KW - mutator

UR - http://www.scopus.com/inward/record.url?scp=85031810803&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031810803&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.09.048

DO - 10.1016/j.cell.2017.09.048

M3 - Article

VL - 171

SP - 1042-1056.e10

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -