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; 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

doi:10.1016/j.cell.2017.09.048

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. GrimmerIvan 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

Pediatrics

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

526 Scopus citations

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 language	English (US)
Pages (from-to)	1042-1056.e10
Journal	Cell
Volume	171
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2017.09.048
State	Published - Nov 16 2017

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2017.09.048

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Campbell, B. B., Light, N., Fabrizio, D., Zatzman, M., Fuligni, F., de Borja, R., Davidson, S., Edwards, M., Elvin, J. A., Hodel, K. P., Zahurancik, W. J., Suo, Z., Lipman, T., Wimmer, K., Kratz, C. P., Bowers, D. C., Laetsch, T. W., Dunn, G. P., Johanns, T. M., ... 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

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

@article{7b22bdd04b1143d1ad0ac86f3771de97,

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{\textquoteright} 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 = "DNA repair, DNA replication, cancer genomics, cancer predisposition, 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",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = nov,

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",

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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 - DNA repair

KW - DNA replication

KW - cancer genomics

KW - cancer predisposition

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

C2 - 29056344

AN - SCOPUS:85031810803

SN - 0092-8674

VL - 171

SP - 1042-1056.e10

JO - Cell

JF - Cell

IS - 5

ER -

Comprehensive Analysis of Hypermutation in Human Cancer

Abstract

Keywords

ASJC Scopus subject areas

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