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PMID: 29056344 Published · ppublish English Journal Article

Comprehensive Analysis of Hypermutation in Human Cancer.

Cell ·Vol. 171 ·No. 5 ·2017-11-16 ·Pages 1042-1056.e10

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

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.

Keywords
DNA repair DNA replication cancer genomics cancer predisposition hypermutation immune checkpoint inhibitors mismatch repair mutator
MeSH Terms
Adult Child Cluster Analysis DNA Polymerase II/genetics DNA Polymerase III/genetics DNA Replication Humans Mutation Neoplasms/classification,genetics,pathology,therapy Poly-ADP-Ribose Binding Proteins/genetics
Chemicals
Poly-ADP-Ribose Binding Proteins POLD1 protein, human DNA Polymerase II DNA Polymerase III POLE protein, human
Authors & Affiliations
62 authors, click to expand affiliations / ORCID
Campbell Brittany B
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Light Nicholas
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Fabrizio David
Foundation Medicine, Inc., Cambridge, MA, USA.
Zatzman Matthew
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Fuligni Fabio
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
de Borja Richard
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Davidson Scott
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
Edwards Melissa
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Elvin Julia A
Foundation Medicine, Inc., Cambridge, MA, USA.
Hodel Karl P
Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
Zahurancik Walter J
The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Suo Zucai
The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Lipman Tatiana
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Wimmer Katharina
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Kratz Christian P
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Bowers Daniel C
Department of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Pauline Allen Gill Center for Cancer and Blood Disorders, Children's Health, Dallas, TX, USA.
Laetsch Theodore W
Department of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Pauline Allen Gill Center for Cancer and Blood Disorders, Children's Health, Dallas, TX, USA.
Dunn Gavin P
Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
Johanns Tanner M
Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Grimmer Matthew R
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Smirnov Ivan V
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Larouche Valérie
Department of Pediatrics, Centre Mère-enfant Soleil du CHU de Québec, CRCHU de Québec, Université Laval, Quebec City, QC, Canada.
Samuel David
Department of Hematology-Oncology, Valley Children's Hospital, Madera, CA, USA.
Bronsema Annika
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Osborn Michael
Department of Haematology and Oncology, Women's and Children's Hospital, North Adelaide, SA, Australia.
Stearns Duncan
Department of Pediatrics-Hematology and Oncology, UH Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
Raman Pichai
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Cole Kristina A
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Storm Phillip B
Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Yalon Michal
Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel Hashomer, Israel.
Opocher Enrico
Pediatric Oncology & Hematology, Azienda Ospedaliera-Università degli Studi di Padova, Via Giustiniani n.1, Padova, Italy.
Mason Gary
Department of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
Thomas Gregory A
Division of Pediatric Hematology-Oncology, Oregon Health & Science University, Portland, OR, USA.
Sabel Magnus
Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
George Ben
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
Ziegler David S
Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW, Australia.
Lindhorst Scott
Neuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA.
Issai Vanan Magimairajan
Department of Pediatric Hematology-Oncology, Cancer Care Manitoba; Research Institute in Oncology and Hematology (RIOH), University of Manitoba, Winnipeg, MB, Canada.
Constantini Shlomi
Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Toledano Helen
Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Elhasid Ronit
Department of Hematology-Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Farah Roula
Department of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon.
Dvir Rina
Department of Pediatric Hematology/Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dirks Peter
Department of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
Huang Annie
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Galati Melissa A
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Chung Jiil
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
Ramaswamy Vijay
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Irwin Meredith S
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Aronson Melyssa
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.
Durno Carol
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada; Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada.
Taylor Michael D
Department of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
Rechavi Gideon
Cancer Research Center and Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Maris John M
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Bouffet Eric
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Hawkins Cynthia
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Costello Joseph F
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Meyn M Stephen
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Center for Human Genomics and Precision Medicine, University of Wisconsin, Madison, WI, USA.
Pursell Zachary F
Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
Malkin David
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
Tabori Uri
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: uri.tabori@sickkids.ca.
Shlien Adam
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: adam.shlien@sickkids.ca.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2017.09.048
Email
uri.tabori@sickkids.ca
adam.shlien@sickkids.ca
Published
2017-11-16
Epub
2017-00-19
Pages
1042-1056.e10
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC5849393
Subset
IM
Grants
NIEHS NIH HHS · R00 ES016780 · United States
NCI NIH HHS · P01 CA118816 · United States
NIEHS NIH HHS · R56 ES026821 · United States
NCI NIH HHS · P50 CA097257 · United States
NIEHS NIH HHS · R01 ES028271 · United States
Corrections
CommentIn
PMID: 29109522
CommentIn
PMID: 29277455
External Links
PubMed source DOI: 10.1016/j.cell.2017.09.048 PMC Full Text View journal details
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