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

Cell. 2017 Nov 16;171(5):1042-1056.e10. doi: 10.1016/j.cell.2017.09.048. Epub 2017 Oct 19.

Authors

Brittany B Campbell¹, Nicholas Light², David Fabrizio³, Matthew Zatzman⁴, Fabio Fuligni⁵, Richard de Borja⁵, Scott Davidson⁶, Melissa Edwards⁵, Julia A Elvin³, Karl P Hodel⁷, Walter J Zahurancik⁸, Zucai Suo⁸, Tatiana Lipman⁵, Katharina Wimmer⁹, Christian P Kratz¹⁰, Daniel C Bowers¹¹, Theodore W Laetsch¹¹, Gavin P Dunn¹², Tanner M Johanns¹³, Matthew R Grimmer¹⁴, Ivan V Smirnov¹⁵, Valérie Larouche¹⁶, David Samuel¹⁷, Annika Bronsema¹⁸, Michael Osborn¹⁹, Duncan Stearns²⁰, Pichai Raman²¹, Kristina A Cole²¹, Phillip B Storm²², Michal Yalon²³, Enrico Opocher²⁴, Gary Mason²⁵, Gregory A Thomas²⁶, Magnus Sabel²⁷, Ben George²⁸, David S Ziegler²⁹, Scott Lindhorst³⁰, Vanan Magimairajan Issai³¹, Shlomi Constantini³², Helen Toledano³², Ronit Elhasid³³, Roula Farah³⁴, Rina Dvir³⁵, Peter Dirks³⁶, Annie Huang³⁷, Melissa A Galati⁵, Jiil Chung⁵, Vijay Ramaswamy³⁸, Meredith S Irwin³⁸, Melyssa Aronson³⁹, Carol Durno⁴⁰, Michael D Taylor³⁶, Gideon Rechavi⁴¹, John M Maris²¹, Eric Bouffet³⁸, Cynthia Hawkins⁴², Joseph F Costello⁴³, M Stephen Meyn⁴⁴, Zachary F Pursell⁷, David Malkin⁴⁵, Uri Tabori⁴⁶, Adam Shlien⁴⁷

Affiliations

¹ 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.
² 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.
³ Foundation Medicine, Inc., Cambridge, MA, USA.
⁴ 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.
⁵ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ 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.
⁷ Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
⁸ The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
⁹ Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
¹⁰ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
¹¹ 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.
¹² Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
¹³ 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.
¹⁴ Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁵ 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.
¹⁶ Department of Pediatrics, Centre Mère-enfant Soleil du CHU de Québec, CRCHU de Québec, Université Laval, Quebec City, QC, Canada.
¹⁷ Department of Hematology-Oncology, Valley Children's Hospital, Madera, CA, USA.
¹⁸ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Department of Haematology and Oncology, Women's and Children's Hospital, North Adelaide, SA, Australia.
²⁰ Department of Pediatrics-Hematology and Oncology, UH Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
²¹ 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.
²² Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²³ Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel Hashomer, Israel.
²⁴ Pediatric Oncology & Hematology, Azienda Ospedaliera-Università degli Studi di Padova, Via Giustiniani n.1, Padova, Italy.
²⁵ Department of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
²⁶ Division of Pediatric Hematology-Oncology, Oregon Health & Science University, Portland, OR, USA.
²⁷ Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
²⁸ Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
²⁹ 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.
³⁰ Neuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA.
³¹ Department of Pediatric Hematology-Oncology, Cancer Care Manitoba; Research Institute in Oncology and Hematology (RIOH), University of Manitoba, Winnipeg, MB, Canada.
³² Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
³³ Department of Hematology-Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
³⁴ Department of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon.
³⁵ 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.
³⁶ Department of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
³⁷ 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.
³⁸ Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
³⁹ Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.
⁴⁰ 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.
⁴¹ Cancer Research Center and Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
⁴² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁴³ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁴⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Center for Human Genomics and Precision Medicine, University of Wisconsin, Madison, WI, USA.
⁴⁵ Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
⁴⁶ 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.
⁴⁷ 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.

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
Neoplasms / genetics*
Neoplasms / pathology
Neoplasms / therapy
Poly-ADP-Ribose Binding Proteins / genetics

Substances

Poly-ADP-Ribose Binding Proteins
POLD1 protein, human
DNA Polymerase II
DNA Polymerase III
POLE protein, human

Abstract

MeSH terms

Substances

Grants and funding