Comprehensive Analysis of Hypermutation in Human Cancer.,Cell

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Comprehensive Analysis of Hypermutation in Human Cancer.
Cell ( IF 45.5 ) Pub Date : 2017-Nov-16 , DOI: 10.1016/j.cell.2017.09.048
Brittany B Campbell ₁ , Nicholas Light ₂ , David Fabrizio ₃ , Matthew Zatzman ₄ , Fabio Fuligni ₅ , Richard de Borja ₅ , Scott Davidson ₆ , Melissa Edwards ₅ , Julia A Elvin ₃ , Karl P Hodel ₇ , Walter J Zahurancik ₈ , Zucai Suo ₈ , Tatiana Lipman ₅ , Katharina Wimmer ₉ , Christian P Kratz ₁₀ , Daniel C Bowers ₁₁ , Theodore W Laetsch ₁₁ , Gavin P Dunn ₁₂ , Tanner M Johanns ₁₃ , Matthew R Grimmer ₁₄ , Ivan V Smirnov ₁₅ , Valérie Larouche ₁₆ , David Samuel ₁₇ , Annika Bronsema ₁₈ , Michael Osborn ₁₉ , Duncan Stearns ₂₀ , Pichai Raman ₂₁ , Kristina A Cole ₂₁ , Phillip B Storm ₂₂ , Michal Yalon ₂₃ , Enrico Opocher ₂₄ , Gary Mason ₂₅ , Gregory A Thomas ₂₆ , Magnus Sabel ₂₇ , Ben George ₂₈ , David S Ziegler ₂₉ , Scott Lindhorst ₃₀ , Vanan Magimairajan Issai ₃₁ , Shlomi Constantini ₃₂ , Helen Toledano ₃₂ , Ronit Elhasid ₃₃ , Roula Farah ₃₄ , Rina Dvir ₃₅ , Peter Dirks ₃₆ , Annie Huang ₃₇ , Melissa A Galati ₅ , Jiil Chung ₅ , Vijay Ramaswamy ₃₈ , Meredith S Irwin ₃₈ , Melyssa Aronson ₃₉ , Carol Durno ₄₀ , Michael D Taylor ₃₆ , Gideon Rechavi ₄₁ , John M Maris ₂₁ , Eric Bouffet ₃₈ , Cynthia Hawkins ₄₂ , Joseph F Costello ₄₃ , M Stephen Meyn ₄₄ , Zachary F Pursell ₇ , David Malkin ₄₅ , Uri Tabori ₄₆ , Adam Shlien ₄₇

Affiliation

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.
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.
Foundation Medicine, Inc., Cambridge, MA, USA.
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.
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
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 Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
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.
Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
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.
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
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.
Department of Pediatrics, Centre Mère-enfant Soleil du CHU de Québec, CRCHU de Québec, Université Laval, Quebec City, QC, Canada.
Department of Hematology-Oncology, Valley Children's Hospital, Madera, CA, USA.
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Haematology and Oncology, Women's and Children's Hospital, North Adelaide, SA, Australia.
Department of Pediatrics-Hematology and Oncology, UH Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
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.
Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel Hashomer, Israel.
Pediatric Oncology & Hematology, Azienda Ospedaliera-Università degli Studi di Padova, Via Giustiniani n.1, Padova, Italy.
Department of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
Division of Pediatric Hematology-Oncology, Oregon Health & Science University, Portland, OR, USA.
Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
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.
Neuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA.
Department of Pediatric Hematology-Oncology, Cancer Care Manitoba; Research Institute in Oncology and Hematology (RIOH), University of Manitoba, Winnipeg, MB, Canada.
Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Department of Hematology-Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Department of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon.
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.
Department of Neurosurgery, 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; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.
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.
Cancer Research Center and Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Center for Human Genomics and Precision Medicine, University of Wisconsin, Madison, WI, USA.
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
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.
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.

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.

中文翻译：

人类癌症超突变的综合分析。

我们通过对来自儿童和成人患者的超过 81,000 个肿瘤进行测序分析，对突变负荷进行了广泛的评估，其中包括由化疗、致癌物或种系改变引起的超突变肿瘤。在以前与高突变负荷无关的肿瘤类型中检测到超突变。复制修复缺陷是一个主要因素。我们发现了复制修复相关 DNA 聚合酶中的新驱动突变，以及微卫星不稳定性和复制修复缺陷对突变负荷规模的明显影响。基于突变背景的无偏聚类揭示了临床相关的亚组，无论肿瘤的组织来源如何，突出了导致超突变的进化动力学的相似性。紫外线等诱变剂与肉瘤和肺癌等意想不到的癌症有关。突变特征的顺序确定了先前的治疗和种系复制修复缺陷，从而改善了对患者和家庭的管理。这些数据将为肿瘤分类、基因检测和临床试验设计提供信息。

更新日期：2017-10-19

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