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
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.
Cell. 2017 Nov 16;171(5):1042-1056.e10. doi: 10.1016/j.cell.2017.09.048. Epub 2017 Oct 19.
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.
我们通过对来自儿科和成年患者的81000多个肿瘤进行测序分析，对突变负担进行了全面评估，其中包括因化疗、致癌物或种系改变导致高突变的肿瘤。在以前未与高突变负担相关的肿瘤类型中检测到了高突变。复制修复缺陷是一个主要促成因素。我们在与复制修复相关的DNA聚合酶中发现了新的驱动突变，以及微卫星不稳定性和复制修复缺陷对突变负荷规模的独特影响。基于突变背景的无偏聚类揭示了临床相关亚组，而不论肿瘤的组织来源如何，突出了导致高突变的进化动力学中的相似性。紫外线等诱变剂与包括肉瘤和肺癌在内的意外癌症有关。突变特征的顺序确定了先前的治疗和种系复制修复缺陷，这改善了对患者及其家庭的管理。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。
