Author:
Gerstung Moritz, ,Jolly Clemency,Leshchiner Ignaty,Dentro Stefan C.,Gonzalez Santiago,Rosebrock Daniel,Mitchell Thomas J.,Rubanova Yulia,Anur Pavana,Yu Kaixian,Tarabichi Maxime,Deshwar Amit,Wintersinger Jeff,Kleinheinz Kortine,Vázquez-García Ignacio,Haase Kerstin,Jerman Lara,Sengupta Subhajit,Macintyre Geoff,Malikic Salem,Donmez Nilgun,Livitz Dimitri G.,Cmero Marek,Demeulemeester Jonas,Schumacher Steven,Fan Yu,Yao Xiaotong,Lee Juhee,Schlesner Matthias,Boutros Paul C.,Bowtell David D.,Zhu Hongtu,Getz Gad,Imielinski Marcin,Beroukhim Rameen,Sahinalp S. Cenk,Ji Yuan,Peifer Martin,Markowetz Florian,Mustonen Ville,Yuan Ke,Wang Wenyi,Morris Quaid D.,Spellman Paul T.,Wedge David C.,Van Loo Peter,
Abstract
AbstractCancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
Publisher
Springer Science and Business Media LLC