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, 578 (7793), 102-111

Analyses of Non-Coding Somatic Drivers in 2,658 Cancer Whole Genomes

Esther Rheinbay  1   2   3 Morten Muhlig Nielsen  4 Federico Abascal  5 Jeremiah A Wala  1   6 Ofer Shapira  1   7 Grace Tiao  1 Henrik Hornshøj  4 Julian M Hess  1 Randi Istrup Juul  4 Ziao Lin  1   8 Lars Feuerbach  9 Radhakrishnan Sabarinathan  10   11 Tobias Madsen  4 Jaegil Kim  1 Loris Mularoni  10   11 Shimin Shuai  12   13 Andrés Lanzós  14   15   16 Carl Herrmann  17   18 Yosef E Maruvka  1   2 Ciyue Shen  19   20 Samirkumar B Amin  21   22 Pratiti Bandopadhayay  1   7 Johanna Bertl  4 Keith A Boroevich  23 John Busanovich  1   7 Joana Carlevaro-Fita  14   15   16 Dimple Chakravarty  24   25 Calvin Wing Yiu Chan  17   26 David Craft  27 Priyanka Dhingra  28   29 Klev Diamanti  30 Nuno A Fonseca  31 Abel Gonzalez-Perez  10   11 Qianyun Guo  32 Mark P Hamilton  33 Nicholas J Haradhvala  1   2 Chen Hong  9   26 Keren Isaev  12   34 Todd A Johnson  23 Malene Juul  4 Andre Kahles  35 Abdullah Kahraman  36 Youngwook Kim  37 Jan Komorowski  30   38 Kiran Kumar  1   7 Sushant Kumar  39 Donghoon Lee  39 Kjong-Van Lehmann  35 Yilong Li  40   41 Eric Minwei Liu  28   29 Lucas Lochovsky  42 Keunchil Park  37 Oriol Pich  10   11 Nicola D Roberts  41 Gordon Saksena  1 Steven E Schumacher  1   7 Nikos Sidiropoulos  43 Lina Sieverling  9   26 Nasa Sinnott-Armstrong  44 Chip Stewart  1 David Tamborero  10   11 Jose M C Tubio  45   46   47 Husen M Umer  30 Liis Uusküla-Reimand  48   49 Claes Wadelius  50 Lina Wadi  12 Xiaotong Yao  51 Cheng-Zhong Zhang  52   53 Jing Zhang  39 James E Haber  54 Asger Hobolth  32 Marcin Imielinski  51   55 Manolis Kellis  1   56 Michael S Lawrence  1   2 Christian von Mering  36 Hidewaki Nakagawa  57 Benjamin J Raphael  58 Mark A Rubin  59   60   61 Chris Sander  19   20 Lincoln D Stein  12   13 Joshua M Stuart  62 Tatsuhiko Tsunoda  23   63   64 David A Wheeler  65 Rory Johnson  14   16 Jüri Reimand  12   34 Mark Gerstein  39   42   66 Ekta Khurana  28   29   60   61 Peter J Campbell  5   41 Núria López-Bigas  10   11   67 PCAWG Drivers and Functional Interpretation Working GroupPCAWG Structural Variation Working GroupJoachim Weischenfeldt  68   69 Rameen Beroukhim  70   71   72 Iñigo Martincorena  73 Jakob Skou Pedersen  74   75 Gad Getz  76   77   78   79 PCAWG Consortium
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Analyses of Non-Coding Somatic Drivers in 2,658 Cancer Whole Genomes

Esther Rheinbay et al. Nature.

Abstract

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

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  • Pan-cancer Analysis of Whole Genomes
    ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Nature 578 (7793), 82-93. PMID 32025007.
    Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1

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