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Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Author

Listed:
  • Esther Rheinbay

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Morten Muhlig Nielsen

    (Aarhus University Hospital)

  • Federico Abascal

    (Wellcome Trust Sanger Institute)

  • Jeremiah A. Wala

    (The Broad Institute of MIT and Harvard
    Harvard University)

  • Ofer Shapira

    (The Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Grace Tiao

    (The Broad Institute of MIT and Harvard)

  • Henrik Hornshøj

    (Aarhus University Hospital)

  • Julian M. Hess

    (The Broad Institute of MIT and Harvard)

  • Randi Istrup Juul

    (Aarhus University Hospital)

  • Ziao Lin

    (The Broad Institute of MIT and Harvard
    Harvard University)

  • Lars Feuerbach

    (German Cancer Research Center (DKFZ))

  • Radhakrishnan Sabarinathan

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra)

  • Tobias Madsen

    (Aarhus University Hospital)

  • Jaegil Kim

    (The Broad Institute of MIT and Harvard)

  • Loris Mularoni

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra)

  • Shimin Shuai

    (Ontario Institute for Cancer Research
    Ontario Institute for Cancer Research)

  • Andrés Lanzós

    (University of Bern
    University of Bern
    University of Bern)

  • Carl Herrmann

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • Yosef E. Maruvka

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Ciyue Shen

    (Harvard Medical School
    Harvard Medical School)

  • Samirkumar B. Amin

    (University of Texas MD Anderson Cancer Center
    Baylor College of Medicine)

  • Pratiti Bandopadhayay

    (The Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Johanna Bertl

    (Aarhus University Hospital)

  • Keith A. Boroevich

    (RIKEN Center for Integrative Medical Sciences)

  • John Busanovich

    (The Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Joana Carlevaro-Fita

    (University of Bern
    University of Bern
    University of Bern)

  • Dimple Chakravarty

    (University of Texas MD Anderson Cancer Center
    Icahn school of Medicine at Mount Sinai)

  • Calvin Wing Yiu Chan

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • David Craft

    (Massachusetts General Hospital)

  • Priyanka Dhingra

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Klev Diamanti

    (Department of Cell and Molecular Biology)

  • Nuno A. Fonseca

    (European Molecular Biology Laboratory)

  • Abel Gonzalez-Perez

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra)

  • Qianyun Guo

    (Aarhus University)

  • Mark P. Hamilton

    (Baylor College of Medicine)

  • Nicholas J. Haradhvala

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Chen Hong

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Keren Isaev

    (Ontario Institute for Cancer Research
    University of Toronto)

  • Todd A. Johnson

    (RIKEN Center for Integrative Medical Sciences)

  • Malene Juul

    (Aarhus University Hospital)

  • Andre Kahles

    (Memorial Sloan Kettering Cancer Center)

  • Abdullah Kahraman

    (University of Zurich)

  • Youngwook Kim

    (Sungkyunkwan University School of Medicine)

  • Jan Komorowski

    (Department of Cell and Molecular Biology
    Polish Academy of Sciences)

  • Kiran Kumar

    (The Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Sushant Kumar

    (Yale University)

  • Donghoon Lee

    (Yale University)

  • Kjong-Van Lehmann

    (Memorial Sloan Kettering Cancer Center)

  • Yilong Li

    (SBGD Inc
    University of Cambridge)

  • Eric Minwei Liu

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Lucas Lochovsky

    (Yale University)

  • Keunchil Park

    (Sungkyunkwan University School of Medicine)

  • Oriol Pich

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra)

  • Nicola D. Roberts

    (University of Cambridge)

  • Gordon Saksena

    (The Broad Institute of MIT and Harvard)

  • Steven E. Schumacher

    (The Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Nikos Sidiropoulos

    (University of Copenhagen)

  • Lina Sieverling

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Nasa Sinnott-Armstrong

    (Stanford University School of Medicine)

  • Chip Stewart

    (The Broad Institute of MIT and Harvard)

  • David Tamborero

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra)

  • Jose M. C. Tubio

    (Universidade de Santiago de Compostela
    Universidade de Santiago de Compostela
    Universidade de Vigo)

  • Husen M. Umer

    (Department of Cell and Molecular Biology
    Science for Life Laboratory, Karolinska Institute)

  • Liis Uusküla-Reimand

    (SickKids Research Institute
    Tallinn University of Technology)

  • Claes Wadelius

    (Uppsala University)

  • Lina Wadi

    (Ontario Institute for Cancer Research)

  • Xiaotong Yao

    (New York Genome Center)

  • Cheng-Zhong Zhang

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Jing Zhang

    (Yale University)

  • James E. Haber

    (Brandeis University)

  • Asger Hobolth

    (Aarhus University)

  • Marcin Imielinski

    (New York Genome Center
    Weill Cornell Medicine)

  • Manolis Kellis

    (The Broad Institute of MIT and Harvard
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Michael S. Lawrence

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Christian Mering

    (University of Zurich)

  • Hidewaki Nakagawa

    (RIKEN Center for Integrative Medical Sciences)

  • Benjamin J. Raphael

    (Princeton University)

  • Mark A. Rubin

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Chris Sander

    (Harvard Medical School
    Harvard Medical School)

  • Lincoln D. Stein

    (Ontario Institute for Cancer Research
    Ontario Institute for Cancer Research)

  • Joshua M. Stuart

    (University of California at Santa Cruz)

  • Tatsuhiko Tsunoda

    (RIKEN Center for Integrative Medical Sciences
    Tokyo Medical and Dental University
    The University of Tokyo)

  • David A. Wheeler

    (Baylor College of Medicine)

  • Rory Johnson

    (University of Bern
    University of Bern)

  • Jüri Reimand

    (Ontario Institute for Cancer Research
    University of Toronto)

  • Mark Gerstein

    (Yale University
    Yale University
    Yale University)

  • Ekta Khurana

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Peter J. Campbell

    (Wellcome Trust Sanger Institute
    University of Cambridge)

  • Núria López-Bigas

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra
    Catalan Institution for Research and Advanced Studies (ICREA))

  • Joachim Weischenfeldt

    (University of Copenhagen
    European Molecular Biology Laboratory (EMBL))

  • Rameen Beroukhim

    (The Broad Institute of MIT and Harvard
    Harvard University
    Dana-Farber Cancer Institute)

  • Iñigo Martincorena

    (Wellcome Trust Sanger Institute)

  • Jakob Skou Pedersen

    (Aarhus University Hospital
    Aarhus University)

  • Gad Getz

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School
    Massachusetts General Hospital)

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.

Suggested Citation

  • Esther Rheinbay & Morten Muhlig Nielsen & Federico Abascal & Jeremiah A. Wala & Ofer Shapira & Grace Tiao & Henrik Hornshøj & Julian M. Hess & Randi Istrup Juul & Ziao Lin & Lars Feuerbach & Radhakris, 2020. "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes," Nature, Nature, vol. 578(7793), pages 102-111, February.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7793:d:10.1038_s41586-020-1965-x
    DOI: 10.1038/s41586-020-1965-x
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    Cited by:

    1. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Alexander Martinez-Fundichely & Austin Dixon & Ekta Khurana, 2022. "Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Martin Boström & Erik Larsson, 2022. "Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Xiaohan Shi & Yunguang Li & Qiuyue Yuan & Shijie Tang & Shiwei Guo & Yehan Zhang & Juan He & Xiaoyu Zhang & Ming Han & Zhuang Liu & Yiqin Zhu & Suizhi Gao & Huan Wang & Xiongfei Xu & Kailian Zheng & W, 2022. "Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Carter J. Barger & Abigail K. Suwala & Katarzyna M. Soczek & Albert S. Wang & Min Y. Kim & Chibo Hong & Jennifer A. Doudna & Susan M. Chang & Joanna J. Phillips & David A. Solomon & Joseph F. Costello, 2022. "Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Akihiko Fukagawa & Natsuko Hama & Yasushi Totoki & Hiromi Nakamura & Yasuhito Arai & Mihoko Saito-Adachi & Akiko Maeshima & Yoshiyuki Matsui & Shinichi Yachida & Tetsuo Ushiku & Tatsuhiro Shibata, 2023. "Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Theodore Sakellaropoulos & Catherine Do & Guimei Jiang & Giulia Cova & Peter Meyn & Dacia Dimartino & Sitharam Ramaswami & Adriana Heguy & Aristotelis Tsirigos & Jane A. Skok, 2024. "MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Sebastian Carrasco Pro & Heather Hook & David Bray & Daniel Berenzy & Devlin Moyer & Meimei Yin & Adam Thomas Labadorf & Ryan Tewhey & Trevor Siggers & Juan Ignacio Fuxman Bass, 2023. "Widespread perturbation of ETS factor binding sites in cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Roberta Esposito & Andrés Lanzós & Tina Uroda & Sunandini Ramnarayanan & Isabel Büchi & Taisia Polidori & Hugo Guillen-Ramirez & Ante Mihaljevic & Bernard Mefi Merlin & Lia Mela & Eugenio Zoni & Lusin, 2023. "Tumour mutations in long noncoding RNAs enhance cell fitness," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    11. Kathiresan Selvam & Smitha Sivapragasam & Gregory M. K. Poon & John J. Wyrick, 2023. "Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    12. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    13. Ting Fu & Kofi Amoah & Tracey W. Chan & Jae Hoon Bahn & Jae-Hyung Lee & Sari Terrazas & Rockie Chong & Sriram Kosuri & Xinshu Xiao, 2024. "Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    14. Christos Miliotis & Yuling Ma & Xanthi-Lida Katopodi & Dimitra Karagkouni & Eleni Kanata & Kaia Mattioli & Nikolas Kalavros & Yered H. Pita-Juárez & Felipe Batalini & Varune R. Ramnarine & Shivani Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    15. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    16. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    17. Richard Culliford & Samuel E. D. Lawrence & Charlie Mills & Zayd Tippu & Daniel Chubb & Alex J. Cornish & Lisa Browning & Ben Kinnersley & Robert Bentham & Amit Sud & Husayn Pallikonda & Anna Frangou , 2024. "Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    18. Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024. "3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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