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

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; Radhakrishnan Sabarinathan; Tobias Madsen; Jaegil Kim; Loris Mularoni; Shimin Shuai; Andrés Lanzós; Carl Herrmann; Yosef E. Maruvka; Ciyue Shen; Samirkumar B. Amin; Pratiti Bandopadhayay; Johanna Bertl; Keith A. Boroevich; John Busanovich; Joana Carlevaro-Fita; Dimple Chakravarty; Calvin Wing Yiu Chan; David Craft; Priyanka Dhingra; Klev Diamanti; Nuno A. Fonseca; Abel Gonzalez-Perez; Qianyun Guo; Mark P. Hamilton; Nicholas J. Haradhvala; Chen Hong; Cheng Zhong Zhang; Asger Hobolth; Jakob Skou Pedersen; PCAWG Consortium

doi:10.1038/s41586-020-1965-x

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

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, Radhakrishnan Sabarinathan, Tobias Madsen, Jaegil Kim, Loris Mularoni, Shimin Shuai, Andrés Lanzós, Carl Herrmann, Yosef E. Maruvka, Ciyue ShenSamirkumar B. Amin, Pratiti Bandopadhayay, Johanna Bertl, Keith A. Boroevich, John Busanovich, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu Chan, David Craft, Priyanka Dhingra, Klev Diamanti, Nuno A. Fonseca, Abel Gonzalez-Perez, Qianyun Guo, Mark P. Hamilton, Nicholas J. Haradhvala, Chen Hong, Cheng Zhong Zhang, Asger Hobolth, Jakob Skou Pedersen, PCAWG Consortium

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Abstract

The discovery of drivers of cancer has traditionally focused on protein-coding genes^1–4. 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 drivers^6,7, 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.

Original language	English
Journal	Nature
Volume	578
Issue	7793
Pages (from-to)	102-111
Number of pages	10
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-020-1965-x
Publication status	Published - Feb 2020

Keywords

ANNOTATION
DISCOVERY
EXPRESSION
GENES
LANDSCAPE
RECURRENT
REGULATORY MUTATIONS
SELECTION
TARGET
TERT PROMOTER MUTATIONS

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Rheinbay, E., Nielsen, M. M., Abascal, F., Wala, J. A., Shapira, O., Tiao, G., Hornshøj, H., Hess, J. M., Juul, R. I., Lin, Z., Feuerbach, L., Sabarinathan, R., Madsen, T., Kim, J., Mularoni, L., Shuai, S., Lanzós, A., Herrmann, C., Maruvka, Y. E., ... PCAWG Consortium (2020). Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature, 578(7793), 102-111. https://doi.org/10.1038/s41586-020-1965-x

@article{8b3918cebf1546dcbd2addf64a39fada,

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

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.",

keywords = "ANNOTATION, DISCOVERY, EXPRESSION, GENES, LANDSCAPE, RECURRENT, REGULATORY MUTATIONS, SELECTION, TARGET, TERT PROMOTER MUTATIONS",

author = "Esther Rheinbay and Nielsen, {Morten Muhlig} and Federico Abascal and Wala, {Jeremiah A.} and Ofer Shapira and Grace Tiao and Henrik Hornsh{\o}j and Hess, {Julian M.} and Juul, {Randi Istrup} and Ziao Lin and Lars Feuerbach and Radhakrishnan Sabarinathan and Tobias Madsen and Jaegil Kim and Loris Mularoni and Shimin Shuai and Andr{\'e}s Lanz{\'o}s and Carl Herrmann and Maruvka, {Yosef E.} and Ciyue Shen and Amin, {Samirkumar B.} and Pratiti Bandopadhayay and Johanna Bertl and Boroevich, {Keith A.} and John Busanovich and Joana Carlevaro-Fita and Dimple Chakravarty and Chan, {Calvin Wing Yiu} and David Craft and Priyanka Dhingra and Klev Diamanti and Fonseca, {Nuno A.} and Abel Gonzalez-Perez and Qianyun Guo and Hamilton, {Mark P.} and Haradhvala, {Nicholas J.} and Chen Hong and Zhang, {Cheng Zhong} and Asger Hobolth and Pedersen, {Jakob Skou} and {PCAWG Consortium}",

year = "2020",

month = feb,

doi = "10.1038/s41586-020-1965-x",

language = "English",

volume = "578",

pages = "102--111",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7793",

}

Rheinbay, E, Nielsen, MM, Abascal, F, Wala, JA, Shapira, O, Tiao, G, Hornshøj, H, Hess, JM, Juul, RI, Lin, Z, Feuerbach, L, Sabarinathan, R, Madsen, T, Kim, J, Mularoni, L, Shuai, S, Lanzós, A, Herrmann, C, Maruvka, YE, Shen, C, Amin, SB, Bandopadhayay, P, Bertl, J, Boroevich, KA, Busanovich, J, Carlevaro-Fita, J, Chakravarty, D, Chan, CWY, Craft, D, Dhingra, P, Diamanti, K, Fonseca, NA, Gonzalez-Perez, A, Guo, Q, Hamilton, MP, Haradhvala, NJ, Hong, C, Zhang, CZ, Hobolth, A , Pedersen, JS & PCAWG Consortium 2020, 'Analyses of non-coding somatic drivers in 2,658 cancer whole genomes', Nature, vol. 578, no. 7793, pp. 102-111. https://doi.org/10.1038/s41586-020-1965-x

TY - JOUR

T1 - Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

AU - Rheinbay, Esther

AU - Nielsen, Morten Muhlig

AU - Abascal, Federico

AU - Wala, Jeremiah A.

AU - Shapira, Ofer

AU - Tiao, Grace

AU - Hornshøj, Henrik

AU - Hess, Julian M.

AU - Juul, Randi Istrup

AU - Lin, Ziao

AU - Feuerbach, Lars

AU - Sabarinathan, Radhakrishnan

AU - Madsen, Tobias

AU - Kim, Jaegil

AU - Mularoni, Loris

AU - Shuai, Shimin

AU - Lanzós, Andrés

AU - Herrmann, Carl

AU - Maruvka, Yosef E.

AU - Shen, Ciyue

AU - Amin, Samirkumar B.

AU - Bandopadhayay, Pratiti

AU - Bertl, Johanna

AU - Boroevich, Keith A.

AU - Busanovich, John

AU - Carlevaro-Fita, Joana

AU - Chakravarty, Dimple

AU - Chan, Calvin Wing Yiu

AU - Craft, David

AU - Dhingra, Priyanka

AU - Diamanti, Klev

AU - Fonseca, Nuno A.

AU - Gonzalez-Perez, Abel

AU - Guo, Qianyun

AU - Hamilton, Mark P.

AU - Haradhvala, Nicholas J.

AU - Hong, Chen

AU - Zhang, Cheng Zhong

AU - Hobolth, Asger

AU - Pedersen, Jakob Skou

AU - PCAWG Consortium

PY - 2020/2

Y1 - 2020/2

N2 - 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.

AB - 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.

KW - ANNOTATION

KW - DISCOVERY

KW - EXPRESSION

KW - GENES

KW - LANDSCAPE

KW - RECURRENT

KW - REGULATORY MUTATIONS

KW - SELECTION

KW - TARGET

KW - TERT PROMOTER MUTATIONS

UR - http://www.scopus.com/inward/record.url?scp=85079047263&partnerID=8YFLogxK

U2 - 10.1038/s41586-020-1965-x

DO - 10.1038/s41586-020-1965-x

M3 - Journal article

C2 - 32025015

AN - SCOPUS:85079047263

SN - 0028-0836

VL - 578

SP - 102

EP - 111

JO - Nature

JF - Nature

IS - 7793

ER -

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

Abstract

Keywords

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Erratum: Author Correction: Analyses of non-coding somatic drivers in 2,658 cancer whole genomes (Nature (2020) 578 7793 (102-111))

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