Dataset Information

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 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.

SUBMITTER: Rheinbay E

PROVIDER: S-EPMC7054214 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Rheinbay Esther E Nielsen Morten Muhlig MM Abascal Federico F Wala Jeremiah A JA Shapira Ofer O Tiao Grace G Hornshøj Henrik H Hess Julian M JM Juul Randi Istrup RI Lin Ziao Z Feuerbach Lars L Sabarinathan Radhakrishnan R Madsen Tobias T Kim Jaegil J Mularoni Loris L Shuai Shimin S Lanzós Andrés A Herrmann Carl C Maruvka Yosef E YE Shen Ciyue C Amin Samirkumar B SB Bandopadhayay Pratiti P Bertl Johanna J Boroevich Keith A KA Busanovich John J Carlevaro-Fita Joana J Chakravarty Dimple D Chan Calvin Wing Yiu CWY Craft David D Dhingra Priyanka P Diamanti Klev K Fonseca Nuno A NA Gonzalez-Perez Abel A Guo Qianyun Q Hamilton Mark P MP Haradhvala Nicholas J NJ Hong Chen C Isaev Keren K Johnson Todd A TA Juul Malene M Kahles Andre A Kahraman Abdullah A Kim Youngwook Y Komorowski Jan J Kumar Kiran K Kumar Sushant S Lee Donghoon D Lehmann Kjong-Van KV Li Yilong Y Liu Eric Minwei EM Lochovsky Lucas L Park Keunchil K Pich Oriol O Roberts Nicola D ND Saksena Gordon G Schumacher Steven E SE Sidiropoulos Nikos N Sieverling Lina L Sinnott-Armstrong Nasa N Stewart Chip C Tamborero David D Tubio Jose M C JMC Umer Husen M HM Uusküla-Reimand Liis L Wadelius Claes C Wadi Lina L Yao Xiaotong X Zhang Cheng-Zhong CZ Zhang Jing J Haber James E JE Hobolth Asger A Imielinski Marcin M Kellis Manolis M Lawrence Michael S MS von Mering Christian C Nakagawa Hidewaki H Raphael Benjamin J BJ Rubin Mark A MA Sander Chris C Stein Lincoln D LD Stuart Joshua M JM Tsunoda Tatsuhiko T Wheeler David A DA Johnson Rory R Reimand Jüri J Gerstein Mark M Khurana Ekta E Campbell Peter J PJ López-Bigas Núria N Weischenfeldt Joachim J Beroukhim Rameen R Martincorena Iñigo I Pedersen Jakob Skou JS Getz Gad G

Nature 20200205 7793

The discovery of drivers of cancer has traditionally focused on protein-coding genes<sup>1-4</sup>. 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) Consortium<sup>5</sup> 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 ...[more]

PMID: 32025015

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Project description:Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (≥30%). These mutations are located close to the GPR126 and PLEKHS1 genes, at the guanine or the cytosine of a TGAACA core motif flanked, on both sides, by a stretch of palindromic sequences. Here, we hypothesize that such a pattern of recurrent non-coding mutations could be a signature of somatic genomic instability specifically involved in bladder cancer. We analyzed 26 additional mutable non-coding sites with the same core motif in a cohort of 103 bladder cancers composed of 44 NMIBC cases and 59 MIBC cases using high-resolution melting (HRM) and Sanger sequencing. Five bladder cancers were additionally analyzed for protein-coding gene mutations using a targeted NGS panel composed of 571 genes. Expression levels of three members of the APOBEC3 family genes were assessed using real-time quantitative RT-PCR. Non-coding somatic mutations were observed for at least one TGAACA core motif locus in 62.1% (64/103) of bladder tumor samples. These non-coding mutations co-occurred in the bladder tumors but were absent in prostate tumor, HPV-positive Head and Neck Squamous Cell Carcinoma, and high microsatellite instability (MSI-H) colorectal tumor series. This signature of palindromic non-coding somatic mutations, specific to bladder tumors, was not associated with patients' outcome and was more frequent in females. Interestingly, this signature was associated with high tumor mutational burden (TMB) and high expression levels of APOBEC3B and interferon inducible genes. We identified a new type of somatic genomic instability targeting the TGAACA core motif loci flanked by palindromic sequences in bladder cancer. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients.

Dataset Information

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

Publications

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

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