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15 results on '"Nakagawa, Hidewaki"'

1. Pan-cancer analysis of whole genomes

Author

Campbell, Peter J, Getz, Gad, Korbel, Jan O, Stuart, Joshua M, Jennings, Jennifer L, Stein, Lincoln D, Perry, Marc D, Nahal-Bose, Hardeep K, Ouellette, BF Francis, Li, Constance H, Rheinbay, Esther, Nielsen, G Petur, Sgroi, Dennis C, Wu, Chin-Lee, Faquin, William C, Deshpande, Vikram, Boutros, Paul C, Lazar, Alexander J, Hoadley, Katherine A, Louis, David N, Dursi, L Jonathan, Yung, Christina K, Bailey, Matthew H, Saksena, Gordon, Raine, Keiran M, Buchhalter, Ivo, Kleinheinz, Kortine, Schlesner, Matthias, Zhang, Junjun, Wang, Wenyi, Wheeler, David A, Ding, Li, Simpson, Jared T, O'Connor, Brian D, Yakneen, Sergei, Ellrott, Kyle, Miyoshi, Naoki, Butler, Adam P, Royo, Romina, Shorser, Solomon I, Vazquez, Miguel, Rausch, Tobias, Tiao, Grace, Waszak, Sebastian M, Rodriguez-Martin, Bernardo, Shringarpure, Suyash, Wu, Dai-Ying, Demidov, German M, Delaneau, Olivier, Hayashi, Shuto, Imoto, Seiya, Habermann, Nina, Segre, Ayellet V, Garrison, Erik, Cafferkey, Andy, Alvarez, Eva G, Maria Heredia-Genestar, Jose, Muyas, Francesc, Drechsel, Oliver, Bruzos, Alicia L, Temes, Javier, Zamora, Jorge, Baez-Ortega, Adrian, Kim, Hyung-Lae, Mashl, R Jay, Ye, Kai, DiBiase, Anthony, Huang, Kuan-lin, Letunic, Ivica, McLellan, Michael D, Newhouse, Steven J, Shmaya, Tal, Kumar, Sushant, Wedge, David C, Wright, Mark H, Yellapantula, Venkata D, Gerstein, Mark, Khurana, Ekta, Marques-Bonet, Tomas, Navarro, Arcadi, Bustamante, Carlos D, Siebert, Reiner, Nakagawa, Hidewaki, Easton, Douglas F, Ossowski, Stephan, Tubio, Jose MC, De La Vega, Francisco M, Estivill, Xavier, Yuen, Denis, Mihaiescu, George L, Omberg, Larsson, Ferretti, Vincent, Sabarinathan, Radhakrishnan, Pich, Oriol, Gonzalez-Perez, Abel, Weiner, Amaro Taylor, Fittall, Matthew W, Demeulemeester, Jonas, Tarabichi, Maxime, and Roberts, Nicola D

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Cancer Genomics, Biotechnology, Human Genome, Cancer, Prevention, 2.1 Biological and endogenous factors, Cell Proliferation, Cellular Senescence, Chromothripsis, Cloud Computing, DNA Mutational Analysis, Evolution, Molecular, Female, Genome, Human, Genomics, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Information Dissemination, Male, Mutagenesis, Mutation, Neoplasms, Oncogenes, Promoter Regions, Genetic, RNA Splicing, Reproducibility of Results, Telomerase, Telomere, ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, General Science & Technology
Abstract

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.

Published
2020

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

Author

Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A, Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M, Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzós, Andrés, Herrmann, Carl, Maruvka, Yosef E, Shen, Ciyue, Amin, Samirkumar B, Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Craft, David, Dhingra, Priyanka, Diamanti, Klev, Fonseca, Nuno A, Gonzalez-Perez, Abel, Guo, Qianyun, Hamilton, Mark P, Haradhvala, Nicholas J, Hong, Chen, Isaev, Keren, Johnson, Todd A, Juul, Malene, Kahles, Andre, Kahraman, Abdullah, Kim, Youngwook, Komorowski, Jan, Kumar, Kiran, Kumar, Sushant, Lee, Donghoon, Lehmann, Kjong-Van, Li, Yilong, Liu, Eric Minwei, Lochovsky, Lucas, Park, Keunchil, Pich, Oriol, Roberts, Nicola D, Saksena, Gordon, Schumacher, Steven E, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stewart, Chip, Tamborero, David, Tubio, Jose MC, Umer, Husen M, Uusküla-Reimand, Liis, Wadelius, Claes, Wadi, Lina, Yao, Xiaotong, Zhang, Cheng-Zhong, Zhang, Jing, Haber, James E, Hobolth, Asger, Imielinski, Marcin, Kellis, Manolis, Lawrence, Michael S, von Mering, Christian, Nakagawa, Hidewaki, Raphael, Benjamin J, Rubin, Mark A, Sander, Chris, Stein, Lincoln D, Stuart, Joshua M, Tsunoda, Tatsuhiko, Wheeler, David A, Johnson, Rory, Reimand, Jüri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J, López-Bigas, Núria, PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Iñigo, Pedersen, Jakob Skou, Getz, Gad, and PCAWG Consortium

Subjects
PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, Humans, Neoplasms, Gene Expression Regulation, Neoplastic, Mutation, Genome, Human, Databases, Genetic, DNA Breaks, INDEL Mutation, Genome-Wide Association Study, Gene Expression Regulation, Neoplastic, Genome, Human, Databases, Genetic, General Science & Technology
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.

Published
2020

3. High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.

Author

Zhang, Yiqun, Chen, Fengju, Fonseca, Nuno A, He, Yao, Fujita, Masashi, Nakagawa, Hidewaki, Zhang, Zemin, Brazma, Alvis, PCAWG Transcriptome Working Group, PCAWG Structural Variation Working Group, Creighton, Chad J, and PCAWG Consortium

Subjects
PCAWG Transcriptome Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, Humans, Neoplasms, DNA Methylation, Gene Expression Regulation, Neoplastic, Regulatory Sequences, Nucleic Acid, Genes, Tumor Suppressor, Oncogenes, Databases, Genetic, Enhancer Elements, Genetic, Genomic Structural Variation, Whole Genome Sequencing, Gene Expression Regulation, Neoplastic, Regulatory Sequences, Nucleic Acid, Genes, Tumor Suppressor, Databases, Genetic, Enhancer Elements
Abstract

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.

Published
2020

4. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

Author

Alioto, Tyler S, Buchhalter, Ivo, Derdak, Sophia, Hutter, Barbara, Eldridge, Matthew D, Hovig, Eivind, Heisler, Lawrence E, Beck, Timothy A, Simpson, Jared T, Tonon, Laurie, Sertier, Anne-Sophie, Patch, Ann-Marie, Jäger, Natalie, Ginsbach, Philip, Drews, Ruben, Paramasivam, Nagarajan, Kabbe, Rolf, Chotewutmontri, Sasithorn, Diessl, Nicolle, Previti, Christopher, Schmidt, Sabine, Brors, Benedikt, Feuerbach, Lars, Heinold, Michael, Gröbner, Susanne, Korshunov, Andrey, Tarpey, Patrick S, Butler, Adam P, Hinton, Jonathan, Jones, David, Menzies, Andrew, Raine, Keiran, Shepherd, Rebecca, Stebbings, Lucy, Teague, Jon W, Ribeca, Paolo, Giner, Francesc Castro, Beltran, Sergi, Raineri, Emanuele, Dabad, Marc, Heath, Simon C, Gut, Marta, Denroche, Robert E, Harding, Nicholas J, Yamaguchi, Takafumi N, Fujimoto, Akihiro, Nakagawa, Hidewaki, Quesada, Víctor, Valdés-Mas, Rafael, Nakken, Sigve, Vodák, Daniel, Bower, Lawrence, Lynch, Andrew G, Anderson, Charlotte L, Waddell, Nicola, Pearson, John V, Grimmond, Sean M, Peto, Myron, Spellman, Paul, He, Minghui, Kandoth, Cyriac, Lee, Semin, Zhang, John, Létourneau, Louis, Ma, Singer, Seth, Sahil, Torrents, David, Xi, Liu, Wheeler, David A, López-Otín, Carlos, Campo, Elías, Campbell, Peter J, Boutros, Paul C, Puente, Xose S, Gerhard, Daniela S, Pfister, Stefan M, McPherson, John D, Hudson, Thomas J, Schlesner, Matthias, Lichter, Peter, Eils, Roland, Jones, David TW, and Gut, Ivo G

Subjects
Humans, Medulloblastoma, Mutation, Genome, Human, Leukemia, Lymphoid, High-Throughput Nucleotide Sequencing, Genome, Human, Leukemia, Lymphoid
Abstract

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

Published
2015

5. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Author

Han, Ying, Hazelett, Dennis J, Wiklund, Fredrik, Schumacher, Fredrick R, Stram, Daniel O, Berndt, Sonja I, Wang, Zhaoming, Rand, Kristin A, Hoover, Robert N, Machiela, Mitchell J, Yeager, Merideth, Burdette, Laurie, Chung, Charles C, Hutchinson, Amy, Yu, Kai, Xu, Jianfeng, Travis, Ruth C, Key, Timothy J, Siddiq, Afshan, Canzian, Federico, Takahashi, Atsushi, Kubo, Michiaki, Stanford, Janet L, Kolb, Suzanne, Gapstur, Susan M, Diver, W Ryan, Stevens, Victoria L, Strom, Sara S, Pettaway, Curtis A, Olama, Ali Amin Al, Kote-Jarai, Zsofia, Eeles, Rosalind A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, Isaacs, William B, Chen, Constance, Lindstrom, Sara, Le Marchand, Loic, Giovannucci, Edward L, Pomerantz, Mark, Long, Henry, Li, Fugen, Ma, Jing, Stampfer, Meir, John, Esther M, Ingles, Sue A, Kittles, Rick A, Murphy, Adam B, Blot, William J, Signorello, Lisa B, Zheng, Wei, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Nemesure, Barbara, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anselm JM, Rybicki, Benjamin A, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Zheng, S Lilly, Witte, John S, Casey, Graham, Riboli, Elio, Li, Qiyuan, Freedman, Matthew L, Hunter, David J, Gronberg, Henrik, Cook, Michael B, Nakagawa, Hidewaki, Kraft, Peter, Chanock, Stephen J, Easton, Douglas F, Henderson, Brian E, Coetzee, Gerhard A, Conti, David V, and Haiman, Christopher A

Subjects
Cancer, Human Genome, Biotechnology, Genetics, Urologic Diseases, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Asian People, Black People, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, Linkage Disequilibrium, Male, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Published
2015

6. International network of cancer genome projects

Author

Hudson (Chairperson), Thomas J, Anderson, Warwick, Aretz, Axel, Barker, Anna D, Bell, Cindy, Bernabé, Rosa R, Bhan, MK, Calvo, Fabien, Eerola, Iiro, Gerhard, Daniela S, Guttmacher, Alan, Guyer, Mark, Hemsley, Fiona M, Jennings, Jennifer L, Kerr, David, Klatt, Peter, Kolar, Patrik, Kusuda, Jun, Lane, David P, Laplace, Frank, Lu, Youyong, Nettekoven, Gerd, Ozenberger, Brad, Peterson, Jane, Rao, TS, Remacle, Jacques, Schafer, Alan J, Shibata, Tatsuhiro, Stratton, Michael R, Vockley, Joseph G, Watanabe, Koichi, Yang, Huanming, Yuen, Matthew MF, Knoppers (Leader), Bartha M, Bobrow, Martin, Cambon-Thomsen, Anne, Dressler, Lynn G, Dyke, Stephanie OM, Joly, Yann, Kato, Kazuto, Kennedy, Karen L, Nicolás, Pilar, Parker, Michael J, Rial-Sebbag, Emmanuelle, Romeo-Casabona, Carlos M, Shaw, Kenna M, Wallace, Susan, Wiesner, Georgia L, Zeps, Nikolajs, Lichter (Leader), Peter, Biankin, Andrew V, Chabannon, Christian, Chin, Lynda, Clément, Bruno, de Alava, Enrique, Degos, Françoise, Ferguson, Martin L, Geary, Peter, Hayes, D Neil, Hudson, Thomas J, Johns, Amber L, Kasprzyk, Arek, Nakagawa, Hidewaki, Penny, Robert, Piris, Miguel A, Sarin, Rajiv, Scarpa, Aldo, van de Vijver, Marc, Futreal (Leader), P Andrew, Aburatani, Hiroyuki, Bayés, Mónica, Bowtell, David DL, Campbell, Peter J, Estivill, Xavier, Grimmond, Sean M, Gut, Ivo, Hirst, Martin, López-Otín, Carlos, Majumder, Partha, Marra, Marco, McPherson, John D, Ning, Zemin, Puente, Xose S, Ruan, Yijun, Stunnenberg, Hendrik G, Swerdlow, Harold, Velculescu, Victor E, Wilson, Richard K, Xue, Hong H, Yang, Liu, Spellman (Leader), Paul T, Bader, Gary D, Boutros, Paul C, and Flicek, Paul

Subjects
Cancer, Genetics, Human Genome, DNA Methylation, DNA Mutational Analysis, Databases, Genetic, Genes, Neoplasm, Genetics, Medical, Genome, Human, Genomics, Humans, Intellectual Property, International Cooperation, Mutation, Neoplasms, International Cancer Genome Consortium, General Science & Technology
Abstract

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Published
2010

7. International network of cancer genome projects.

Author

International Cancer Genome Consortium, Hudson, Thomas J, Anderson, Warwick, Artez, Axel, Barker, Anna D, Bell, Cindy, Bernabé, Rosa R, Bhan, MK, Calvo, Fabien, Eerola, Iiro, Gerhard, Daniela S, Guttmacher, Alan, Guyer, Mark, Hemsley, Fiona M, Jennings, Jennifer L, Kerr, David, Klatt, Peter, Kolar, Patrik, Kusada, Jun, Lane, David P, Laplace, Frank, Youyong, Lu, Nettekoven, Gerd, Ozenberger, Brad, Peterson, Jane, Rao, TS, Remacle, Jacques, Schafer, Alan J, Shibata, Tatsuhiro, Stratton, Michael R, Vockley, Joseph G, Watanabe, Koichi, Yang, Huanming, Yuen, Matthew MF, Knoppers, Bartha M, Bobrow, Martin, Cambon-Thomsen, Anne, Dressler, Lynn G, Dyke, Stephanie OM, Joly, Yann, Kato, Kazuto, Kennedy, Karen L, Nicolás, Pilar, Parker, Michael J, Rial-Sebbag, Emmanuelle, Romeo-Casabona, Carlos M, Shaw, Kenna M, Wallace, Susan, Wiesner, Georgia L, Zeps, Nikolajs, Lichter, Peter, Biankin, Andrew V, Chabannon, Christian, Chin, Lynda, Clément, Bruno, de Alava, Enrique, Degos, Françoise, Ferguson, Martin L, Geary, Peter, Hayes, D Neil, Johns, Amber L, Kasprzyk, Arek, Nakagawa, Hidewaki, Penny, Robert, Piris, Miguel A, Sarin, Rajiv, Scarpa, Aldo, van de Vijver, Marc, Futreal, P Andrew, Aburatani, Hiroyuki, Bayés, Mónica, Botwell, David DL, Campbell, Peter J, Estivill, Xavier, Grimmond, Sean M, Gut, Ivo, Hirst, Martin, López-Otín, Carlos, Majumder, Partha, Marra, Marco, McPherson, John D, Ning, Zemin, Puente, Xose S, Ruan, Yijun, Stunnenberg, Hendrik G, Swerdlow, Harold, Velculescu, Victor E, Wilson, Richard K, Xue, Hong H, Yang, Liu, Spellman, Paul T, Bader, Gary D, and Boutros, Paul C

Subjects
International Cancer Genome Consortium, Humans, Neoplasms, DNA Mutational Analysis, Genetics, Medical, Genomics, DNA Methylation, Mutation, Genome, Human, International Cooperation, Intellectual Property, Databases, Genetic, Genes, Neoplasm, Genetics, Medical, Genome, Human, Databases, Genetic, Genes, Neoplasm, General Science & Technology
Abstract

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Published
2010

8. Comprehensive molecular characterization of mitochondrial genomes in human cancers

Author

Yuan, Yuan, Ju, Young Seok, Kim, Youngwook, Li, Jun, Wang, Yumeng, Yoon, Christopher J, Yang, Yang, Martincorena, Inigo, Creighton, Chad J, Weinstein, John N, Xu, Yanxun, Han, Leng, Kim, Hyung-Lae, Nakagawa, Hidewaki, Park, Keunchil, Campbell, Peter J, Liang, Han, PCAWG Consortium, Yuan, Yuan [0000-0003-4706-7897], Ju, Young Seok [0000-0002-5514-4189], Kim, Youngwook [0000-0002-1106-3037], Li, Jun [0000-0002-1171-7141], Creighton, Chad J [0000-0002-6090-703X], Weinstein, John N [0000-0001-9401-6908], Han, Leng [0000-0002-7380-2640], Park, Keunchil [0000-0002-4846-7449], Campbell, Peter J [0000-0002-3921-0510], Liang, Han [0000-0001-7633-286X], and Apollo - University of Cambridge Repository

Subjects
DNA Copy Number Variations, DNA Repair, Whole Genome Sequencing, Genome, Human, Sequence Analysis, RNA, Neoplasms, Cell Cycle, Genome, Mitochondrial, Mutation, Humans, DNA, Mitochondrial, Oxidative Phosphorylation
Abstract

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

Published
2020

9. Butler enables rapid cloud-based analysis of thousands of human genomes

Author

Yakneen, Sergei, Waszak, Sebastian M, Gertz, Michael, Korbel, Jan O, Aminou, Brice, Bartolome, Javier, Boroevich, Keith A, Boyce, Rich, Brooks, Angela N, Buchanan, Alex, Buchhalter, Ivo, Butler, Adam P, Byrne, Niall J, Cafferkey, Andy, Campbell, Peter J, Chen, Zhaohong, Cho, Sunghoon, Choi, Wan, Clapham, Peter, Davis-Dusenbery, Brandi N, De La Vega, Francisco M, Demeulemeester, Jonas, Dow, Michelle T, Dursi, Lewis Jonathan, Eils, Juergen, Eils, Roland, Ellrott, Kyle, Farcas, Claudiu, Favero, Francesco, Fayzullaev, Nodirjon, Ferretti, Vincent, Flicek, Paul, Fonseca, Nuno A, Gelpi, Josep Ll, Getz, Gad, Gibson, Bob, Grossman, Robert L, Harismendy, Olivier, Heath, Allison P, Heinold, Michael C, Hess, Julian M, Hofmann, Oliver, Hong, Jongwhi H, Hudson, Thomas J, Hutter, Barbara, Hutter, Carolyn M, Huebschmann, Daniel, Imoto, Seiya, Ivkovic, Sinisa, Jeon, Seung-Hyup, Jiao, Wei, Jung, Jongsun, Kabbe, Rolf, Kahles, Andre, Kerssemakers, Jules NA, Kim, Hyung-Lae, Kim, Hyunghwan, Kim, Jihoon, Kim, Youngwook, Kleinheinz, Kortine, Koscher, Michael, Koures, Antonios, Kovacevic, Milena, Lawerenz, Chris, Leshchiner, Ignaty, Liu, Jia, Livitz, Dimitri, Mihaiescu, George L, Mijalkovic, Sanja, Lazic, Ana Mijalkovic, Miyano, Satoru, Miyoshi, Naoki, Nahal-Bose, Hardeep K, Nakagawa, Hidewaki, Nastic, Mia, Newhouse, Steven J, Nicholson, Jonathan, O'Connor, Brian D, Ocana, David, Ohi, Kazuhiro, Ohno-Machado, Lucila, Omberg, Larsson, Ouellette, BF Francis, Paramasivam, Nagarajan, Perry, Marc D, Pihl, Todd D, Prinz, Manuel, Puiggros, Montserrat, Radovic, Petar, Raine, Keiran M, Rheinbay, Esther, Rosenberg, Mara, Royo, Romina, Raetsch, Gunnar, Saksena, Gordon, Schlesner, Matthias, Shorser, Solomon, Short, Charles, Sofia, Heidi J, Spring, Jonathan, Stein, Lincoln D, Struck, Adam J, Tiao, Grace, Tijanic, Nebojsa, Torrents, David, Van Loo, Peter, Vazquez, Miguel, Vicente, David, Wala, Jeremiah A, Wang, Zhining, Weischenfeldt, Joachim, Werner, Johannes, Williams, Ashley, Woo, Youngchoon, Wright, Adam J, Xiang, Qian, Yang, Liming, Yuen, Denis, Yung, Christina K, Zhang, Junjun, Graduate School, Laboratory Genetic Metabolic Diseases, AGEM - Endocrinology, metabolism and nutrition, and AGEM - Inborn errors of metabolism

Subjects
Computer science, Biomedical Engineering, Bioengineering, Cloud computing, computer.software_genre, Brief Communication, Genome informatics, Genoma humà, Applied Microbiology and Biotechnology, Genome, Biologia computacional, Computational biology, 03 medical and health sciences, 0302 clinical medicine, Software, Computational platforms and environments, Cancer genome, Neoplasms, Humans, Hardware and infrastructure, ddc:610, 030304 developmental biology, VARIANT DISCOVERY, 0303 health sciences, Data processing, Science & Technology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Human genome, business.industry, Genome, Human, Computational Biology, Cloud Computing, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Biotechnology & Applied Microbiology, Molecular Medicine, Anomaly detection, Data mining, business, computer, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Biotechnology
Abstract

Cloud computing offers easy and economical access to computational capacity at a scale that had previously been available to only the largest research institutions. To take advantage, large biological datasets are increasingly analyzed on various cloud computing platforms, using public, private and hybrid clouds1 with the aid of workflow systems. When employed in global projects, such systems must be flexible in their ability to operate in different environments, including academic clouds, to allow researchers to bring their computational pipelines to the data, especially in cases where the raw data themselves cannot be moved. The recently developed cloud-based scientific workflow frameworks Nextflow2, Toil3 and GenomeVIP4 focus their support largely on individual commercial cloud computing environments—mostly Amazon Web Services—and lack complete functionality for other major providers. This limits their use in studies that require multi-cloud operation due to practical and regulatory requirements5,6. Butler, in contrast, provides full support for operation on OpenStack-based commercial and academic clouds, Amazon Web Services, Microsoft Azure and Google Compute Platform, and can thus enable international collaborations involving the analysis of hundreds of thousands of samples where distributed cloud-based computation is pursued in different jurisdictions5,6,7., Nature Biotechnology, 38 (3), ISSN:1546-1696, ISSN:1087-0156

Published
2020

10. Author Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers

Author

Yuan, Yuan, Ju, Young Seok, Kim, Youngwook, Li, Jun, Wang, Yumeng, Yoon, Christopher J., Yang, Yang, Martincorena, Inigo, Creighton, Chad J., Weinstein, John N., Xu, Yanxun, Han, Leng, Kim, Hyung-Lae, Nakagawa, Hidewaki, Park, Keunchil, Campbell, Peter J., and Liang, Han

Subjects
DNA Copy Number Variations, DNA Repair, Whole Genome Sequencing, Genome, Human, Sequence Analysis, RNA, Cell Cycle, DNA, Mitochondrial, Oxidative Phosphorylation, Neoplasms, Genome, Mitochondrial, Mutation, Genetics, Humans, Author Correction
Abstract

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

Published
2020

11. miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

Author

Van Renne, Nicolaas, Roca Suarez, Armando Andres, Duong, Francois H T, Gondeau, Claire, Calabrese, Diego, Fontaine, Nelly, Ababsa, Amina, Bandiera, Simonetta, Croonenborghs, Tom, Pochet, Nathalie, De Blasi, Vito, Pessaux, Patrick, Piardi, Tullio, Sommacale, Daniele, Ono, Atsushi, Chayama, Kazuaki, Fujita, Masashi, Nakagawa, Hidewaki, Hoshida, Yujin, Zeisel, Mirjam B, Heim, Markus H, Baumert, Thomas F, Lupberger, Joachim, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Basel [Basel], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Université de Reims Champagne-Ardenne (URCA), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Hiroshima University, RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Interaction virus-hôte et maladies du foie, Philips, Alexandre, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Adult, Male, STAT3 Transcription Factor, Carcinoma, Hepatocellular, Carcinogenesis, [SDV]Life Sciences [q-bio], Blotting, Western, Aucun, Down-Regulation, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Humans, HEPATOCELLULAR CARCINOMA, RNA, Messenger, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Aged, Aged, 80 and over, Hepatology, Liver Neoplasms, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Middle Aged, Hepatitis C, digestive system diseases, [SDV] Life Sciences [q-bio], MicroRNAs, Liver, SIGNALING, HCV, Hepatocytes, Female, Signal Transduction
Abstract

BACKGROUND AND AIMS: HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. METHODS: We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. RESULTS: We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. CONCLUSIONS: We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD-STAT3 axis potentially driving malignant progression of HCV-associated liver disease.

Published
2018

12. High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

Author

Zhang, Yiqun, Chen, Fengju, Fonseca, Nuno A., He, Yao, Fujita, Masashi, Nakagawa, Hidewaki, Zhang, Zemin, Brazma, Alvis, Amin, Samirkumar B., Awadalla, Philip, Bailey, Peter J., Brooks, Angela N., Calabrese, Claudia, Chateigner, Aurélien, Cortés-Ciriano, Isidro, Craft, Brian, Craft, David, Creighton, Chad J., Davidson, Natalie R., Demircioğlu, Deniz, Erkek, Serap, Frenkel-Morgenstern, Milana, Goldman, Mary J., Greger, Liliana, Göke, Jonathan, Hoadley, Katherine A., Hou, Yong, Huska, Matthew R., Kahles, Andre, Khurana, Ekta, Kilpinen, Helena, Korbel, Jan O., Lamaze, Fabien C., Lehmann, Kjong Van, Li, Chang, Li, Siliang, Li, Xiaobo, Li, Xinyue, Liu, Dongbing, Liu, Fenglin, Liu, Xingmin, Nielsen, Morten Muhlig, Pedersen, Jakob Skou, Wu, Kui, Zhu, Shida, Sidiropoulos, Nikos, Weischenfeldt, Joachim, University of St Andrews. School of Medicine, University of St Andrews. Statistics, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, Fonseca, Nuno A [0000-0003-4832-578X], Fujita, Masashi [0000-0002-1457-6233], Brazma, Alvis [0000-0001-5988-7409], Creighton, Chad J [0000-0002-6090-703X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Chemistry(all), Medizin, General Physics and Astronomy, Regulatory Sequences, Nucleic Acid, Genome, 0302 clinical medicine, Ecology,Evolution & Ethology, Neoplasms, Databases, Genetic, Cancer genomics, 2.1 Biological and endogenous factors, Genes, Tumor Suppressor, Aetiology, lcsh:Science, Càncer, Cancer, Regulation of gene expression, Genetics, Human Biology & Physiology, Multidisciplinary, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], 3rd-DAS, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, Regulatory sequence, 030220 oncology & carcinogenesis, DNA methylation, PCAWG Structural Variation Working Group, Genetics & Genomics, Tumor Suppressor, Biotechnology, PCAWG Transcriptome Working Group, Enhancer Elements, Science, Repressor, QH426 Genetics, Biology, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, RC0254, 03 medical and health sciences, Databases, Rare Diseases, Genetic, SDG 3 - Good Health and Well-being, Humans, Enhancer, Gene, QH426, Computational & Systems Biology, Neoplastic, Nucleic Acid, Whole Genome Sequencing, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Biochemistry, Genetics and Molecular Biology(all), Human Genome, Breakpoint, PCAWG Consortium, General Chemistry, Oncogenes, Tumour Biology, DNA Methylation, Genòmica, 030104 developmental biology, Gene Expression Regulation, Genes, Genomic Structural Variation, lcsh:Q, Gene expression, Digestive Diseases, Regulatory Sequences, Genètica
Abstract

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements., In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Published
2017

13. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V, Darst, Burcu F, Moss, Lilit C, Saunders, Edward J, Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R, Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N, Sahimi, Ali, Hoffmann, Thomas J, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bojesen, Stig E, Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M, Ghoussaini, Maya, Travis, Ruth C, Key, Tim J, Riboli, Elio, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J, Mucci, Lorelei A, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J, Penney, Kathryn L, Turman, Constance, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L, Ostrander, Elaine A, Geybels, Milan S, Koutros, Stella, Freeman, Laura E Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L, Hoover, Robert N, Machiela, Mitchell J, Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J, Zheng, Wei, Yeboah, Edward D, Mensah, James E, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, West, Catharine ML, Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M, Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A, Stern, Mariana C, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Teixeira, Manuel R, Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T, Fontham, Elizabeth TH, Mohler, James, Taylor, Jack A, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C, Huff, Chad D, Strom, Sara S, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J, Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A, Hsing, Ann W, Kittles, Rick A, Murphy, Adam B, Logothetis, Christopher J, Kim, Jeri, Neuhausen, Susan L, Steele, Linda, Ding, Yuan Chun, Isaacs, William B, Nemesure, Barbara, Hennis, Anselm JM, Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F, Lin, Daniel W, Fowke, Jay H, Neslund-Dudas, Christine, Rybicki, Benjamin A, Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van Den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A, Aukim-Hastie, Claire, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Srivastava, Shiv, Cullen, Jennifer C, Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J, Jenster, Guido, Van Schaik, Ron HN, Hu, Jennifer J, Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I, Van Den Eeden, Stephen K, Easton, Douglas F, Chanock, Stephen J, Cook, Michael B, Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S, Eeles, Rosalind A, Kote-Jarai, Zsofia, and Haiman, Christopher A

Subjects
Male, Genetic Loci, Risk Factors, Racial Groups, Odds Ratio, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Molecular Sequence Annotation, Neoplasm Invasiveness, Middle Aged, 3. Good health, Genome-Wide Association Study
Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

14. Comprehensive molecular characterization of mitochondrial genomes in human cancers

Author

Yuan, Yuan, Ju, Young Seok, Kim, Youngwook, Li, Jun, Wang, Yumeng, Yoon, Christopher J, Yang, Yang, Martincorena, Inigo, Creighton, Chad J, Weinstein, John N, Xu, Yanxun, Han, Leng, Kim, Hyung-Lae, Nakagawa, Hidewaki, Park, Keunchil, Campbell, Peter J, Liang, Han, and PCAWG Consortium

Subjects
DNA Copy Number Variations, DNA Repair, Whole Genome Sequencing, Genome, Human, Sequence Analysis, RNA, Neoplasms, Cell Cycle, Genome, Mitochondrial, Mutation, Humans, DNA, Mitochondrial, Oxidative Phosphorylation, 3. Good health
Abstract

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

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

Author

Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A, Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M, Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzós, Andrés, Herrmann, Carl, Maruvka, Yosef E, Shen, Ciyue, Amin, Samirkumar B, Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Craft, David, Dhingra, Priyanka, Diamanti, Klev, Fonseca, Nuno A, Gonzalez-Perez, Abel, Guo, Qianyun, Hamilton, Mark P, Haradhvala, Nicholas J, Hong, Chen, Isaev, Keren, Johnson, Todd A, Juul, Malene, Kahles, Andre, Kahraman, Abdullah, Kim, Youngwook, Komorowski, Jan, Kumar, Kiran, Kumar, Sushant, Lee, Donghoon, Lehmann, Kjong-Van, Li, Yilong, Liu, Eric Minwei, Lochovsky, Lucas, Park, Keunchil, Pich, Oriol, Roberts, Nicola D, Saksena, Gordon, Schumacher, Steven E, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stewart, Chip, Tamborero, David, Tubio, Jose MC, Umer, Husen M, Uusküla-Reimand, Liis, Wadelius, Claes, Wadi, Lina, Yao, Xiaotong, Zhang, Cheng-Zhong, Zhang, Jing, Haber, James E, Hobolth, Asger, Imielinski, Marcin, Kellis, Manolis, Lawrence, Michael S, Von Mering, Christian, Nakagawa, Hidewaki, Raphael, Benjamin J, Rubin, Mark A, Sander, Chris, Stein, Lincoln D, Stuart, Joshua M, Tsunoda, Tatsuhiko, Wheeler, David A, Johnson, Rory, Reimand, Jüri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J, López-Bigas, Núria, PCAWG Drivers And Functional Interpretation Working Group, PCAWG Structural Variation Working Group, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Iñigo, Pedersen, Jakob Skou, Getz, Gad, and PCAWG Consortium

Subjects
Gene Expression Regulation, Neoplastic, INDEL Mutation, Genome, Human, Neoplasms, DNA Breaks, Databases, Genetic, Mutation, Humans, 3. Good health, Genome-Wide Association Study
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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