Anatomy and Neuroscience - Research Publications

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    Isoform Age-Splice Isoform Profiling Using Long-Read Technologies (vol 8, 744, 2021)
    De Paoli-Iseppi, R ; Gleeson, J ; Clark, MB (FRONTIERS MEDIA SA, 2021-09-27)
    [This corrects the article DOI: 10.3389/fmolb.2021.711733.].
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    Transcriptional and epi-transcriptional dynamics of SARS-CoV-2 during cellular infection
    Chang, JJ-Y ; Rawlinson, D ; Pitt, ME ; Taiaroa, G ; Gleeson, J ; Zhou, C ; Mordant, FL ; De Paoli-Iseppi, R ; Caly, L ; Purcell, DFJ ; Stinear, TP ; Londrigan, SL ; Clark, MB ; Williamson, DA ; Subbarao, K ; Coin, LJM (CELL PRESS, 2021-05-11)
    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses subgenomic RNA (sgRNA) to produce viral proteins for replication and immune evasion. We apply long-read RNA and cDNA sequencing to in vitro human and primate infection models to study transcriptional dynamics. Transcription-regulating sequence (TRS)-dependent sgRNA upregulates earlier in infection than TRS-independent sgRNA. An abundant class of TRS-independent sgRNA consisting of a portion of open reading frame 1ab (ORF1ab) containing nsp1 joins to ORF10, and the 3' untranslated region (UTR) upregulates at 48 h post-infection in human cell lines. We identify double-junction sgRNA containing both TRS-dependent and -independent junctions. We find multiple sites at which the SARS-CoV-2 genome is consistently more modified than sgRNA and that sgRNA modifications are stable across transcript clusters, host cells, and time since infection. Our work highlights the dynamic nature of the SARS-CoV-2 transcriptome during its replication cycle.
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    The long and the short of it: unlocking nanopore long-read RNA sequencing data with short-read differential expression analysis tools
    Dong, X ; Tian, L ; Gouil, Q ; Kariyawasam, H ; Su, S ; De Paoli-Iseppi, R ; Prawer, YDJ ; Clark, MB ; Breslin, K ; Iminitoff, M ; Blewitt, ME ; Law, CW ; Ritchie, ME (Oxford University Press, 2021-06-01)
    Application of Oxford Nanopore Technologies' long-read sequencing platform to transcriptomic analysis is increasing in popularity. However, such analysis can be challenging due to the high sequence error and small library sizes, which decreases quantification accuracy and reduces power for statistical testing. Here, we report the analysis of two nanopore RNA-seq datasets with the goal of obtaining gene- and isoform-level differential expression information. A dataset of synthetic, spliced, spike-in RNAs ('sequins') as well as a mouse neural stem cell dataset from samples with a null mutation of the epigenetic regulator Smchd1 was analysed using a mix of long-read specific tools for preprocessing together with established short-read RNA-seq methods for downstream analysis. We used limma-voom to perform differential gene expression analysis, and the novel FLAMES pipeline to perform isoform identification and quantification, followed by DRIMSeq and limma-diffSplice (with stageR) to perform differential transcript usage analysis. We compared results from the sequins dataset to the ground truth, and results of the mouse dataset to a previous short-read study on equivalent samples. Overall, our work shows that transcriptomic analysis of long-read nanopore data using long-read specific preprocessing methods together with short-read differential expression methods and software that are already in wide use can yield meaningful results.
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    Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10
    Helman, G ; Compton, AG ; Hock, DH ; Walkiewicz, M ; Brett, GR ; Pais, L ; Tan, TY ; De Paoli-Iseppi, R ; Clark, MB ; Christodoulou, J ; White, SM ; Thorburn, DR ; Stroud, DA ; Stark, Z ; Simons, C (WILEY-HINDAWI, 2021-01)
    The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet need. Following uninformative exome and genome sequencing of a family quartet including two siblings with suspected mitochondrial disorder, RNA sequencing (RNAseq) was pursued in one sibling. Long-read amplicon sequencing was used to determine and quantify transcript structure. Immunoblotting studies and quantitative proteomics were performed to demonstrate functional impact. Differential expression analysis of RNAseq data identified significantly decreased expression of the mitochondrial OXPHOS Complex I subunit NDUFB10 associated with a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. The cryptic exon contained a rare intronic variant that was homozygous in both affected siblings. Immunoblot and quantitative proteomic analysis of fibroblasts revealed decreased abundance of Complex I subunits, providing evidence of isolated Complex I deficiency. Through multiomic analysis we present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two individuals, providing further support of the gene-disease association. This study highlights the importance of transcriptomic and proteomic analyses as complementary diagnostic tools in patients undergoing genome-wide diagnostic evaluation.
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    Pan-cancer analysis of whole genomes
    Campbell, PJ ; Getz, G ; Korbel, JO ; Stuart, JM ; Jennings, JL ; Stein, LD ; Perry, MD ; Nahal-Bose, HK ; Ouellette, BFF ; Li, CH ; Rheinbay, E ; Nielsen, GP ; Sgroi, DC ; Wu, C-L ; Faquin, WC ; Deshpande, V ; Boutros, PC ; Lazar, AJ ; Hoadley, KA ; Louis, DN ; Dursi, LJ ; Yung, CK ; Bailey, MH ; Saksena, G ; Raine, KM ; Buchhalter, I ; Kleinheinz, K ; Schlesner, M ; Zhang, J ; Wang, W ; Wheeler, DA ; Ding, L ; Simpson, JT ; O'Connor, BD ; Yakneen, S ; Ellrott, K ; Miyoshi, N ; Butler, AP ; Royo, R ; Shorser, S ; Vazquez, M ; Rausch, T ; Tiao, G ; Waszak, SM ; Rodriguez-Martin, B ; Shringarpure, S ; Wu, D-Y ; Demidov, GM ; Delaneau, O ; Hayashi, S ; Imoto, S ; Habermann, N ; Segre, A ; Garrison, E ; Cafferkey, A ; Alvarez, EG ; Maria Heredia-Genestar, J ; Muyas, F ; Drechsel, O ; Bruzos, AL ; Temes, J ; Zamora, J ; Baez-Ortega, A ; Kim, H-L ; Mashl, RJ ; Ye, K ; DiBiase, A ; Huang, K-L ; Letunic, I ; McLellan, MD ; Newhouse, SJ ; Shmaya, T ; Kumar, S ; Wedge, DC ; Wright, MH ; Yellapantula, VD ; Gerstein, M ; Khurana, E ; Marques-Bonet, T ; Navarro, A ; Bustamante, CD ; Siebert, R ; Nakagawa, H ; Easton, DF ; Ossowski, S ; Tubio, JMC ; De La Vega, FM ; Estivill, X ; Yuen, D ; Mihaiescu, GL ; Omberg, L ; Ferretti, V ; Sabarinathan, R ; Pich, O ; Gonzalez-Perez, A ; Weiner, AT ; Fittall, MW ; Demeulemeester, J ; Tarabichi, M ; Roberts, ND ; Van Loo, P ; Cortes-Ciriano, I ; Urban, L ; Park, P ; Bin, Z ; Pitkaenen, E ; Li, Y ; Saini, N ; Klimczak, LJ ; Weischenfeldt, J ; Sidiropoulos, N ; Alexandrov, LB ; Rabionet, R ; Escaramis, G ; Bosio, M ; Holik, AZ ; Susak, H ; Prasad, A ; Erkek, S ; Calabrese, C ; Raeder, B ; Harrington, E ; Mayes, S ; Turner, D ; Juul, S ; Roberts, SA ; Song, L ; Koster, R ; Mirabello, L ; Hua, X ; Tanskanen, TJ ; Tojo, M ; Chen, J ; Aaltonen, LA ; Ratsch, G ; Schwarz, RF ; Butte, AJ ; Brazma, A ; Chanock, SJ ; Chatterjee, N ; Stegle, O ; Harismendy, O ; Bova, GS ; Gordenin, DA ; Haan, D ; Sieverling, L ; Feuerbach, L ; Chalmers, D ; Joly, Y ; Knoppers, B ; Molnar-Gabor, F ; Phillips, M ; Thorogood, A ; Townend, D ; Goldman, M ; Fonseca, NA ; Xiang, Q ; Craft, B ; Pineiro-Yanez, E ; Munoz, A ; Petryszak, R ; Fullgrabe, A ; Al-Shahrour, F ; Keays, M ; Haussler, D ; Weinstein, J ; Huber, W ; Valencia, A ; Papatheodorou, I ; Zhu, J ; Fan, Y ; Torrents, D ; Bieg, M ; Chen, K ; Chong, Z ; Cibulskis, K ; Eils, R ; Fulton, RS ; Gelpi, JL ; Gonzalez, S ; Gut, IG ; Hach, F ; Heinold, M ; Hu, T ; Huang, V ; Hutter, B ; Jaeger, N ; Jung, J ; Kumar, Y ; Lalansingh, C ; Leshchiner, I ; Livitz, D ; Ma, EZ ; Maruvka, YE ; Milovanovic, A ; Nielsen, MM ; Paramasivam, N ; Pedersen, JS ; Puiggros, M ; Sahinalp, SC ; Sarrafi, I ; Stewart, C ; Stobbe, MD ; Wala, JA ; Wang, J ; Wendl, M ; Werner, J ; Wu, Z ; Xue, H ; Yamaguchi, TN ; Yellapantula, V ; Davis-Dusenbery, BN ; Grossman, RL ; Kim, Y ; Heinold, MC ; Hinton, J ; Jones, DR ; Menzies, A ; Stebbings, L ; Hess, JM ; Rosenberg, M ; Dunford, AJ ; Gupta, M ; Imielinski, M ; Meyerson, M ; Beroukhim, R ; Reimand, J ; Dhingra, P ; Favero, F ; Dentro, S ; Wintersinger, J ; Rudneva, V ; Park, JW ; Hong, EP ; Heo, SG ; Kahles, A ; Kjong-Van, L ; Soulette, CM ; Shiraishi, Y ; Liu, F ; He, Y ; Demircioglu, D ; Davidson, NR ; Greger, L ; Li, S ; Liu, D ; Stark, SG ; Zhang, F ; Amin, SB ; Bailey, P ; Chateigner, A ; Frenkel-Morgenstern, M ; Hou, Y ; Huska, MR ; Kilpinen, H ; Lamaze, FC ; Li, C ; Li, X ; Li, X ; Liu, X ; Marin, MG ; Markowski, J ; Nandi, T ; Ojesina, A ; Pan-Hammarstrom, Q ; Park, PJ ; Pedamallu, CS ; Su, H ; Tan, P ; Teh, BT ; Wang, J ; Xiong, H ; Ye, C ; Yung, C ; Zhang, X ; Zheng, L ; Zhu, S ; Awadalla, P ; Creighton, CJ ; Wu, K ; Yang, H ; Goke, J ; Zhang, Z ; Brooks, AN ; Martincorena, I ; Rubio-Perez, C ; Juul, M ; Schumacher, S ; Shapira, O ; Tamborero, D ; Mularoni, L ; Hornshoj, H ; Deu-Pons, J ; Muinos, F ; Bertl, J ; Guo, Q ; Bazant, W ; Barrera, E ; Al-Sedairy, ST ; Aretz, A ; Bell, C ; Betancourt, M ; Buchholz, C ; Calvo, F ; Chomienne, C ; Dunn, M ; Edmonds, S ; Green, E ; Gupta, S ; Hutter, CM ; Jegalian, K ; Jones, N ; Lu, Y ; Nakagama, H ; Nettekoven, G ; Planko, L ; Scott, D ; Shibata, T ; Shimizu, K ; Stratton, MR ; Yugawa, T ; Tortora, G ; VijayRaghavan, K ; Zenklusen, JC ; Knoppers, BM ; Aminou, B ; Bartolome, J ; Boroevich, KA ; Boyce, R ; Buchanan, A ; Byrne, NJ ; Chen, Z ; Cho, S ; Choi, W ; Clapham, P ; Dow, MT ; Dursi, LJ ; Eils, J ; Farcas, C ; Fayzullaev, N ; Flicek, P ; Heath, AP ; Hofmann, O ; Hong, JH ; Hudson, TJ ; Huebschmann, D ; Ivkovic, S ; Jeon, S-H ; Jiao, W ; Kabbe, R ; Kerssemakers, JNA ; Kim, H ; Kim, J ; Koscher, M ; Koures, A ; Kovacevic, M ; Lawerenz, C ; Liu, J ; Mijalkovic, S ; Mijalkovic-Lazic, AM ; Miyano, S ; Nastic, M ; Nicholson, J ; Ocana, D ; Ohi, K ; Ohno-Machado, L ; Pihl, TD ; Prinz, M ; Radovic, P ; Short, C ; Sofia, HJ ; Spring, J ; Struck, AJ ; Tijanic, N ; Vicente, D ; Wang, Z ; Williams, A ; Woo, Y ; Wright, AJ ; Yang, L ; Hamilton, MP ; Johnson, TA ; Kahraman, A ; Kellis, M ; Polak, P ; Sallari, R ; Sinnott-Armstrong, N ; von Mering, C ; Beltran, S ; Gerhard, DS ; Gut, M ; Trotta, J-R ; Whalley, JP ; Niu, B ; Espiritu, SMG ; Gao, S ; Huang, Y ; Lalansingh, CM ; Teague, JW ; Wendl, MC ; Abascal, F ; Bader, GD ; Bandopadhayay, P ; Barenboim, J ; Brunak, S ; Fita, JC ; Chakravarty, D ; Chan, CWY ; Choi, JK ; Diamanti, K ; Fink, JL ; Frigola, J ; Gambacorti-Passerini, C ; Garsed, DW ; Haradhvala, NJ ; Harmanci, AO ; Helmy, M ; Herrmann, C ; Hobolth, A ; Hodzic, E ; Hong, C ; Isaev, K ; Izarzugaza, JMG ; Johnson, R ; Juul, RI ; Kim, J ; Kim, JK ; Komorowski, J ; Lanzos, A ; Larsson, E ; Lee, D ; Li, S ; Li, X ; Lin, Z ; Liu, EM ; Lochovsky, L ; Lou, S ; Madsen, T ; Marchal, K ; Fundichely, AM ; McGillivray, PD ; Meyerson, W ; Paczkowska, M ; Park, K ; Park, K ; Pons, T ; Pulido-Tamayo, S ; Reyes Salazar, I ; Reyna, MA ; Rubin, MA ; Salichos, L ; Sander, C ; Schumacher, SE ; Shackleton, M ; Shen, C ; Shrestha, R ; Shuai, S ; Tsunoda, T ; Umer, HM ; Uuskula-Reimand, L ; Verbeke, LPC ; Wadelius, C ; Wadi, L ; Warrell, J ; Wu, G ; Yu, J ; Zhang, J ; Zhang, X ; Zhang, Y ; Zhao, Z ; Zou, L ; Lawrence, MS ; Raphael, BJ ; Bailey, PJ ; Craft, D ; Goldman, MJ ; Aburatani, H ; Binder, H ; Dinh, HQ ; Heath, SC ; Hoffmann, S ; Imbusch, CD ; Kretzmer, H ; Laird, PW ; Martin-Subero, J ; Nagae, G ; Shen, H ; Wang, Q ; Weichenhan, D ; Zhou, W ; Berman, BP ; Brors, B ; Plass, C ; Akdemir, KC ; Bowtell, DDL ; Burns, KH ; Busanovich, J ; Chan, K ; Dueso-Barroso, A ; Edwards, PA ; Etemadmoghadam, D ; Haber, JE ; Jones, DTW ; Ju, YS ; Kazanov, MD ; Koh, Y ; Kumar, K ; Lee, EA ; Lee, JJ-K ; Lynch, AG ; Macintyre, G ; Markowetz, F ; Navarro, FCP ; Pearson, J ; Rippe, K ; Scully, R ; Villasante, I ; Waddell, N ; Yang, L ; Yao, X ; Yoon, S-S ; Zhang, C-Z ; Bergstrom, EN ; Boot, A ; Covington, K ; Fujimoto, A ; Huang, MN ; Islam, SMA ; McPherson, JR ; Morganella, S ; Mustonen, V ; Ng, AWT ; Prokopec, SD ; Vazquez-Garcia, I ; Wu, Y ; Yousif, F ; Yu, W ; Rozen, SG ; Rudneva, VA ; Shringarpure, SS ; Turner, DJ ; Xia, T ; Atwal, G ; Chang, DK ; Cooke, SL ; Faltas, BM ; Haider, S ; Kaiser, VB ; Karlic, R ; Kato, M ; Kubler, K ; Margolin, A ; Martin, S ; Nik-Zainal, S ; P'ng, C ; Semple, CA ; Smith, J ; Sun, RX ; Thai, K ; Wright, DW ; Yuan, K ; Biankin, A ; Garraway, L ; Grimmond, SM ; Adams, DJ ; Anur, P ; Cao, S ; Christie, EL ; Cmero, M ; Cun, Y ; Dawson, KJ ; Dentro, SC ; Deshwar, AG ; Donmez, N ; Drews, RM ; Gerstung, M ; Ha, G ; Haase, K ; Jerman, L ; Ji, Y ; Jolly, C ; Lee, J ; Lee-Six, H ; Malikic, S ; Mitchell, TJ ; Morris, QD ; Oesper, L ; Peifer, M ; Peto, M ; Rosebrock, D ; Rubanova, Y ; Salcedo, A ; Sengupta, S ; Shi, R ; Shin, SJ ; Spiro, O ; Vembu, S ; Wintersinger, JA ; Yang, T-P ; Yu, K ; Zhu, H ; Spellman, PT ; Weinstein, JN ; Chen, Y ; Fujita, M ; Han, L ; Hasegawa, T ; Komura, M ; Li, J ; Mizuno, S ; Shimizu, E ; Wang, Y ; Xu, Y ; Yamaguchi, R ; Yang, F ; Yang, Y ; Yoon, CJ ; Yuan, Y ; Liang, H ; Alawi, M ; Borozan, I ; Brewer, DS ; Cooper, CS ; Desai, N ; Grundhoff, A ; Iskar, M ; Su, X ; Zapatka, M ; Lichter, P ; Alsop, K ; Bruxner, TJC ; Christ, AN ; Cordner, SM ; Cowin, PA ; Drapkin, R ; Fereday, S ; George, J ; Hamilton, A ; Holmes, O ; Hung, JA ; Kassahn, KS ; Kazakoff, SH ; Kennedy, CJ ; Leonard, CR ; Mileshkin, L ; Miller, DK ; Arnau, GM ; Mitchell, C ; Newell, F ; Nones, K ; Patch, A-M ; Quinn, MC ; Taylor, DF ; Thorne, H ; Traficante, N ; Vedururu, R ; Waddell, NM ; Waring, PM ; Wood, S ; Xu, Q ; DeFazio, A ; Anderson, MJ ; Antonello, D ; Barbour, AP ; Bassi, C ; Bersani, S ; Cataldo, I ; Chantrill, LA ; Chiew, Y-E ; Chou, A ; Cingarlini, S ; Cloonan, N ; Corbo, V ; Davi, MV ; Duthie, FR ; Gill, AJ ; Graham, JS ; Harliwong, I ; Jamieson, NB ; Johns, AL ; Kench, JG ; Landoni, L ; Lawlor, RT ; Mafficini, A ; Merrett, ND ; Miotto, M ; Musgrove, EA ; Nagrial, AM ; Oien, KA ; Pajic, M ; Pinese, M ; Robertson, AJ ; Rooman, I ; Rusev, BC ; Samra, JS ; Scardoni, M ; Scarlett, CJ ; Scarpa, A ; Sereni, E ; Sikora, KO ; Simbolo, M ; Taschuk, ML ; Toon, CW ; Vicentini, C ; Wu, J ; Zeps, N ; Behren, A ; Burke, H ; Cebon, J ; Dagg, RA ; De Paoli-Iseppi, R ; Dutton-Regester, K ; Field, MA ; Fitzgerald, A ; Hersey, P ; Jakrot, V ; Johansson, PA ; Kakavand, H ; Kefford, RF ; Lau, LMS ; Long, G ; Pickett, HA ; Pritchard, AL ; Pupo, GM ; Saw, RPM ; Schramm, S-J ; Shang, CA ; Shang, P ; Spillane, AJ ; Stretch, JR ; Tembe, V ; Thompson, JF ; Vilain, RE ; Wilmott, JS ; Yang, JY ; Hayward, NK ; Mann, GJ ; Scolyer, RA ; Bartlett, J ; Bavi, P ; Chadwick, DE ; Chan-Seng-Yue, M ; Cleary, S ; Connor, AA ; Czajka, K ; Denroche, RE ; Dhani, NC ; Eagles, J ; Gallinger, S ; Grant, RC ; Hedley, D ; Hollingsworth, MA ; Jang, GH ; Johns, J ; Kalimuthu, S ; Liang, S-B ; Lungu, I ; Luo, X ; Mbabaali, F ; McPherson, TA ; Miller, JK ; Moore, MJ ; Notta, F ; Pasternack, D ; Petersen, GM ; Roehrl, MHA ; Sam, M ; Selander, I ; Serra, S ; Shahabi, S ; Thayer, SP ; Timms, LE ; Wilson, GW ; Wilson, JM ; Wouters, BG ; McPherson, JD ; Beck, TA ; Bhandari, V ; Collins, CC ; Fleshner, NE ; Fox, NS ; Fraser, M ; Heisler, LE ; Lalonde, E ; Livingstone, J ; Meng, A ; Sabelnykova, VY ; Shiah, Y-J ; Van Der Kwast, T ; Bristow, RG ; Ding, S ; Fan, D ; Li, L ; Nie, Y ; Xiao, X ; Xing, R ; Yang, S ; Yu, Y ; Zhou, Y ; Banks, RE ; Bourque, G ; Brennan, P ; Letourneau, L ; Riazalhosseini, Y ; Scelo, G ; Vasudev, N ; Viksna, J ; Lathrop, M ; Tost, J ; Ahn, S-M ; Aparicio, S ; Arnould, L ; Aure, MR ; Bhosle, SG ; Birney, E ; Borg, A ; Boyault, S ; Brinkman, AB ; Brock, JE ; Broeks, A ; Borresen-Dale, A-L ; Caldas, C ; Chin, S-F ; Davies, H ; Desmedt, C ; Dirix, L ; Dronov, S ; Ehinger, A ; Eyfjord, JE ; Fatima, A ; Foekens, JA ; Futreal, PA ; Garred, O ; Giri, DD ; Glodzik, D ; Grabau, D ; Hilmarsdottir, H ; Hooijer, GK ; Jacquemier, J ; Jang, SJ ; Jonasson, JG ; Jonkers, J ; Kim, H-Y ; King, TA ; Knappskog, S ; Kong, G ; Krishnamurthy, S ; Lakhani, SR ; Langerod, A ; Larsimont, D ; Lee, HJ ; Lee, J-Y ; Lee, MTM ; Lingjaerde, OC ; MacGrogan, G ; Martens, JWM ; O'Meara, S ; Pauporte, I ; Pinder, S ; Pivot, X ; Provenzano, E ; Purdie, CA ; Ramakrishna, M ; Ramakrishnan, K ; Reis-Filho, J ; Richardson, AL ; Ringner, M ; Rodriguez, JB ; Rodriguez-Gonzalez, FG ; Romieu, G ; Salgado, R ; Sauer, T ; Shepherd, R ; Sieuwerts, AM ; Simpson, PT ; Smid, M ; Sotiriou, C ; Span, PN ; Stefansson, OA ; Stenhouse, A ; Stunnenberg, HG ; Sweep, F ; Tan, BKT ; Thomas, G ; Thompson, AM ; Tommasi, S ; Treilleux, I ; Tutt, A ; Ueno, NT ; Van Laere, S ; Van den Eynden, GG ; Vermeulen, P ; Viari, A ; Vincent-Salomon, A ; Wong, BH ; Yates, L ; Zou, X ; van Deurzen, CHM ; van de Vijver, MJ ; van't Veer, L ; Ammerpohl, O ; Aukema, S ; Bergmann, AK ; Bernhart, SH ; Borkhardt, A ; Borst, C ; Burkhardt, B ; Claviez, A ; Goebler, ME ; Haake, A ; Haas, S ; Hansmann, M ; Hoell, J ; Hummel, M ; Karsch, D ; Klapper, W ; Kneba, M ; Kreuz, M ; Kube, D ; Kueppers, R ; Lenze, D ; Loeffler, M ; Lopez, C ; Mantovani-Loeffler, L ; Moeller, P ; Ott, G ; Radlwimmer, B ; Richter, J ; Rohde, M ; Rosenstiel, PC ; Rosenwald, A ; Schilhabel, MB ; Schreiber, S ; Stadler, PF ; Staib, P ; Stilgenbauer, S ; Sungalee, S ; Szczepanowski, M ; Toprak, UH ; Truemper, LHP ; Wagener, R ; Zenz, T ; Hovestadt, V ; von Kalle, C ; Kool, M ; Korshunov, A ; Landgraf, P ; Lehrach, H ; Northcott, PA ; Pfister, SM ; Reifenberger, G ; Warnatz, H-J ; Wolf, S ; Yaspo, M-L ; Assenov, Y ; Gerhauser, C ; Minner, S ; Schlomm, T ; Simon, R ; Sauter, G ; Sueltmann, H ; Biswas, NK ; Maitra, A ; Majumder, PP ; Sarin, R ; Barbi, S ; Bonizzato, G ; Cantu, C ; Dei Tos, AP ; Fassan, M ; Grimaldi, S ; Luchini, C ; Malleo, G ; Marchegiani, G ; Milella, M ; Paiella, S ; Pea, A ; Pederzoli, P ; Ruzzenente, A ; Salvia, R ; Sperandio, N ; Arai, Y ; Hama, N ; Hiraoka, N ; Hosoda, F ; Nakamura, H ; Ojima, H ; Okusaka, T ; Totoki, Y ; Urushidate, T ; Fukayama, M ; Ishikawa, S ; Katai, H ; Katoh, H ; Komura, D ; Rokutan, H ; Saito-Adachi, M ; Suzuki, A ; Taniguchi, H ; Tatsuno, K ; Ushiku, T ; Yachida, S ; Yamamoto, S ; Aikata, H ; Arihiro, K ; Ariizumi, S-I ; Chayama, K ; Furuta, M ; Gotoh, K ; Hayami, S ; Hirano, S ; Kawakami, Y ; Maejima, K ; Nakamura, T ; Nakano, K ; Ohdan, H ; Sasaki-Oku, A ; Tanaka, H ; Ueno, M ; Yamamoto, M ; Yamaue, H ; Choo, SP ; Cutcutache, I ; Khuntikeo, N ; Ong, CK ; Pairojkul, C ; Popescu, I ; Ahn, KS ; Aymerich, M ; Lopez-Guillermo, A ; Lopez-Otin, C ; Puente, XS ; Campo, E ; Amary, F ; Baumhoer, D ; Behjati, S ; Bjerkehagen, B ; Futreal, PA ; Myklebost, O ; Pillay, N ; Tarpey, P ; Tirabosco, R ; Zaikova, O ; Flanagan, AM ; Boultwood, J ; Bowen, DT ; Cazzola, M ; Green, AR ; Hellstrom-Lindberg, E ; Malcovati, L ; Nangalia, J ; Papaemmanuil, E ; Vyas, P ; Ang, Y ; Barr, H ; Beardsmore, D ; Eldridge, M ; Gossage, J ; Grehan, N ; Hanna, GB ; Hayes, SJ ; Hupp, TR ; Khoo, D ; Lagergren, J ; Lovat, LB ; MacRae, S ; O'Donovan, M ; O'Neill, JR ; Parsons, SL ; Preston, SR ; Puig, S ; Roques, T ; Sanders, G ; Sothi, S ; Tavare, S ; Tucker, O ; Turkington, R ; Underwood, TJ ; Welch, I ; Fitzgerald, RC ; Berney, DM ; De Bono, JS ; Cahill, D ; Camacho, N ; Dennis, NM ; Dudderidge, T ; Edwards, SE ; Fisher, C ; Foster, CS ; Ghori, M ; Gill, P ; Gnanapragasam, VJ ; Gundem, G ; Hamdy, FC ; Hawkins, S ; Hazell, S ; Howat, W ; Isaacs, WB ; Karaszi, K ; Kay, JD ; Khoo, V ; Kote-Jarai, Z ; Kremeyer, B ; Kumar, P ; Lambert, A ; Leongamornlert, DA ; Livni, N ; Lu, Y-J ; Luxton, HJ ; Marsden, L ; Massie, CE ; Matthews, L ; Mayer, E ; McDermott, U ; Merson, S ; Neal, DE ; Ng, A ; Nicol, D ; Ogden, C ; Rowe, EW ; Shah, NC ; Thomas, S ; Thompson, A ; Verrill, C ; Visakorpi, T ; Warren, AY ; Whitaker, HC ; Zhang, H ; van As, N ; Eeles, RA ; Abeshouse, A ; Agrawal, N ; Akbani, R ; Al Ahmadie, H ; Albert, M ; Aldape, K ; Ally, A ; Appelbaum, EL ; Armenia, J ; Asa, S ; Auman, JT ; Balasundaram, M ; Balu, S ; Barnholtz-Sloan, J ; Bathe, OF ; Baylin, SB ; Benz, C ; Berchuck, A ; Berrios, M ; Bigner, D ; Birrer, M ; Bodenheimer, T ; Boice, L ; Bootwalla, MS ; Bosenberg, M ; Bowlby, R ; Boyd, J ; Broaddus, RR ; Brock, M ; Brooks, D ; Bullman, S ; Caesar-Johnson, SJ ; Carey, TE ; Carlsen, R ; Cerfolio, R ; Chandan, VS ; Chen, H-W ; Cherniack, AD ; Chien, J ; Cho, J ; Chuah, E ; Cibulskis, C ; Cope, L ; Cordes, MG ; Curley, E ; Czerniak, B ; Danilova, L ; Davis, IJ ; Defreitas, T ; Demchok, JA ; Dhalla, N ; Dhir, R ; Doddapaneni, H ; El-Naggar, A ; Felau, I ; Ferguson, ML ; Finocchiaro, G ; Fong, KM ; Frazer, S ; Friedman, W ; Fronick, CC ; Fulton, LA ; Gabriel, SB ; Gao, J ; Gehlenborg, N ; Gershenwald, JE ; Ghossein, R ; Giama, NH ; Gibbs, RA ; Gomez, C ; Govindan, R ; Hayes, DN ; Hegde, AM ; Heiman, D ; Heins, Z ; Hepperla, AJ ; Holbrook, A ; Holt, RA ; Hoyle, AP ; Hruban, RH ; Hu, J ; Huang, M ; Huntsman, D ; Huse, J ; Donahue, CAI ; Ittmann, M ; Jayaseelan, JC ; Jefferys, SR ; Jones, CD ; Jones, SJM ; Juhl, H ; Kang, KJ ; Karlan, B ; Kasaian, K ; Kebebew, E ; Kim, HK ; Korchina, V ; Kundra, R ; Lai, PH ; Lander, E ; Le, X ; Lee, D ; Levine, DA ; Lewis, L ; Ley, T ; Li, HI ; Lin, P ; Linehan, WM ; Liu, FF ; Lu, Y ; Lype, L ; Ma, Y ; Maglinte, DT ; Mardis, ER ; Marks, J ; Marra, MA ; Matthew, TJ ; Mayo, M ; McCune, K ; Meier, SR ; Meng, S ; Mieczkowski, PA ; Mikkelsen, T ; Miller, CA ; Mills, GB ; Moore, RA ; Morrison, C ; Mose, LE ; Moser, CD ; Mungall, AJ ; Mungall, K ; Mutch, D ; Muzny, DM ; Myers, J ; Newton, Y ; Noble, MS ; O'Donnell, P ; O'Neill, BP ; Ochoa, A ; Park, J-W ; Parker, JS ; Pass, H ; Pastore, A ; Pennell, NA ; Perou, CM ; Petrelli, N ; Potapova, O ; Rader, JS ; Ramalingam, S ; Rathmell, WK ; Reuter, V ; Reynolds, SM ; Ringel, M ; Roach, J ; Roberts, LR ; Robertson, AG ; Sadeghi, S ; Saller, C ; Sanchez-Vega, F ; Schadendorf, D ; Schein, JE ; Schmidt, HK ; Schultz, N ; Seethala, R ; Senbabaoglu, Y ; Shelton, T ; Shi, Y ; Shih, J ; Shmulevich, I ; Shriver, C ; Signoretti, S ; Simons, J ; Singer, S ; Sipahimalani, P ; Skelly, TJ ; McCune, KS ; Socci, ND ; Soloway, MG ; Sood, AK ; Tam, A ; Tan, D ; Tarnuzzer, R ; Thiessen, N ; Thompson, RH ; Thorne, LB ; Tsao, M ; Umbricht, C ; Van Den Berg, DJ ; Van Meir, EG ; Veluvolu, U ; Voet, D ; Wang, L ; Weinberger, P ; Weisenberger, DJ ; Wigle, D ; Wilkerson, MD ; Wilson, RK ; Winterhoff, B ; Wiznerowicz, M ; Wong, T ; Wong, W ; Xi, L ; Yau, C ; Zhang, H ; Zhang, H ; Zhang, J (NATURE PUBLISHING GROUP, 2020-02-06)
    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.