Browsing by Subject "SOMATIC MUTATIONS"

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  • Jones, W; Gong, BS; Novoradovskaya, N; Li, D; Kusko, R; Richmond, TA; Johann, DJ; Bisgin, H; Sahraeian, SME; Bushel, PR; Pirooznia, M; Wilkins, K; Chierici, M; Bao, WJ; Basehore, LS; Lucas, AB; Burgess, D; Butler, DJ; Cawley, S; Chang, CJ; Chen, GC; Chen, T; Chen, YC; Craig, DJ; Del Pozo, A; Foox, J; Francescatto, M; Fu, YT; Furlanello, C; Giorda, K; Grist, KP; Guan, MJ; Hao, YY; Happe, S; Hariani, G; Haseley, N; Jasper, J; Jurman, G; Kreil, DP; Labaj, P; Lai, K; Li, JY; Li, QZ; Li, YL; Li, ZG; Liu, ZC; Lopez, MS; Miclaus, K; Miller, R; Mittal, VK; Mohiyuddin, M; Pabon-Pena, C; Parsons, BL; Qiu, FJ; Scherer, A; Shi, TL; Stiegelmeyer, S; Suo, C; Tom, N; Wang, D; Wen, ZN; Wu, LH; Xiao, WZ; Xu, C; Yu, Y; Zhang, JY; Zhang, YF; Zhang, ZH; Zheng, YT; Mason, CE; Willey, JC; Tong, WD; Shi, LM; Xu, J (2021)
    BackgroundOncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance.ResultsIn reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100x more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels.ConclusionThese new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.
  • Martinez-Corral, Ines; Zhang, Yan; Petkova, Milena; Ortsater, Henrik; Sjoberg, Sofie; Castillo, Sandra D.; Brouillard, Pascal; Libbrecht, Louis; Saur, Dieter; Graupera, Mariona; Alitalo, Kari; Boon, Laurence; Vikkula, Miikka; Mäkinen, Taija (2020)
    Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA(H1047R) mutation, resulting in constitutive activation of the p110 alpha PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA(H1047R)-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110 alpha activation determining the LM subtype. In the postnatal vasculature, PIK3CA(H1047R) promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.
  • PCAWG Evolution Heterogeneity Work; PCAWG Consortium; Dentro, Stefan C.; Mustonen, Ville (2021)
    Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1 %) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones, We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
  • Karihtala, Peeter; Porvari, Katja; Roininen, Nelli; Voutilainen, Sari; Mattson, Johanna; Heikkilä, Päivi; Haapasaari, Kirsi-Maria; Selander, Katri (2022)
    The pathophysiology and the optimal treatment of breast neuroendocrine tumours (NETs) are unknown. We compared the mutational profiles of breast NETs (n = 53) with those of 724 publicly available invasive ductal carcinoma (IDC) and 98 pancreatic NET (PNET) cases. The only significantly different pathogenetic or unknown variant rate between breast NETs and IDCs was detected in the TP53 (11.3% in breast NETs and 41% in IDCs, adjusted p value 0.027) and ADCK2 (9.4% in breast NETs vs. 0.28% in IDCs, adjusted p value 0.045) genes. Between breast NETs and PNETs, different pathogenetic or unknown variant frequencies were detected in 30 genes. For example, MEN1 was mutated in only 6% of breast NETs and 37% in PNETs (adjusted p value 0.00050), and GATA3 pathogenetic or unknown variants were only found in 17.0% of breast NETs and 0% in PNETs (adjusted p value 0.0010). The most commonly affected oncogenic pathways in the breast NET cases were PI3K/Akt/mTOR, NOTCH and RTK-RAS pathways. Breast NETs had typically clock-like mutational signatures and signatures associated with defective DNA mismatch repair in their mutational landscape. Our results suggest that the breast NET mutational profile more closely resembles that of IDCs than that of PNETs. These results also revealed several potentially druggable targets, such as MMRd, in breast NETs. In conclusion, breast NETs are indeed a separate breast cancer entity, but their optimal treatment remains to be elucidated.
  • Alkodsi, Amjad; Cervera, Alejandra; Zhang, Kaiyang; Louhimo, Riku; Meriranta, Leo; Pasanen, Annika; Leivonen, Suvi-Katri; Holte, Harald; Leppä, Sirpa; Lehtonen, Rainer; Hautaniemi, Sampsa (2019)
    Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease whose personalized clinical management requires robust molecular stratification. Here, we show that somatic hypermutation (SHM) patterns constitute a marker for DLBCL molecular classification. The activity of SHM mutational processes delineated the cell of origin (COO) in DLBCL. Expression of the herein identified 36 SHM target genes stratified DLBCL into four novel SHM subtypes. In a meta-analysis of patients with DLBCL treated with immunochemotherapy, the SHM subtypes were significantly associated with overall survival (1642 patients) and progression-free survival (795 patients). Multivariate analysis of survival indicated that the prognostic impact of the SHM subtypes is independent from the COO classification and the International Prognostic Index. Furthermore, the SHM subtypes had a distinct clinical outcome within each of the COO subtypes, and strikingly, even within unclassified DLBCL. The genetic landscape of the four SHM subtypes indicated unique associations with driver alterations and oncogenic signaling in DLBCL, which suggests a possibility for therapeutic exploitation. These findings provide a biologically driven classification system in DLBCL with potential clinical applications.
  • Porkka, Noora; Lahtinen, Laura; Ahtiainen, Maarit; Böhm, Jan P.; Kuopio, Teijo; Eldfors, Samuli; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Peltomäki, Päivi (2019)
    Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p <0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.
  • Niestroj, Lisa-Marie; Du, Juanjiangmeng; Nothnagel, Michael; May, Patrick; Palotie, Aarno; Daly, Mark J.; Nürnberg, Peter; Blümcke, Ingmar; Lal, Dennis (2018)
    Objective Increasing availability of surgically resected brain tissue from patients with focal epilepsy and focal cortical dysplasia or low-grade glioneuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germ line and somatic variants remains difficult. Here, we present a state-of-the-art evaluation of reported genes and variants associated with epileptic brain lesions. Methods Results We critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven of 11 genes to be likely disease-associated according to the reported disease mechanism, whereas 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance, 37 (36.6%) as being likely pathogenic, and 3 (3%) as being pathogenic. Significance We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging, and application of current ACMG guidelines is recommended for interpretation and prediction.
  • Maki-Nevala, Satu; Sarhadi, Virinder Kaur; Ronty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuuttila, Aija; Knuutila, Sakari (2016)
    Objectives: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Materials and methods: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Results: Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PlIC3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Conclusion: Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Mäkinen, Taija; Boon, Laurence M.; Vikkula, Miikka; Alitalo, Kari (2021)
    Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell-autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.
  • Saarinen, Lilli; Nummela, Pirjo; Thiel, Alexandra; Lehtonen, Rainer; Järvinen, Petrus; Järvinen, Heikki; Aaltonen, Lauri A.; Lepisto, Anna; Hautaniemi, Sampsa; Ristimaki, Ari (2017)
    Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma mainly restricted to the peritoneal cavity and most commonly originating from the appendix. The genetic background of PMP is poorly understood and no targeted treatments are currently available for this fatal disease. While RAS signaling pathway is affected in most if not all PMP cases and over half of them also have a mutation in the GNAS gene, other genetic alterations and affected pathways are, to a large degree, poorly known. In this study, we sequenced whole coding genome of nine PMP tumors and paired normal tissues in order to identify additional, commonly mutated genes and signaling pathways affected in PMP. These exome sequencing results were validated with an ultra-deep amplicon sequencing method, leading to 14 validated variants. The validated results contain seven genes that contribute to the protein kinase A (PKA) pathway. PKA pathway, which also contains GNAS, is a major player of overproduction of mucin, which is the characteristic feature of PMP. In addition to PKA pathway, we identified mutations in six genes that belong to the transforming growth factor beta (TGF-beta) pathway, which is a key regulator of cell proliferation. Since either GNAS mutation or an alternative mutation in the PKA pathway was identified in 8/9 patients, inhibition of the PKA pathway might reduce mucin production in most of the PMP patients and potentially suppress disease progression.
  • Demir, Hande; Donner, Iikki; Kivipelto, Leena; Kuismin, Outi; Schalin-Jantti, Camilla; De Menis, Ernesto; Karhu, Auli (2014)
  • Wise, Jillian F.; Nakken, Sigve; Steen, Chloe B.; Vodak, Daniel; Troen, Gunhild; Johannessen, Bjarne; Lingjxrde, Ole Christian; Hilden, Vera; Blaker, Yngvild Nuvin; Bai, Baoyan; Aasheim, Lars Birger; Pasanen, Annika; Lorenz, Susanne; Sveen, Anita; Lothe, Ragnhild A.; Myklebost, Ola; Leppa, Sirpa; Meza-Zepeda, Leonardo A.; Beiske, Klaus; Lawrence, Michael S.; Hovig, Eivind; Myklebust, June Helen; Smeland, Erlend B.; Holte, Harald (2020)
  • 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, B. F. 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; 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; 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; 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 M. C.; 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; Roberts, Nicola D.; Van Loo, Peter; Cortes-Ciriano, Isidro; Urban, Lara; Park, Peter; Bin Zhu, Lingli; Pitkaenen, Esa; Li, Yilong; Saini, Natalie; Klimczak, Leszek J.; Weischenfeldt, Joachim; Sidiropoulos, Nikos; Alexandrov, Ludmil B.; Rabionet, Raquel; Escaramis, Georgia; Bosio, Mattia; Holik, Aliaksei Z.; Susak, Hana; Prasad, Aparna; Erkek, Serap; Calabrese, Claudia; Raeder, Benjamin; Harrington, Eoghan; Mayes, Simon; Turner, Daniel; Juul, Sissel; Roberts, Steven A.; Song, Lei; Koster, Roelof; Mirabello, Lisa; Hua, Xing; Tanskanen, Tomas J.; Tojo, Marta; Chen, Jieming; Aaltonen, Lauri A.; Ratsch, Gunnar; Schwarz, Roland F.; Butte, Atul J.; Brazma, Alvis; Chanock, Stephen J.; Chatterjee, Nilanjan; Stegle, Oliver; Harismendy, Olivier; Bova, G. Steven; Gordenin, Dmitry A.; Haan, David; Sieverling, Lina; Feuerbach, Lars; Chalmers, Don; Joly, Yann; Knoppers, Bartha M.; Molnar-Gabor, Fruzsina; Phillips, Mark; Thorogood, Adrian; Townend, David; Goldman, Mary; Fonseca, Nuno A.; Xiang, Qian; Craft, Brian; Pineiro-Yanez, Elena; Munoz, Alfonso; Petryszak, Robert; Fullgrabe, Anja; Al-Shahrour, Fatima; Keays, Maria; Haussler, David; Weinstein, John; Huber, Wolfgang; Valencia, Alfonso; Papatheodorou, Irene; Zhu, Jingchun; Fan, Yu; Torrents, David; Bieg, Matthias; Chen, Ken; Chong, Zechen; Cibulskis, Kristian; Eils, Roland; Fulton, Robert S.; Gelpi, Josep L.; Gonzalez, Santiago; Gut, Ivo G.; Hach, Faraz; Heinold, Michael; Hu, Taobo; Huang, Vincent; Hutter, Barbara; Jaeger, Natalie; Jung, Jongsun; Kumar, Yogesh; Lalansingh, Christopher; Leshchiner, Ignaty; Livitz, Dimitri; Ma, Eric Z.; Maruvka, Yosef E.; Milovanovic, Ana; Nielsen, Morten Muhlig; Paramasivam, Nagarajan; Pedersen, Jakob Skou; Puiggros, Montserrat; Sahinalp, S. Cenk; Sarrafi, Iman; Stewart, Chip; Stobbe, Miranda D.; Wala, Jeremiah A.; Wang, Jiayin; Wendl, Michael C.; Werner, Johannes; Wu, Zhenggang; Xue, Hong; Yamaguchi, Takafumi N.; Yellapantula, Venkata; Davis-Dusenbery, Brandi N.; Grossman, Robert L.; Kim, Youngwook; Heinold, Michael C.; Hinton, Jonathan; Jones, David R.; Menzies, Andrew; Stebbings, Lucy; Hess, Julian M.; Rosenberg, Mara; Dunford, Andrew J.; Gupta, Manaswi; Imielinski, Marcin; Meyerson, Matthew; Beroukhim, Rameen; Reimand, Juri; Dhingra, Priyanka; Favero, Francesco; Dentro, Stefan C.; Wintersinger, Jeff; Rudneva, Vasilisa; Park, Ji Wan; Hong, Eun Pyo; Heo, Seong Gu; Kahles, Andre; Kjong-Van Lehmann; Soulette, Cameron M.; Shiraishi, Yuichi; Liu, Fenglin; He, Yao; Demircioglu, Deniz; Davidson, Natalie R.; Greger, Liliana; Li, Siliang; Liu, Dongbing; Stark, Stefan G.; Zhang, Fan; Amin, Samirkumar B.; Bailey, Peter J.; Chateigner, Aurelien; Frenkel-Morgenstern, Milana; Hou, Yong; Huska, Matthew R.; Kilpinen, Helena; Lamaze, Fabien C.; Li, Chang; Li, Xiaobo; Li, Xinyue; Liu, Xingmin; Marin, Maximillian G.; Markowski, Julia; Nandi, Tannistha; Ojesina, Akinyemi; Pan-Hammarstrom, Qiang; Park, Peter J.; Pedamallu, Chandra Sekhar; Su, Hong; Tan, Patrick; Teh, Bin Tean; Wang, Jian; Xiong, Heng; Ye, Chen; Yung, Christina; Zhang, Xiuqing; Zheng, Liangtao; Zhu, Shida; Awadalla, Philip; Creighton, Chad J.; Wu, Kui; Yang, Huanming; Goke, Jonathan; Zhang, Zemin; Brooks, Angela N.; Martincorena, Inigo; Rubio-Perez, Carlota; Juul, Malene; Schumacher, Steven; Shapira, Ofer; Tamborero, David; Mularoni, Loris; Hornshoj, Henrik; Deu-Pons, Jordi; Muinos, Ferran; Bertl, Johanna; Guo, Qianyun; Bazant, Wojciech; Barrera, Elisabet; Al-Sedairy, Sultan T.; Aretz, Axel; Bell, Cindy; Betancourt, Miguel; Buchholz, Christiane; Calvo, Fabien; Chomienne, Christine; Dunn, Michael; Edmonds, Stuart; Green, Eric; Gupta, Shailja; Hutter, Carolyn M.; Jegalian, Karine; Jones, Nic; Lu, Youyong; Nakagama, Hitoshi; Nettekoven, Gerd; Planko, Laura; Scott, David; Shibata, Tatsuhiro; Shimizu, Kiyo; Stratton, Michael R.; Yugawa, Takashi; Tortora, Giampaolo; VijayRaghavan, K.; Zenklusen, Jean C.; Knoppers, Bartha M.; Aminou, Brice; Bartolome, Javier; Boroevich, Keith A.; Boyce, Rich; Buchanan, Alex; Byrne, Niall J.; Chen, Zhaohong; Cho, Sunghoon; Choi, Wan; Clapham, Peter; Dow, Michelle T.; Dursi, Lewis Jonathan; Eils, Juergen; Farcas, Claudiu; Fayzullaev, Nodirjon; Flicek, Paul; Heath, Allison P.; Hofmann, Oliver; Hong, Jongwhi H.; Hudson, Thomas J.; Huebschmann, Daniel; Ivkovic, Sinisa; Jeon, Seung-Hyup; Jiao, Wei; Kabbe, Rolf; Kerssemakers, Jules N. A.; Kim, Hyunghwan; Kim, Jihoon; Koscher, Michael; Koures, Antonios; Kovacevic, Milena; Lawerenz, Chris; Liu, Jia; Mijalkovic, Sanja; Mijalkovic-Lazic, Ana Mijalkovic; Miyano, Satoru; Nastic, Mia; Nicholson, Jonathan; Ocana, David; Ohi, Kazuhiro; Ohno-Machado, Lucila; Pihl, Todd D.; Prinz, Manuel; Radovic, Petar; Short, Charles; Sofia, Heidi J.; Spring, Jonathan; Struck, Adam J.; Tijanic, Nebojsa; Vicente, David; Wang, Zhining; Williams, Ashley; Woo, Youngchoon; Wright, Adam J.; Yang, Liming; Hamilton, Mark P.; Johnson, Todd A.; Kahraman, Abdullah; Kellis, Manolis; Polak, Paz; Sallari, Richard; Sinnott-Armstrong, Nasa; von Mering, Christian; Beltran, Sergi; Gerhard, Daniela S.; Gut, Marta; Trotta, Jean-Remi; Whalley, Justin P.; Niu, Beifang; Espiritu, Shadrielle M. G.; Gao, Shengjie; Huang, Yi; Lalansingh, Christopher M.; Teague, Jon W.; Wendl, Michael C.; Abascal, Federico; Bader, Gary D.; Bandopadhayay, Pratiti; Barenboim, Jonathan; Brunak, Soren; Fita, Joana Carlevaro; Chakravarty, Dimple; Chan, Calvin Wing Yiu; Choi, Jung Kyoon; Diamanti, Klev; Fink, J. Lynn; Frigola, Joan; Gambacorti-Passerini, Carlo; Garsed, Dale W.; Haradhvala, Nicholas J.; Harmanci, Arif O.; Helmy, Mohamed; Herrmann, Carl; Hobolth, Asger; Hodzic, Ermin; Hong, Chen; Isaev, Keren; Izarzugaza, Jose M. G.; Johnson, Rory; Juul, Randi Istrup; Kim, Jaegil; Kim, Jong K.; Komorowski, Jan; Lanzos, Andres; Larsson, Erik; Lee, Donghoon; Li, Shantao; Li, Xiaotong; Lin, Ziao; Liu, Eric Minwei; Lochovsky, Lucas; Lou, Shaoke; Madsen, Tobias; Marchal, Kathleen; Fundichely, Alexander Martinez; McGillivray, Patrick D.; Meyerson, William; Paczkowska, Marta; Park, Keunchil; Park, Kiejung; Pons, Tirso; Pulido-Tamayo, Sergio; Reyes Salazar, Iker; Reyna, Matthew A.; Rubin, Mark A.; Salichos, Leonidas; Sander, Chris; Schumacher, Steven E.; Shackleton, Mark; Shen, Ciyue; Shrestha, Raunak; Shuai, Shimin; Tsunoda, Tatsuhiko; Umer, Husen M.; Uuskula-Reimand, Liis; Verbeke, Lieven P. C.; Wadelius, Claes; Wadi, Lina; Warrell, Jonathan; Wu, Guanming; Yu, Jun; Zhang, Jing; Zhang, Xuanping; Zhang, Yan; Zhao, Zhongming; Zou, Lihua; Lawrence, Michael S.; Raphael, Benjamin J.; Bailey, Peter J.; Craft, David; Goldman, Mary J.; Aburatani, Hiroyuki; Binder, Hans; Dinh, Huy Q.; Heath, Simon C.; Hoffmann, Steve; Imbusch, Charles David; Kretzmer, Helene; Laird, Peter W.; Martin-Subero, Jose; Nagae, Genta; Shen, Hui; Wang, Qi; Weichenhan, Dieter; Zhou, Wanding; Berman, Benjamin P.; Brors, Benedikt; Plass, Christoph; Akdemir, Kadir C.; Bowtell, David D. L.; Burns, Kathleen H.; Busanovich, John; Chan, Kin; Dueso-Barroso, Ana; Edwards, Paul A.; Etemadmoghadam, Dariush; Haber, James E.; Jones, David T. W.; Ju, Young Seok; Kazanov, Marat D.; Koh, Youngil; Kumar, Kiran; Lee, Eunjung Alice; Lee, Jake June-Koo; Lynch, Andy G.; Macintyre, Geoff; Markowetz, Florian; Navarro, Fabio C. P.; Pearson, John; Rippe, Karsten; Scully, Ralph; Villasante, Izar; Waddell, Nicola; Yang, Lixing; Yao, Xiaotong; Yoon, Sung-Soo; Zhang, Cheng-Zhong; Bergstrom, Erik N.; Boot, Arnoud; Covington, Kyle; Fujimoto, Akihiro; Huang, Mi Ni; Islam, S. M. Ashiqul; McPherson, John R.; Morganella, Sandro; Mustonen, Ville; Ng, Alvin Wei Tian; Prokopec, Stephenie D.; Vazquez-Garcia, Ignacio; Wu, Yang; Yousif, Fouad; Yu, Willie; Rozen, Steven G.; Rudneva, Vasilisa A.; Shringarpure, Suyash S.; Turner, Daniel J.; Xia, Tian; Atwal, Gurnit; Chang, David K.; Cooke, Susanna L.; Faltas, Bishoy M.; Haider, Syed; Kaiser, Vera B.; Karlic, Rosa; Kato, Mamoru; Kubler, Kirsten; Margolin, Adam; Martin, Sancha; Nik-Zainal, Serena; P'ng, Christine; Semple, Colin A.; Smith, Jaclyn; Sun, Ren X.; Thai, Kevin; Wright, Derek W.; Yuan, Ke; Biankin, Andrew; Garraway, Levi; Grimmond, Sean M.; Adams, David J.; Anur, Pavana; Cao, Shaolong; Christie, Elizabeth L.; Cmero, Marek; Cun, Yupeng; Dawson, Kevin J.; Dentro, Stefan C.; Deshwar, Amit G.; Donmez, Nilgun; Drews, Ruben M.; Gerstung, Moritz; Ha, Gavin; Haase, Kerstin; Jerman, Lara; Ji, Yuan; Jolly, Clemency; Lee, Juhee; Lee-Six, Henry; Malikic, Salem; Mitchell, Thomas J.; Morris, Quaid D.; Oesper, Layla; Peifer, Martin; Peto, Myron; Rosebrock, Daniel; Rubanova, Yulia; Salcedo, Adriana; Sengupta, Subhajit; Shi, Ruian; Shin, Seung Jun; Spiro, Oliver; Vembu, Shankar; Wintersinger, Jeffrey A.; Yang, Tsun-Po; Yu, Kaixian; Zhu, Hongtu; Spellman, Paul T.; Weinstein, John N.; Chen, Yiwen; Fujita, Masashi; Han, Leng; Hasegawa, Takanori; Komura, Mitsuhiro; Li, Jun; Mizuno, Shinichi; Shimizu, Eigo; Wang, Yumeng; Xu, Yanxun; Yamaguchi, Rui; Yang, Fan; Yang, Yang; Yoon, Christopher J.; Yuan, Yuan; Liang, Han; Alawi, Malik; Borozan, Ivan; Brewer, Daniel S.; Cooper, Colin S.; Desai, Nikita; Grundhoff, Adam; Iskar, Murat; Su, Xiaoping; Zapatka, Marc; Lichter, Peter; Alsop, Kathryn; Bruxner, Timothy J. C.; Christ, Angelika N.; Cordner, Stephen M.; Cowin, Prue A.; Drapkin, Ronny; Fereday, Sian; George, Joshy; Hamilton, Anne; Holmes, Oliver; Hung, Jillian A.; Kassahn, Karin S.; Kazakoff, Stephen H.; Kennedy, Catherine J.; Leonard, Conrad R.; Mileshkin, Linda; Miller, David K.; Arnau, Gisela Mir; Mitchell, Chris; Newell, Felicity; Nones, Katia; Patch, Ann-Marie; Quinn, Michael C.; Taylor, Darrin F.; Thorne, Heather; Traficante, Nadia; Vedururu, Ravikiran; Waddell, Nick M.; Waring, Paul M.; Wood, Scott; Xu, Qinying; DeFazio, Anna; Anderson, Matthew J.; Antonello, Davide; Barbour, Andrew P.; Bassi, Claudio; Bersani, Samantha; Cataldo, Ivana; Chantrill, Lorraine A.; Chiew, Yoke-Eng; Chou, Angela; Cingarlini, Sara; Cloonan, Nicole; Corbo, Vincenzo; Davi, Maria Vittoria; Duthie, Fraser R.; Gill, Anthony J.; Graham, Janet S.; Harliwong, Ivon; Jamieson, Nigel B.; Johns, Amber L.; Kench, James G.; Landoni, Luca; Lawlor, Rita T.; Mafficini, Andrea; Merrett, Neil D.; Miotto, Marco; Musgrove, Elizabeth A.; Nagrial, Adnan M.; Oien, Karin A.; Pajic, Marina; Pinese, Mark; Robertson, Alan J.; Rooman, Ilse; Rusev, Borislav C.; Samra, Jaswinder S.; Scardoni, Maria; Scarlett, Christopher J.; Scarpa, Aldo; Sereni, Elisabetta; Sikora, Katarzyna O.; Simbolo, Michele; Taschuk, Morgan L.; Toon, Christopher W.; Vicentini, Caterina; Wu, Jianmin; Zeps, Nikolajs; Behren, Andreas; Burke, Hazel; Cebon, Jonathan; Dagg, Rebecca A.; De Paoli-Iseppi, Ricardo; Dutton-Regester, Ken; Field, Matthew A.; Fitzgerald, Anna; Hersey, Peter; Jakrot, Valerie; Johansson, Peter A.; Kakavand, Hojabr; Kefford, Richard F.; Lau, Loretta M. S.; Long, Georgina; Pickett, Hilda A.; Pritchard, Antonia L.; Pupo, Gulietta M.; Saw, Robyn P. M.; Schramm, Sarah-Jane; Shang, Catherine A.; Shang, Ping; Spillane, Andrew J.; Stretch, Jonathan R.; Tembe, Varsha; Thompson, John F.; Vilain, Ricardo E.; Wilmott, James S.; Yang, Jean Y.; Hayward, Nicholas K.; Mann, Graham J.; Scolyer, Richard A.; Bartlett, John; Bavi, Prashant; Chadwick, Dianne E.; Chan-Seng-Yue, Michelle; Cleary, Sean; Connor, Ashton A.; Czajka, Karolina; Denroche, Robert E.; Dhani, Neesha C.; Eagles, Jenna; Gallinger, Steven; Grant, Robert C.; Hedley, David; Hollingsworth, Michael A.; Jang, Gun Ho; Johns, Jeremy; Kalimuthu, Sangeetha; Liang, Sheng-Ben; Lungu, Ilinca; Luo, Xuemei; Mbabaali, Faridah; McPherson, Treasa A.; Miller, Jessica K.; Moore, Malcolm J.; Notta, Faiyaz; Pasternack, Danielle; Petersen, Gloria M.; Roehrl, Michael H. A.; Sam, Michelle; Selander, Iris; Serra, Stefano; Shahabi, Sagedeh; Thayer, Sarah P.; Timms, Lee E.; Wilson, Gavin W.; Wilson, Julie M.; Wouters, Bradly G.; McPherson, John D.; Beck, Timothy A.; Bhandari, Vinayak; Collins, Colin C.; Fleshner, Neil E.; Fox, Natalie S.; Fraser, Michael; Heisler, Lawrence E.; Lalonde, Emilie; Livingstone, Julie; Meng, Alice; Sabelnykova, Veronica Y.; Shiah, Yu-Jia; Van Der Kwast, Theodorus; Bristow, Robert G.; Ding, Shuai; Fan, Daiming; Li, Lin; Nie, Yongzhan; Xiao, Xiao; Xing, Rui; Yang, Shanlin; Yu, Yingyan; Zhou, Yong; Banks, Rosamonde E.; Bourque, Guillaume; Brennan, Paul; Letourneau, Louis; Riazalhosseini, Yasser; Scelo, Ghislaine; Vasudev, Naveen; Viksna, Juris; Lathrop, Mark; Tost, Jorg; Ahn, Sung-Min; Aparicio, Samuel; Arnould, Laurent; Aure, M. R.; Bhosle, Shriram G.; Birney, Ewan; Borg, Ake; Boyault, Sandrine; Brinkman, Arie B.; Brock, Jane E.; Broeks, Annegien; Borresen-Dale, Anne-Lise; Caldas, Carlos; Chin, Suet-Feung; Davies, Helen; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Ehinger, Anna; Eyfjord, Jorunn E.; Fatima, Aquila; Foekens, John A.; Futreal, P. A.; Garred, Oystein; Giri, Dilip D.; Glodzik, Dominik; Grabau, Dorthe; Hilmarsdottir, Holmfridur; Hooijer, Gerrit K.; Jacquemier, Jocelyne; Jang, Se Jin; Jonasson, Jon G.; Jonkers, Jos; Kim, Hyung-Yong; King, Tari A.; Knappskog, Stian; Kong, Gu; Krishnamurthy, Savitri; Lakhani, Sunil R.; Langerod, Anita; Larsimont, Denis; Lee, Hee Jin; Lee, Jeong-Yeon; Lee, Ming Ta Michael; Lingjaerde, Ole Christian; MacGrogan, Gaetan; Martens, John W. M.; O'Meara, Sarah; Pauporte, Iris; Pinder, Sarah; Pivot, Xavier; Provenzano, Elena; Purdie, Colin A.; Ramakrishna, Manasa; Ramakrishnan, Kamna; Reis-Filho, Jorge; Richardson, Andrea L.; Ringner, Markus; Rodriguez, Javier Bartolome; Rodriguez-Gonzalez, F. German; Romieu, Gilles; Salgado, Roberto; Sauer, Torill; Shepherd, Rebecca; Sieuwerts, Anieta M.; Simpson, Peter T.; Smid, Marcel; Sotiriou, Christos; Span, Paul N.; Stefansson, Olafur Andri; Stenhouse, Alasdair; Stunnenberg, Henk G.; Sweep, Fred; Tan, Benita Kiat Tee; Thomas, Gilles; Thompson, Alastair M.; Tommasi, Stefania; Treilleux, Isabelle; Tutt, Andrew; Ueno, Naoto T.; Van Laere, Steven; Van den Eynden, Gert G.; Vermeulen, Peter; Viari, Alain; Vincent-Salomon, Anne; Wong, Bernice H.; Yates, Lucy; Zou, Xueqing; van Deurzen, Carolien H. M.; van de Vijver, Marc J.; van't Veer, Laura; Ammerpohl, Ole; Aukema, Sietse; Bergmann, Anke K.; Bernhart, Stephan H.; Borkhardt, Arndt; Borst, Christoph; Burkhardt, Birgit; Claviez, Alexander; Goebler, Maria Elisabeth; Haake, Andrea; Haas, Siegfried; Hansmann, Martin; Hoell, Jessica; Hummel, Michael; Karsch, Dennis; Klapper, Wolfram; Kneba, Michael; Kreuz, Markus; Kube, Dieter; Kueppers, Ralf; Lenze, Dido; Loeffler, Markus; Lopez, Cristina; Mantovani-Loeffler, Luisa; Moeller, Peter; Ott, German; Radlwimmer, Bernhard; Richter, Julia; Rohde, Marius; Rosenstiel, Philip C.; Rosenwald, Andreas; Schilhabel, Markus B.; Schreiber, Stefan; Stadler, Peter F.; Staib, Peter; Stilgenbauer, Stephan; Sungalee, Stephanie; Szczepanowski, Monika; Toprak, Umut H.; Truemper, Lorenz H. P.; Wagener, Rabea; Zenz, Thorsten; Hovestadt, Volker; von Kalle, Christof; Kool, Marcel; Korshunov, Andrey; Landgraf, Pablo; Lehrach, Hans; Northcott, Paul A.; Pfister, Stefan M.; Reifenberger, Guido; Warnatz, Hans-Joerg; Wolf, Stephan; Yaspo, Marie-Laure; Assenov, Yassen; Gerhauser, Clarissa; Minner, Sarah; Schlomm, Thorsten; Simon, Ronald; Sauter, Guido; Sueltmann, Holger; Biswas, Nidhan K.; Maitra, Arindam; Majumder, Partha P.; Sarin, Rajiv; Barbi, Stefano; Bonizzato, Giada; Cantu, Cinzia; Dei Tos, Angelo P.; Fassan, Matteo; Grimaldi, Sonia; Luchini, Claudio; Malleo, Giuseppe; Marchegiani, Giovanni; Milella, Michele; Paiella, Salvatore; Pea, Antonio; Pederzoli, Paolo; Ruzzenente, Andrea; Salvia, Roberto; Sperandio, Nicola; Arai, Yasuhito; Hama, Natsuko; Hiraoka, Nobuyoshi; Hosoda, Fumie; Nakamura, Hiromi; Ojima, Hidenori; Okusaka, Takuji; Totoki, Yasushi; Urushidate, Tomoko; Fukayama, Masashi; Ishikawa, Shumpei; Katai, Hitoshi; Katoh, Hiroto; Komura, Daisuke; Rokutan, Hirofumi; Saito-Adachi, Mihoko; Suzuki, Akihiro; Taniguchi, Hirokazu; Tatsuno, Kenji; Ushiku, Tetsuo; Yachida, Shinichi; Yamamoto, Shogo; Aikata, Hiroshi; Arihiro, Koji; Ariizumi, Shun-ichi; Chayama, Kazuaki; Furuta, Mayuko; Gotoh, Kunihito; Hayami, Shinya; Hirano, Satoshi; Kawakami, Yoshiiku; Maejima, Kazuhiro; Nakamura, Toru; Nakano, Kaoru; Ohdan, Hideki; Sasaki-Oku, Aya; Tanaka, Hiroko; Ueno, Masaki; Yamamoto, Masakazu; Yamaue, Hiroki; Choo, Su Pin; Cutcutache, Ioana; Khuntikeo, Narong; Ong, Choon Kiat; Pairojkul, Chawalit; Popescu, Irinel; Ahn, Keun Soo; Aymerich, Marta; Lopez-Guillermo, Armando; Lopez-Otin, Carlos; Puente, Xose S.; Campo, Elias; Amary, Fernanda; Baumhoer, Daniel; Behjati, Sam; Bjerkehagen, Bodil; Futreal, P. A.; Myklebost, Ola; Pillay, Nischalan; Tarpey, Patrick; Tirabosco, Roberto; Zaikova, Olga; Flanagan, Adrienne M.; Boultwood, Jacqueline; Bowen, David T.; Cazzola, Mario; Green, Anthony R.; Hellstrom-Lindberg, Eva; Malcovati, Luca; Nangalia, Jyoti; Papaemmanuil, Elli; Vyas, Paresh; Ang, Yeng; Barr, Hugh; Beardsmore, Duncan; Eldridge, Matthew; Gossage, James; Grehan, Nicola; Hanna, George B.; Hayes, Stephen J.; Hupp, Ted R.; Khoo, David; Lagergren, Jesper; Lovat, Laurence B.; MacRae, Shona; O'Donovan, Maria; O'Neill, J. Robert; Parsons, Simon L.; Preston, Shaun R.; Puig, Sonia; Roques, Tom; Sanders, Grant; Sothi, Sharmila; Tavare, Simon; Tucker, Olga; Turkington, Richard; Underwood, Timothy J.; Welch, Ian; Fitzgerald, Rebecca C.; Berney, Daniel M.; De Bono, Johann S.; Cahill, Declan; Camacho, Niedzica; Dennis, Nening M.; Dudderidge, Tim; Edwards, Sandra E.; Fisher, Cyril; Foster, Christopher S.; Ghori, Mohammed; Gill, Pelvender; Gnanapragasam, Vincent J.; Gundem, Gunes; Hamdy, Freddie C.; Hawkins, Steve; Hazell, Steven; Howat, William; Isaacs, William B.; Karaszi, Katalin; Kay, Jonathan D.; Khoo, Vincent; Kote-Jarai, Zsofia; Kremeyer, Barbara; Kumar, Pardeep; Lambert, Adam; Leongamornlert, Daniel A.; Livni, Naomi; Lu, Yong-Jie; Luxton, Hayley J.; Marsden, Luke; Massie, Charlie E.; Matthews, Lucy; Mayer, Erik; McDermott, Ultan; Merson, Sue; Neal, David E.; Ng, Anthony; Nicol, David; Ogden, Christopher; Rowe, Edward W.; Shah, Nimish C.; Thomas, Sarah; Thompson, Alan; Verrill, Clare; Visakorpi, Tapio; Warren, Anne Y.; Whitaker, Hayley C.; Zhang, Hongwei; van As, Nicholas; Eeles, Rosalind A.; Abeshouse, Adam; Agrawal, Nishant; Akbani, Rehan; Al Ahmadie, Hikmat; Albert, Monique; Aldape, Kenneth; Ally, Adrian; Appelbaum, Elizabeth L.; Armenia, Joshua; Asa, Sylvia; Auman, J. Todd; Balasundaram, Miruna; Balu, Saianand; Barnholtz-Sloan, Jill; Bathe, Oliver F.; Baylin, Stephen B.; Benz, Christopher; Berchuck, Andrew; Berrios, Mario; Bigner, Darell; Birrer, Michael; Bodenheimer, Tom; Boice, Lori; Bootwalla, Moiz S.; Bosenberg, Marcus; Bowlby, Reanne; Boyd, Jeffrey; Broaddus, Russell R.; Brock, Malcolm; Brooks, Denise; Bullman, Susan; Caesar-Johnson, Samantha J.; Carey, Thomas E.; Carlsen, Rebecca; Cerfolio, Robert; Chandan, Vishal S.; Chen, Hsiao-Wei; Cherniack, Andrew D.; Chien, Jeremy; Cho, Juok; Chuah, Eric; Cibulskis, Carrie; Cope, Leslie; Cordes, Matthew G.; Curley, Erin; Czerniak, Bogdan; Danilova, Ludmila; Davis, Ian J.; Defreitas, Timothy; Demchok, John A.; Dhalla, Noreen; Dhir, Rajiv; Doddapaneni, HarshaVardhan; El-Naggar, Adel; Felau, Ina; Ferguson, Martin L.; Finocchiaro, Gaetano; Fong, Kwun M.; Frazer, Scott; Friedman, William; Fronick, Catrina C.; Fulton, Lucinda A.; Gabriel, Stacey B.; Gao, Jianjiong; Gehlenborg, Nils; Gershenwald, Jeffrey E.; Ghossein, Ronald; Giama, Nasra H.; Gibbs, Richard A.; Gomez, Carmen; Govindan, Ramaswamy; Hayes, D. Neil; Hegde, Apurva M.; Heiman, David; Heins, Zachary; Hepperla, Austin J.; Holbrook, Andrea; Holt, Robert A.; Hoyle, Alan P.; Hruban, Ralph H.; Hu, Jianhong; Huang, Mei; Huntsman, David; Huse, Jason; Donahue, Christine A. Iacobuzio; Ittmann, Michael; Jayaseelan, Joy C.; Jefferys, Stuart R.; Jones, Corbin D.; Jones, Steven J. M.; Juhl, Hartmut; Kang, Koo Jeong; Karlan, Beth; Kasaian, Katayoon; Kebebew, Electron; Kim, Hark Kyun; Korchina, Viktoriya; Kundra, Ritika; Lai, Phillip H.; Lander, Eric; Le, Xuan; Lee, Darlene; Levine, Douglas A.; Lewis, Lora; Ley, Tim; Li, Haiyan Irene; Lin, Pei; Linehan, W. M.; Liu, Fei Fei; Lu, Yiling; Lype, Lisa; Ma, Yussanne; Maglinte, Dennis T.; Mardis, Elaine R.; Marks, Jeffrey; Marra, Marco A.; Matthew, Thomas J.; Mayo, Michael; McCune, Karen; Meier, Samuel R.; Meng, Shaowu; Mieczkowski, Piotr A.; Mikkelsen, Tom; Miller, Christopher A.; Mills, Gordon B.; Moore, Richard A.; Morrison, Carl; Mose, Lisle E.; Moser, Catherine D.; Mungall, Andrew J.; Mungall, Karen; Mutch, David; Muzny, Donna M.; Myers, Jerome; Newton, Yulia; Noble, Michael S.; O'Donnell, Peter; O'Neill, Brian Patrick; Ochoa, Angelica; Park, Joong-Won; Parker, Joel S.; Pass, Harvey; Pastore, Alessandro; Pennell, Nathan A.; Perou, Charles M.; Petrelli, Nicholas; Potapova, Olga; Rader, Janet S.; Ramalingam, Suresh; Rathmell, W. Kimryn; Reuter, Victor; Reynolds, Sheila M.; Ringel, Matthew; Roach, Jeffrey; Roberts, Lewis R.; Robertson, A. Gordon; Sadeghi, Sara; Saller, Charles; Sanchez-Vega, Francisco; Schadendorf, Dirk; Schein, Jacqueline E.; Schmidt, Heather K.; Schultz, Nikolaus; Seethala, Raja; Senbabaoglu, Yasin; Shelton, Troy; Shi, Yan; Shih, Juliann; Shmulevich, Ilya; Shriver, Craig; Signoretti, Sabina; Simons, Janae; Singer, Samuel; Sipahimalani, Payal; Skelly, Tara J.; McCune, Karen Smith; Socci, Nicholas D.; Soloway, Matthew G.; Sood, Anil K.; Tam, Angela; Tan, Donghui; Tarnuzzer, Roy; Thiessen, Nina; Thompson, R. Houston; Thorne, Leigh B.; Tsao, Ming; Umbricht, Christopher; Van Den Berg, David J.; Van Meir, Erwin G.; Veluvolu, Umadevi; Voet, Douglas; Wang, Linghua; Weinberger, Paul; Weisenberger, Daniel J.; Wigle, Dennis; Wilkerson, Matthew D.; Wilson, Richard K.; Winterhoff, Boris; Wiznerowicz, Maciej; Wong, Tina; Wong, Winghing; Xi, Liu; Yau, Christina; Zhang, Hailei; Zhang, Hongxin; Zhang, Jiashan (2020)
    Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). 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 promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).
  • Zhang, Xi; Kong, Weikaixin; Gao, Miaomiao; Huang, Weiran; Peng, Chao; Huang, Zhuo; Xie, Zhengwei; Guo, Hongyan (2022)
    Immune infiltration of ovarian cancer (OV) is a critical factor in determining patient's prognosis. Using data from TCGA and GTEx database combined with WGCNA and ESTIMATE methods, 46 genes related to OV occurrence and immune infiltration were identified. Lasso and multivariate Cox regression were applied to define a prognostic score (IGCI score) based on 3 immune genes and 3 types of clinical information. The IGCI score has been verified by K-M curves, ROC curves and C-index on test set. In test set, IGCI score (C-index = 0.630) is significantly better than AJCC stage (C-index = 0.541, p < 0.05) and CIN25 (C-index = 0.571, p < 0.05). In addition, we identified key mutations to analyse prognosis of patients and the process related to immunity. Chi-squared tests revealed that 6 mutations are significantly (p < 0.05) related to immune infiltration: BRCA1, ZNF462, VWF, RBAK, RB1 and ADGRV1. According to mutation survival analysis, we found 5 key mutations significantly related to patient prognosis (p < 0.05): CSMD3, FLG2, HMCN1, TOP2A and TRRAP. RB1 and CSMD3 mutations had small p-value (p < 0.1) in both chi-squared tests and survival analysis. The drug sensitivity analysis of key mutation showed when RB1 mutation occurs, the efficacy of six anti-tumour drugs has changed significantly (p < 0.05).
  • Pietilä, Mika; Sahgal, Pranshu; Peuhu, Emilia; Jäntti, Niklas Z.; Paatero, Ilkka; Närvä, Elisa; Al-Akhrass, Hussein; Lilja, Johanna; Georgiadou, Maria; Andersen, Olav M.; Padzik, Artur; Sihto, Harri; Joensuu, Heikki; Blomqvist, Matias; Saarinen, Irena; Boström, Peter J.; Taimen, Pekka; Ivaska, Johanna (2019)
    The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.
  • Rajala, Hanna L. M.; Olson, Thomas; Clemente, Michael J.; Lagstrom, Sonja; Ellonen, Pekka; Lundan, Tuija; Hamm, David E.; Zaman, Syed Arshi Uz; Marti, Jesus M. Lopez; Andersson, Emma I.; Jerez, Andres; Porkka, Kimmo; Maciejewski, Jaroslaw P.; Loughran, Thomas P.; Mustjoki, Satu (2015)
  • Kumar, Ashwini; Kankainen, Matti; Parsons, Alun; Kallioniemi, Olli; Mattila, Pirkko; Heckman, Caroline A. (2017)
    Background: RNA sequencing (RNA-seq) has become an indispensable tool to identify disease associated transcriptional profiles and determine the molecular underpinnings of diseases. However, the broad adaptation of the methodology into the clinic is still hampered by inconsistent results from different RNA-seq protocols and involves further evaluation of its analytical reliability using patient samples. Here, we applied two commonly used RNA-seq library preparation protocols to samples from acute leukemia patients to understand how poly-A-tailed mRNA selection (PA) and ribo-depletion (RD) based RNA-seq library preparation protocols affect gene fusion detection, variant calling, and gene expression profiling. Results: Overall, the protocols produced similar results with consistent outcomes. Nevertheless, the PA protocol was more efficient in quantifying expression of leukemia marker genes and showed better performance in the expression-based classification of leukemia. Independent qRT-PCR experiments verified that the PA protocol better represented total RNA compared to the RD protocol. In contrast, the RD protocol detected a higher number of non-coding RNA features and had better alignment efficiency. The RD protocol also recovered more known fusion-gene events, although variability was seen in fusion gene predictions. Conclusion: The overall findings provide a framework for the use of RNA-seq in a precision medicine setting with limited number of samples and suggest that selection of the library preparation protocol should be based on the objectives of the analysis.
  • PCAWG Mutational Signatures Workin; PCAWG Consortium (2020)
    Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature(1). Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium(2) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses(3-15), enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
  • Peltomäki, Paivi; Olkinuora, Alisa; Nieminen, Taina T. (2020)
    ABSTRACT Introduction Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment. Areas covered The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed. Expert commentary LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.