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1.  ICGC PedBrain: Dissecting the genomic complexity underlying medulloblastoma 
Jones, David TW | Jäger, Natalie | Kool, Marcel | Zichner, Thomas | Hutter, Barbara | Sultan, Marc | Cho, Yoon-Jae | Pugh, Trevor J | Hovestadt, Volker | Stütz, Adrian M | Rausch, Tobias | Warnatz, Hans-Jörg | Ryzhova, Marina | Bender, Sebastian | Sturm, Dominik | Pleier, Sabrina | Cin, Huriye | Pfaff, Elke | Sieber, Laura | Wittmann, Andrea | Remke, Marc | Witt, Hendrik | Hutter, Sonja | Tzaridis, Theophilos | Weischenfeldt, Joachim | Raeder, Benjamin | Avci, Meryem | Amstislavskiy, Vyacheslav | Zapatka, Marc | Weber, Ursula D | Wang, Qi | Lasitschka, Bärbel | Bartholomae, Cynthia C | Schmidt, Manfred | von Kalle, Christof | Ast, Volker | Lawerenz, Chris | Eils, Jürgen | Kabbe, Rolf | Benes, Vladimir | van Sluis, Peter | Koster, Jan | Volckmann, Richard | Shih, David | Betts, Matthew J | Russell, Robert B | Coco, Simona | Tonini, Gian Paolo | Schüller, Ulrich | Hans, Volkmar | Graf, Norbert | Kim, Yoo-Jin | Monoranu, Camelia | Roggendorf, Wolfgang | Unterberg, Andreas | Herold-Mende, Christel | Milde, Till | Kulozik, Andreas E | von Deimling, Andreas | Witt, Olaf | Maass, Eberhard | Rössler, Jochen | Ebinger, Martin | Schuhmann, Martin U | Frühwald, Michael C | Hasselblatt, Martin | Jabado, Nada | Rutkowski, Stefan | von Bueren, André O | Williamson, Dan | Clifford, Steven C | McCabe, Martin G | Collins, V. Peter | Wolf, Stephan | Wiemann, Stefan | Lehrach, Hans | Brors, Benedikt | Scheurlen, Wolfram | Felsberg, Jörg | Reifenberger, Guido | Northcott, Paul A | Taylor, Michael D | Meyerson, Matthew | Pomeroy, Scott L | Yaspo, Marie-Laure | Korbel, Jan O | Korshunov, Andrey | Eils, Roland | Pfister, Stefan M | Lichter, Peter
Nature  2012;488(7409):100-105.
Medulloblastoma is an aggressively-growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and displays tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life.
Four tumour subgroups with distinct clinical, biological and genetic profiles are currently discriminated2,3. WNT tumours, displaying activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 & 4 tumours are molecularly less well-characterised, and also present the greatest clinical challenges2,3,5. The full repertoire of genetic events driving this distinction, however, remains unclear.
Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs. Tetraploidy was identified as a frequent early event in Group 3 & 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA-sequencing confirmed these alterations, and revealed the expression of the first medulloblastoma fusion genes. Chromatin modifiers were frequently altered across all subgroups.
These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 & 4 patients.
PMCID: PMC3662966  PMID: 22832583
Neuro-Oncology  2014;16(Suppl 3):iii24.
BACKGROUND: Although childhood malignancies have become curable in about 75% of cases due to empirically developed multi-modal therapeutic concepts applied in nation-wide collaborative trials, for children with a relapse, cure remains the exception. In the framework of the ICGC project PedBrain many new potentially druggable genetic lesions have been identified. However, it will not be feasible to conduct traditional phase I trials for all these new drugs in these overall rare entities. To still have our young patients participating in the recent advances in molecular targeted drug treatment, we initiated a novel innovative way of introducing these drugs in a clinical setting based on an individualized molecular rationale, a concept called INFORM (INdividualized therapy For Relapsed Malignancies in childhood). METHODS: Exome- and low-coverage whole-genome sequencing, RNA sequencing, gene expression profiling, DNA methylation profiling, bioinformatic prediction of drug targets and compound selection are carried out aiming at a turnaround time of 4 weeks or less after re-biopsy of the tumor. In the current feasibility phase, drug targets and prioritization are offered to the treating physician in the local hospital for individual treatment decisions. RESULTS: Ten patients were recruited to the INFORM-pilot study by now. For all but two, druggable targets have been identified. The first two patients with early follow-up MRIs after 6 weeks had stable disease (medulloblastoma) and 50% tumor volume reduction (myofibroblastc tumor), respectively. In an additional case with pontine glioma, molecular diagnostics significantly contributed to the establishment of an unambiguous diagnosis. CONCLUSIONS: This is the first population-based study using next-generation sequencing technologies to guide treatment decisions in a clinical setting. In addition to this advance in “next-generation” clinical oncology, INFORM will also reveal the largest comprehensive molecular datasets of relapsed tumors to date, and since primary tumor material from the same patient will also be analyzed whenever available, will likely identify key biological properties of relapsing malignancies and recurrent mechanisms of drug resistance across entities. SECONDARY CATEGORY: Pediatrics.
PMCID: PMC4144608
3.  Human genome meeting 2016 
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R. | Guelly, C. | Abilova, Z. | Rakhimova, S. | Akhmetova, A. | Kairov, U. | Trajanoski, S. | Zhumadilov, Z. | Bekbossynova, M. | Schumacher, C. | Sandhu, S. | Harkins, T. | Makarov, V. | Doddapaneni, H. | Glenn, R. | Momin, Z. | Dilrukshi, B. | Chao, H. | Meng, Q. | Gudenkauf, B. | Kshitij, R. | Jayaseelan, J. | Nessner, C. | Lee, S. | Blankenberg, K. | Lewis, L. | Hu, J. | Han, Y. | Dinh, H. | Jireh, S. | Walker, K. | Boerwinkle, E. | Muzny, D. | Gibbs, R. | Hu, J. | Walker, K. | Buhay, C. | Liu, X. | Wang, Q. | Sanghvi, R. | Doddapaneni, H. | Ding, Y. | Veeraraghavan, N. | Yang, Y. | Boerwinkle, E. | Beaudet, A. L. | Eng, C. M. | Muzny, D. M. | Gibbs, R. A. | Worley, K. C. C. | Liu, Y. | Hughes, D. S. T. | Murali, S. C. | Harris, R. A. | English, A. C. | Qin, X. | Hampton, O. A. | Larsen, P. | Beck, C. | Han, Y. | Wang, M. | Doddapaneni, H. | Kovar, C. L. | Salerno, W. J. | Yoder, A. | Richards, S. | Rogers, J. | Lupski, J. R. | Muzny, D. M. | Gibbs, R. A. | Meng, Q. | Bainbridge, M. | Wang, M. | Doddapaneni, H. | Han, Y. | Muzny, D. | Gibbs, R. | Harris, R. A. | Raveenedran, M. | Xue, C. | Dahdouli, M. | Cox, L. | Fan, G. | Ferguson, B. | Hovarth, J. | Johnson, Z. | Kanthaswamy, S. | Kubisch, M. | Platt, M. | Smith, D. | Vallender, E. | Wiseman, R. | Liu, X. | Below, J. | Muzny, D. | Gibbs, R. | Yu, F. | Rogers, J. | Lin, J. | Zhang, Y. | Ouyang, Z. | Moore, A. | Wang, Z. | Hofmann, J. | Purdue, M. | Stolzenberg-Solomon, R. | Weinstein, S. | Albanes, D. | Liu, C. S. | Cheng, W. L. | Lin, T. T. | Lan, Q. | Rothman, N. | Berndt, S. | Chen, E. S. | Bahrami, H. | Khoshzaban, A. | Keshal, S. Heidari | Bahrami, H. | Khoshzaban, A. | Keshal, S. Heidari | Alharbi, K. K. R. | Zhalbinova, M. | Akilzhanova, A. | Rakhimova, S. | Bekbosynova, M. | Myrzakhmetova, S. | Matar, M. | Mili, N. | Molinari, R. | Ma, Y. | Guerrier, S. | Elhawary, N. | Tayeb, M. | Bogari, N. | Qotb, N. | McClymont, S. A. | Hook, P. W. | Goff, L. A. | McCallion, A. | Kong, Y. | Charette, J. R. | Hicks, W. L. | Naggert, J. K. | Zhao, L. | Nishina, P. M. | Edrees, B. M. | Athar, M. | Al-Allaf, F. A. | Taher, M. M. | Khan, W. | Bouazzaoui, A. | Harbi, N. A. | Safar, R. | Al-Edressi, H. | Anazi, A. | Altayeb, N. | Ahmed, M. A. | Alansary, K. | Abduljaleel, Z. | Kratz, A. | Beguin, P. | Poulain, S. | Kaneko, M. | Takahiko, C. | Matsunaga, A. | Kato, S. | Suzuki, A. M. | Bertin, N. | Lassmann, T. | Vigot, R. | Carninci, P. | Plessy, C. | Launey, T. | Graur, D. | Lee, D. | Kapoor, A. | Chakravarti, A. | Friis-Nielsen, J. | Izarzugaza, J. M. | Brunak, S. | Chakraborty, A. | Basak, J. | Mukhopadhyay, A. | Soibam, B. S. | Das, D. | Biswas, N. | Das, S. | Sarkar, S. | Maitra, A. | Panda, C. | Majumder, P. | Morsy, H. | Gaballah, A. | Samir, M. | Shamseya, M. | Mahrous, H. | Ghazal, A. | Arafat, W. | Hashish, M. | Gruber, J. 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E. | Ona, D. | Llanes, E. | Santos-Cortes, R. L. | Tiongco, R. | Aherrera, J. | Abrahan, L. | Pagauitan-Alan, P. | Morelli, K. H. | Domire, J. S. | Pyne, N. | Harper, S. | Burgess, R. | Zhalbinova, M. | Akilzhanova, A. | Rakhimova, S. | Bekbosynova, M. | Myrzakhmetova, S. | Gari, M. A. | Dallol, A. | Alsehli, H. | Gari, A. | Gari, M. | Abuzenadah, A. | Thomas, M. | Sukhai, M. | Garg, S. | Misyura, M. | Zhang, T. | Schuh, A. | Stockley, T. | Kamel-Reid, S. | Sherry, S. | Xiao, C. | Slotta, D. | Rodarmer, K. | Feolo, M. | Kimelman, M. | Godynskiy, G. | O’Sullivan, C. | Yaschenko, E. | Xiao, C. | Yaschenko, E. | Sherry, S. | Rangel-Escareño, C. | Rueda-Zarate, H. | Tayubi, I. A. | Mohammed, R. | Ahmed, I. | Ahmed, T. | Seth, S. | Amin, S. | Song, X. | Mao, X. | Sun, H. | Verhaak, R. G. | Futreal, A. | Zhang, J. | Whiite, S. 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Human Genomics  2016;10(Suppl 1):12.
Table of contents
O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder
A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson
O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents
R. Polimanti, J. Gelernter
O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort
X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group
O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus
A. Kapoor, D. Lee, A. Chakravarti
O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells
C. Maercker, F. Graf, M. Boutros
O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies
G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis
O7 Role of microRNA in LCL to IPSC reprogramming
S. Kumar, J. Curran, J. Blangero
O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease
S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti
O9 Metabolomic profiling for the diagnosis of neurometabolic disorders
T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea
O10 A novel causal methylation network approach to Alzheimer’s disease
Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett
O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway
A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni
O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types
B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest
O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types
C. A. Semple
O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer
E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project
O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer
F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu
O16 Modeling genetic interactions associated with molecular subtypes of breast cancer
B. Ji, A. Tyler, G. Ananda, G. Carter
O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors
H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski
O18 Predictive biomarkers to metastatic pancreatic cancer treatment
J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman
O19 DDIT4 gene expression as a prognostic marker in several malignant tumors
L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto
O20 Spatial organization of the genome and genomic alterations in human cancers
K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group
O21 Landscape of targeted therapies in solid tumors
S. Patterson, C. Statz, S. Mockus
O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma
S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis
O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis
S. Likhitrattanapisal
O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study
S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen
O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array
T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada
O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation
A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics
O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4
C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung
O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13
K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone
O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data
N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh
O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review
S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs
O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio
S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle
O32 Legal interoperability: a sine qua non for international data sharing
A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group
O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target
H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci
O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs
J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio
O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes
R. Ghosh, S. Plon
O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing
S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs
O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma
T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman
O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver
E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker
O40 A general statistic framework for genome-based disease risk prediction
M. Xiong, L. Ma, N. Lin, C. Amos
O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies
N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong
O42 Big data and NGS data analysis: the cloud to the rescue
O. Dobretsberger, M. Egger, F. Leimgruber
O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing
S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance
O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data
V. A. A. Antonio, N. Ono, Clark Kendrick C. Go
O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data
Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar
O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans
C. Zeng, J. Shao
O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations
H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula
O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing
Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng
O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes?
I. Campbell, M.-A. Young, P. James, Lifepool
O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS
C. Schumacher, S. Sandhu, T. Harkins, V. Makarov
O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform
H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs
O55 Rapid capture methods for clinical sequencing
J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs
O56 A diploid personal human genome model for better genomes from diverse sequence data
K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs
O57 Development of PacBio long range capture for detection of pathogenic structural variants
Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs
O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans
R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers
O59 Assessing RNA structure disruption induced by single-nucleotide variation
J. Lin, Y. Zhang, Z. Ouyang
P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number
A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt
P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility
E. S. Chen
P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients
H. Bahrami, A. Khoshzaban, S. Heidari Keshal
P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population
K. K. R. Alharbi
P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding
M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova
P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population
M. Matar
P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization
N. Mili, R. Molinari, Y. Ma, S. Guerrier
P9 Vulnerability of genetic variants to the risk of autism among Saudi children
N. Elhawary, M. Tayeb, N. Bogari, N. Qotb
P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction
S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion
P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice
Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina
P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients
B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel
P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments
A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey
P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome
D. Graur
P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients
J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak
P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns
B. S. Soibam
P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer
D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder
P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes
J. J. Gruber, N. Jaeger, M. Snyder
P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors
K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson
P23 RNA sequencing identifies gene mutations for neuroblastoma
K. Zhang
P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines
M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales
P25 Targeted Methylation Sequencing of Prostate Cancer
N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder
P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico
S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía
P28 Genetic modifiers of Alström syndrome
J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina
P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos
E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group
P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D
K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess
P34 Molecular regulation of chondrogenic human induced pluripotent stem cells
M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah
P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting
M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid
P36 Accessing genomic evidence for clinical variants at NCBI
S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko
P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA
C. Xiao, E. Yaschenko, S. Sherry
P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling
C. Rangel-Escareño, H. Rueda-Zarate
P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr
S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang
P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data
S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs
P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells
T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium
P43 Rapid and scalable typing of structural variants for disease cohorts
W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs
P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population
A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim
P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations
J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras
P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits
L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups
P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study
S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu
P49 Common variants in casr gene are associated with serum calcium levels in koreans
S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung
P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions
Y. Zhou, S. Xu
P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies
X. Wang, V. Philip, G. Carter
P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment
A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol
P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling
A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar
P54 Direct enrichment for the rapid preparation of targeted NGS libraries
C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel
P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System
R. Nitsche, L. Prieto-Lafuente
P57 ClinVar: a multi-source archive for variant interpretation
M. Landrum, J. Lee, W. Rubinstein, D. Maglott
P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad
P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation
A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler
P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia
F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar
PMCID: PMC4896275  PMID: 27294413
4.  Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma 
Jones, David T.W. | Hutter, Barbara | Jäger, Natalie | Korshunov, Andrey | Kool, Marcel | Warnatz, Hans-Jörg | Zichner, Thomas | Lambert, Sally R. | Ryzhova, Marina | Quang, Dong Anh Khuong | Fontebasso, Adam M. | Stütz, Adrian M. | Hutter, Sonja | Zuckermann, Marc | Sturm, Dominik | Gronych, Jan | Lasitschka, Bärbel | Schmidt, Sabine | Şeker-Cin, Huriye | Witt, Hendrik | Sultan, Marc | Ralser, Meryem | Northcott, Paul A. | Hovestadt, Volker | Bender, Sebastian | Pfaff, Elke | Stark, Sebastian | Faury, Damien | Schwartzentruber, Jeremy | Majewski, Jacek | Weber, Ursula D. | Zapatka, Marc | Raeder, Benjamin | Schlesner, Matthias | Worth, Catherine L. | Bartholomae, Cynthia C. | von Kalle, Christof | Imbusch, Charles D. | Radomski, Sylwester | Lawerenz, Chris | van Sluis, Peter | Koster, Jan | Volckmann, Richard | Versteeg, Rogier | Lehrach, Hans | Monoranu, Camelia | Winkler, Beate | Unterberg, Andreas | Herold-Mende, Christel | Milde, Till | Kulozik, Andreas E. | Ebinger, Martin | Schuhmann, Martin U. | Cho, Yoon-Jae | Pomeroy, Scott L. | von Deimling, Andreas | Witt, Olaf | Taylor, Michael D. | Wolf, Stephan | Karajannis, Matthias A. | Eberhart, Charles G. | Scheurlen, Wolfram | Hasselblatt, Martin | Ligon, Keith L. | Kieran, Mark W. | Korbel, Jan O. | Yaspo, Marie-Laure | Brors, Benedikt | Felsberg, Jörg | Reifenberger, Guido | Collins, V. Peter | Jabado, Nada | Eils, Roland | Lichter, Peter | Pfister, Stefan M.
Nature genetics  2013;45(8):927-932.
Pilocytic astrocytoma, the most common childhood brain tumor1, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations2. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression3 and often becoming a chronic disease with substantial morbidities4.
Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n=73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and novel NTRK2 fusion genes in non-cerebellar tumors. New BRAF activating changes were also observed. MAPK pathway alterations affected 100% of tumors analyzed, with no other significant mutations, indicating pilocytic astrocytoma as predominantly a single-pathway disease.
Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in NF15. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
PMCID: PMC3951336  PMID: 23817572
5.  GOT1/AST1 expression status as a prognostic biomarker in pancreatic ductal adenocarcinoma 
Oncotarget  2015;6(6):4516-4526.
Prognostication in pancreatic ductal adenocarcinoma (PDAC) remains a challenge. Recently, a link between mutated KRAS and glutamic-oxaloacetic transaminase (GOT1/AST1) has been described as part of the metabolic reprogramming in PDAC. The clinical relevance of this novel metabolic KRAS-GOT1 link has not been determined in primary human patient samples. Here we studied the GOT1 expression status as a prognostic biomarker in PDAC. We employed three independent PDAC cohorts with clinicopathological- and follow-up data: a) ICGC, comprising 57 patients with whole-exome sequencing and genome-wide expression profiling; b) ULM, composed of 122 surgically-treated patients with tissue-samples and KRAS status; c) a validation cohort of 140 primary diagnostic biopsy samples. GOT1 expression was assessed by RNA level (ICGC) or immunolabeling (ULM/validation cohort). GOT1 expression varied (ICGC) and correlation with the KRAS mutation- and expression status was imperfect (P = 0.2, ICGC; P = 0.8, ULM). Clinicopathological characteristics did not differ when patients were separated based on GOT1 high vs. low (P = 0.08–1.0); however, overall survival was longer in patients with GOT1-expressing tumors (P = 0.093, ICGC; P = 0.049, ULM). Multivariate analysis confirmed GOT1 as an independent prognostic marker (P = 0.009). Assessment in univariate (P = 0.002) and multivariate models in the validation cohort (P = 0.019), containing 66% stage IV patients, confirmed the independency of GOT1.
We propose the GOT1 expression status as a simple and reliable prognostic biomarker in pancreatic ductal adenocarcinoma.
PMCID: PMC4414208  PMID: 25595905
pancreatic cancer; glutamic oxaloacetatic transaminase 1; KRAS; PDAC; biomarker
6.  International Cancer Genome Consortium Data Portal—a one-stop shop for cancer genomics data 
The International Cancer Genome Consortium (ICGC) is a collaborative effort to characterize genomic abnormalities in 50 different cancer types. To make this data available, the ICGC has created the ICGC Data Portal. Powered by the BioMart software, the Data Portal allows each ICGC member institution to manage and maintain its own databases locally, while seamlessly presenting all the data in a single access point for users. The Data Portal currently contains data from 24 cancer projects, including ICGC, The Cancer Genome Atlas (TCGA), Johns Hopkins University, and the Tumor Sequencing Project. It consists of 3478 genomes and 13 cancer types and subtypes. Available open access data types include simple somatic mutations, copy number alterations, structural rearrangements, gene expression, microRNAs, DNA methylation and exon junctions. Additionally, simple germline variations are available as controlled access data. The Data Portal uses a web-based graphical user interface (GUI) to offer researchers multiple ways to quickly and easily search and analyze the available data. The web interface can assist in constructing complicated queries across multiple data sets. Several application programming interfaces are also available for programmatic access. Here we describe the organization, functionality, and capabilities of the ICGC Data Portal.
Database URL:
PMCID: PMC3263593  PMID: 21930502
Neuro-Oncology  2014;16(Suppl 5):v101.
Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoural heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and Group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. In an effort to uncover novel drivers in these poorly characterized subgroups, we analyzed whole-genome sequencing data derived from 137 primary Group 3 and Group 4 medulloblastoma samples and performed a systematic, high-resolution screen for chromosomal breakpoints recurrently targeting putative candidate genes. This comprehensive analysis of structural variants identified highly disparate genomic structural variants, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Diverse mechanisms of structural variation, including duplications, deletions, inversions, translocations, and other complex variants were observed in nearly all GFI1/GFI1B-activated cases. Integration of genome sequencing data with sample-matched ChIP-seq data for enhancer histone marks established that somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating their oncogenic activity. Functional experiments performed in mice confirmed the oncogenicity of both GFI1 and GFI1B in the context of medulloblastoma and demonstrated apparent functional synergy between both of these candidates and MYC. These studies establish GFI1 and GFI1B as novel, highly prevalent medulloblastoma oncogenes specifically active in Group 3 and Group 4. Given their high frequencies of activation, GFI1 and GFI1B represent excellent candidates for prioritization of molecularly targeted therapy aimed at treatment of a significant proportion of Group 3 and Group 4 medulloblastoma patients. Moreover, our data implicates ‘enhancer hijacking’ as an efficient mechanism capable of driving oncogene activation in a childhood cancer.
PMCID: PMC4218187
8.  Recovery and characterization of a Citrus clementina Hort. ex Tan. 'Clemenules' haploid plant selected to establish the reference whole Citrus genome sequence 
BMC Plant Biology  2009;9:110.
In recent years, the development of structural genomics has generated a growing interest in obtaining haploid plants. The use of homozygous lines presents a significant advantage for the accomplishment of sequencing projects. Commercial citrus species are characterized by high heterozygosity, making it difficult to assemble large genome sequences. Thus, the International Citrus Genomic Consortium (ICGC) decided to establish a reference whole citrus genome sequence from a homozygous plant. Due to the existence of important molecular resources and previous success in obtaining haploid clementine plants, haploid clementine was selected as the target for the implementation of the reference whole genome citrus sequence.
To obtain haploid clementine lines we used the technique of in situ gynogenesis induced by irradiated pollen. Flow cytometry, chromosome counts and SSR marker (Simple Sequence Repeats) analysis facilitated the identification of six different haploid lines (2n = x = 9), one aneuploid line (2n = 2x+4 = 22) and one doubled haploid plant (2n = 2x = 18) of 'Clemenules' clementine. One of the haploids, obtained directly from an original haploid embryo, grew vigorously and produced flowers after four years. This is the first haploid plant of clementine that has bloomed and we have, for the first time, characterized the histology of haploid and diploid flowers of clementine. Additionally a double haploid plant was obtained spontaneously from this haploid line.
The first haploid plant of 'Clemenules' clementine produced directly by germination of a haploid embryo, which grew vigorously and produced flowers, has been obtained in this work. This haploid line has been selected and it is being used by the ICGC to establish the reference sequence of the nuclear genome of citrus.
PMCID: PMC2747335  PMID: 19698121
9.  Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome 
Journal of Clinical Oncology  2010;29(11):1424-1430.
Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.
Patients and Methods
We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization–based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.
Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.
Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
PMCID: PMC3082983  PMID: 21098324
Neuro-Oncology  2014;16(Suppl 3):iii24.
BACKGROUND: Genomics has illuminated the extensive intertumoural heterogeneity of medulloblastoma and identified at least four distinct molecular subgroups of the disease. Group 3 and Group 4 subgroup medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Exome and genome sequencing studies have confirmed a paucity of recurrent gene-level mutations in Group 3 and Group 4, suggesting that alternative oncogenic mechanisms must account for the large fraction of cases that cannot currently be explained by single-nucleotide variants or insertions/deletions alone. METHODS: Analysis of whole-genome sequencing data consisting of 128 primary Group 3 and Group 4 medulloblastoma samples facilitated a systematic, high-resolution screen for chromosomal breakpoints recurrently targeting novel medulloblastoma drivers by structural variation. A non-overlapping set of 22 medulloblastomas was sequenced by long-range paired-end mapping in order to validate structural variants observed in our discovery cohort. Select cases of interest were also investigated at the epigenome-level using a combination of whole-genome bisulphite sequencing and enhancer histone mark ChIP-sequencing. RESULTS: Our systematic analysis of structural variants identified highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation, including duplications, deletions, inversions, translocations, and other complex genomic variants were observed in nearly all GFI1/1B-activated cases. Comprehensive characterization of these structural variants established that GFI1/GFI1B expression becomes activated through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Functional analyses performed in mice confirmed the oncogenicity of Gfi1/Gfi1b in the context of medulloblastoma and demonstrated apparent synergy between both of these candidates and the c-Myc oncogene. CONCLUSIONS: These studies establish GFI1 and GFI1B as novel, highly prevalent medulloblastoma oncogenes specifically active in Group 3 and Group 4. Given their high frequencies of activation, GFI1 and GFI1B represent excellent candidates for prioritization of molecularly targeted therapy aimed at treatment of a significant proportion of Group 3 and Group 4 medulloblastoma patients. SECONDARY CATEGORY: Pediatrics.
PMCID: PMC4144586
11.  The Pancreatic Expression database: 2011 update 
Nucleic Acids Research  2010;39(Database issue):D1023-D1028.
The Pancreatic Expression database (PED, has established itself as the main repository for pancreatic-derived -omics data. For the past 3 years, its data content and access have increased substantially. Here we describe several of its new and improved features, such as data content, which now includes over 60 000 measurements derived from transcriptomics, proteomics, genomics and miRNA profiles from various pancreas-centred reports on a broad range of specimen and experimental types. We also illustrate the capabilities of its interface, which allows integrative queries that can combine PED data with a growing number of biological resources such as NCBI, Ensembl, UniProt and Reactome. Thus, PED is capable of retrieving and integrating different types of -omics, annotations and clinical data. We also focus on the importance of data sharing and interoperability in the cancer field, and the integration of PED into the International Cancer Genome Consortium (ICGC) data portal.
PMCID: PMC3013788  PMID: 20959292
Nature  2012;488(7409):106-110.
Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.
PMCID: PMC3413789  PMID: 22820256
13.  Aberrant Topological Patterns of Structural Cortical Networks in Psychogenic Erectile Dysfunction 
Male sexual arousal (SA) has been known as a multidimensional experience involving closely interrelated and coordinated neurobehavioral components that rely on widespread brain regions. Recent functional neuroimaging studies have shown relation between abnormal/altered dynamics in these circuits and male sexual dysfunction. However, alterations in the topological1 organization of structural brain networks in male sexual dysfunction are still unclear. Here, we used graph theory2 to investigate the topological properties of large-scale structural brain networks, which were constructed using inter-regional correlations of cortical thickness between 78 cortical regions in 40 patients with psychogenic erectile dysfunction (pED) and 39 normal controls. Compared with normal controls, pED patients exhibited a less optimal global topological organization with reduced global and increased local efficiencies. Our results suggest disrupted neural integration among distant brain regions in pED patients, consistent with previous reports of impaired white matter structure and abnormal functional integrity in pED. Additionally, disrupted global network topology in pED was observed to be primarily relevant to altered subnetwork and nodal properties within the networks mediating the cognitive, motivational and inhibitory processes of male SA, possibly indicating disrupted integration of these networks in the whole brain networks and might account for pED patients' abnormal cognitive, motivational and inhibitory processes for male SA. In total, our findings provide evidence for disrupted integrity in large-scale brain networks underlying the neurobehavioral processes of male SA in pED and provide new insights into the understanding of the pathophysiological mechanisms of pED.
PMCID: PMC4683194  PMID: 26733849
male sexual arousal; magnetic resonance imaging; network topology; graph theory; psychogenic erectile dysfunction
14.  Genomics of chromophobe renal cell carcinoma: implications from a rare tumor for pan-cancer studies 
Oncoscience  2015;2(2):81-90.
Chromophobe Renal Cell Carcinoma (ChRCC) is a rare subtype of the renal cell carcinomas, a heterogenous group of cancers arising from the nephron. Recently, The Cancer Genome Atlas (TCGA) profiled this understudied disease using multiple data platforms, including whole exome sequencing, whole genome sequencing (WGS), and mitochondrial DNA (mtDNA) sequencing. The insights gained from this study would have implications for other types of kidney cancer as well as for cancer biology in general. Global molecular patterns in ChRCC provided clues as to this cancer's cell of origin, which is distinct from that of the other renal cell carcinomas, illustrating an approach that might be applied towards elucidating the cell of origin of other cancer types. MtDNA sequencing revealed loss-of-function mutations in NADH dehydrogenase subunits, highlighting the role of deregulated metabolism in this and other cancers. Analysis of WGS data led to the discovery of recurrent genomic rearrangements involving TERT promoter region, which were associated with very high expression levels of TERT, pointing to a potential mechanism for TERT deregulation that might be found in other cancers. WGS data, generated by large scale efforts such as TCGA and the International Cancer Genomics Consortium (ICGC), could be more extensively mined across various cancer types, to uncover structural variants, mtDNA mutations, themes of tumor metabolic properties, as well as noncoding point mutations. TCGA's data on ChRCC should continue to serve as a resource for future pan-cancer as well as kidney cancer studies, and highlight the value of investigations into rare tumor types to globally inform principals of cancer biology.
PMCID: PMC4381700  PMID: 25859550
ChRCC; chromophobe; kidney cancer; genomics; TERT; TCGA; mitochondria
15.  Tumor-Derived Cell Lines as Molecular Models of Cancer Pharmacogenomics 
Compared with normal cells, tumor cells have undergone an array of genetic and epigenetic alterations. Often, these changes underlie cancer development, progression, and drug resistance, so the utility of model systems rests on their ability to recapitulate the genomic aberrations observed in primary tumors. Tumor-derived cell lines have long been used to study the underlying biologic processes in cancer, as well as screening platforms for discovering and evaluating the efficacy of anticancer therapeutics. Multiple -omic measurements across more than a thousand cancer cell lines have been produced following advances in high-throughput technologies and multigroup collaborative projects. These data complement the large, international cancer genomic sequencing efforts to characterize patient tumors, such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). Given the scope and scale of data that have been generated, researchers are now in a position to evaluate the similarities and differences that exist in genomic features between cell lines and patient samples. As pharmacogenomics models, cell lines offer the advantages of being easily grown, relatively inexpensive, and amenable to high-throughput testing of therapeutic agents. Data generated from cell lines can then be used to link cellular drug response to genomic features, where the ultimate goal is to build predictive signatures of patient outcome. This review highlights the recent work that has compared -omic profiles of cell lines with primary tumors, and discusses the advantages and disadvantages of cancer cell lines as pharmacogenomic models of anticancer therapies.
PMCID: PMC4828339  PMID: 26248648
16.  The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non‐coding RNA and synonymous mutations 
EMBO Molecular Medicine  2016;8(5):442-457.
Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis.
PMCID: PMC5126213  PMID: 26992833
alternative polyadenylation; enhancer; mutation; non‐coding RNA; synonymous mutation; Cancer; Chromatin, Epigenetics, Genomics & Functional Genomics
17.  Returning individual research results for genome sequences of pancreatic cancer 
Genome Medicine  2014;6(5):42.
Disclosure of individual results to participants in genomic research is a complex and contentious issue. There are many existing commentaries and opinion pieces on the topic, but little empirical data concerning actual cases describing how individual results have been returned. Thus, the real life risks and benefits of disclosing individual research results to participants are rarely if ever presented as part of this debate.
The Australian Pancreatic Cancer Genome Initiative (APGI) is an Australian contribution to the International Cancer Genome Consortium (ICGC), that involves prospective sequencing of tumor and normal genomes of study participants with pancreatic cancer in Australia. We present three examples that illustrate different facets of how research results may arise, and how they may be returned to individuals within an ethically defensible and clinically practical framework. This framework includes the necessary elements identified by others including consent, determination of the significance of results and which to return, delineation of the responsibility for communication and the clinical pathway for managing the consequences of returning results.
Of 285 recruited patients, we returned results to a total of 25 with no adverse events to date. These included four that were classified as medically actionable, nine as clinically significant and eight that were returned at the request of the treating clinician. Case studies presented depict instances where research results impacted on cancer susceptibility, current treatment and diagnosis, and illustrate key practical challenges of developing an effective framework.
We suggest that return of individual results is both feasible and ethically defensible but only within the context of a robust framework that involves a close relationship between researchers and clinicians.
PMCID: PMC4067993  PMID: 24963353
18.  Computational approaches to identify functional genetic variants in cancer genomes 
Nature methods  2013;10(8):723-729.
The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor, but only a minority drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype.
PMCID: PMC3919555  PMID: 23900255
19.  Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia 
Frontiers in Oncology  2015;5:191.
Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8-year-old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented 8 months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here, we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization, and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2, and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia.
PMCID: PMC4550790  PMID: 26380221
BRCA2 6174delT; Fanconi anemia; group 4 medulloblastoma; MYC; medulloblastoma cell lines
20.  Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma1 
Neuro-Oncology  2007;9(2):135-144.
Medulloblastoma is a heterogeneous pediatric brain tumor with significant therapy-related morbidity, its five-year survival rates ranging from 30% to 70%. Improvement in diagnosis and therapy requires better understanding of medulloblastoma pathology. We used whole-genome microarray analysis to identify putative tumor suppressor genes silenced by epigenetic mechanisms in medulloblastoma. This analysis yielded 714 up-regulated genes in immortalized medulloblastoma cell line D283 on treatment with histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Dickkopf-1 (DKK1), a Wnt antagonist, was found to be up-regulated on HDAC inhibition. We examined DKK1 expression in primary medulloblastoma cells and patient samples by reverse transcriptase PCR and found it to be significantly down-regulated relative to normal cerebellum. Transfection of a DKK1 gene construct into D283 cell lines suppressed medulloblastoma tumor growth in colony focus assays by 60% (P < 0.001). In addition, adenoviral vector– mediated expression of DKK1 in medulloblastoma cells increased apoptosis fourfold (P < 0.001). These data reveal that inappropriate histone modifications might deregulate DKK1 expression in medulloblastoma tumorigenesis and block its tumor-suppressive activity.
PMCID: PMC1871668  PMID: 17329407
Dickkopf-1; epigenetic; histone deacetylation; medulloblastoma; tumor suppressor
21.  α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth 
Acta neuropathologica  2013;127(4):593-603.
Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors, and importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABR5, which encodes the α-subunit of the GABAA receptor complex, in aggressive MYC-driven, “Group 3” medulloblastomas. We hypothesized that modulation of α-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABR5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABR5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOX5 target gene expression. siRNA-mediated knockdown of HOX5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABR5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOX5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.
PMCID: PMC3974267  PMID: 24196163
medulloblastoma; GABRA5; QHii066; HOXA5; MYC
22.  Genetic and Epigenetic Inactivation of Kruppel-like Factor 4 in Medulloblastoma1 
Neoplasia (New York, N.Y.)  2010;12(1):20-27.
Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4) in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time polymerase chain reaction (PCR). Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate dense methylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanisms in a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.
PMCID: PMC2805880  PMID: 20072650
Neuro-Oncology  2014;16(Suppl 3):iii7.
BACKGROUND: The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. In particular we studied the plasma of 14 medulloblastoma, 13 WHO grade 2-3 glioma and 14 WHO grade IV astrocytoma cases for levels of ctDNA. METHODS: The basis of our approach is to differentiate DNA shed by normal cells from DNA derived from tumor cells. In order to distinguish the two populations of cell-free DNA, we first identify a tumor-specific alteration. We then query for that exact mutation in matching plasma from the same patient to generate a personalized tumor biomarker. Only DNA derived from the tumor will harbor the genetic alteration. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 individuals. DNA was extracted from less than 5 ml of plasma in each case. The majority of plasma samples were queried for levels of ctDNA using a high fidelity next-generation sequencing approach coined Safe-SeqS. RESULTS: We found that at least one tumor-specific mutant molecule could be identified in <5 mL of plasma in >75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. Approximately 40% of medulloblastoma and 10% of low or high grade glioma cases had detectable levels of ctDNA. In patients with localized non-CNS tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 colorectal cancer patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: Taken together, these data suggest that ctDNA is a sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. For individuals with CNS neoplasms, alternate strategies may need to be developed in order to detect cell-free tumor derived DNA at levels that are clinically meaningful. ABSTRACT CATEGORY: Neuropathology & Tumor Biomarkers.
PMCID: PMC4144489
Neuro-Oncology  2014;16(Suppl 5):v100-v101.
Recurrence of the childhood brain cancer medulloblastoma is almost universally fatal. The current strategy for clinical trials is to test novel therapies at the time of recurrence, using targets discovered at diagnosis. To define the relationship between naïve and post-treatment medulloblastoma, we developed a functional genomic transposon-driven mouse-model. Deep sequencing of the commonly inserted genes in diagnostic and recurrent tumors revealed dramatic divergence post-therapy, with recurrences demonstrating a convergence on the TP53 pathway. Loss of function insertions in Tp53 are clonal in the recurrence, result in loss of expression of the Tp53 target gene P21, and arise through selection of minor subclones present before therapy. The majority of insertions identified at diagnosis are no longer present at recurrence, and therefore represent futile targets for therapy. To validate these findings, we studied 36 pairs of human primary/recurrent tumors by whole genome sequencing. When comparing SNVs, indels or structural aberrations, we found minimal genetic overlap between the dominant clones at diagnosis versus recurrence. Recurrent tumors have more genomic aberrations than their paired diagnostic sample, and commonly display alterations in the TP53 (SHH), or the TP53 and TGF-β pathways (Group 3/4 tumors). Clonal dynamics between primary and recurrent tumors was measured using ultra-deep sequencing (1,500X). Overall, recurrent tumors share little genetic identity with their diagnostic tumor, arise through clonal selection, target specific signaling pathways to avoid cell death, and assume clinical dominance after therapy. Our findings undermine the key assumption that diagnostic medulloblastoma samples provide rational targets for therapy in recurrent disease, and provide a simple reason for the failure of prior trials of targeted therapy. Repeated genetic convergence on specific signaling pathways at the time of recurrence suggests that it may be possible to develop ‘anticipatory therapy’ delivered up front to prevent the later emergence of minor resistant clones driving recurrence.
PMCID: PMC4218185
25.  Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1 
Brain  2008;131(7):1831-1844.
Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome.
PMCID: PMC2442425  PMID: 18577546
GLUT1; paroxysmal dyskinesia; exercise-induced; GLUT1 deficiency syndrome; ketogenic diet

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