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6. Comprehensive molecular profiling of lung adenocarcinoma

Author

Collisson, Eric A, Campbell, Joshua D, Brooks, Angela N, Berger, Alice H, Lee, William, Chmielecki, Juliann, Beer, David G, Cope, Leslie, Creighton, Chad J, Danilova, Ludmila, Ding, Li, Getz, Gad, Hammerman, Peter S, Neil Hayes, D, Hernandez, Bryan, Herman, James G, Heymach, John V, Jurisica, Igor, Kucherlapati, Raju, Kwiatkowski, David, Ladanyi, Marc, Robertson, Gordon, Schultz, Nikolaus, Shen, Ronglai, Sinha, Rileen, Sougnez, Carrie, Tsao, Ming-Sound, Travis, William D, Weinstein, John N, Wigle, Dennis A, Wilkerson, Matthew D, Chu, Andy, Cherniack, Andrew D, Hadjipanayis, Angela, Rosenberg, Mara, Weisenberger, Daniel J, Laird, Peter W, Radenbaugh, Amie, Ma, Singer, Stuart, Joshua M, Averett Byers, Lauren, Baylin, Stephen B, Govindan, Ramaswamy, Meyerson, Matthew, Gabriel, Stacey B, Cibulskis, Kristian, Kim, Jaegil, Stewart, Chip, Lichtenstein, Lee, Lander, Eric S, Lawrence, Michael S, Kandoth, Cyriac, Fulton, Robert, Fulton, Lucinda L, McLellan, Michael D, Wilson, Richard K, Ye, Kai, Fronick, Catrina C, Maher, Christopher A, Miller, Christopher A, Wendl, Michael C, Cabanski, Christopher, Mardis, Elaine, Wheeler, David, Balasundaram, Miruna, Butterfield, Yaron SN, Carlsen, Rebecca, Chuah, Eric, Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Lee, Darlene, Li, Haiyan I, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Varhol, Richard, Gordon Robertson, A, Wye, Natasja, Thiessen, Nina, Holt, Robert A, Jones, Steven JM, Marra, Marco A, Imielinski, Marcin, Onofrio, Robert C, Hodis, Eran, and Zack, Travis

Subjects
Rare Diseases, Genetics, Biotechnology, Clinical Research, Lung Cancer, Human Genome, Cancer, Lung, Aetiology, 2.1 Biological and endogenous factors, Adenocarcinoma, Adenocarcinoma of Lung, Cell Cycle Proteins, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms, Male, Molecular Typing, Mutation, Oncogenes, Sex Factors, Transcriptome, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2014

8. The Cancer Genome Atlas Pan-Cancer analysis project

Author

Chang, Kyle, Creighton, Chad J, Davis, Caleb, Donehower, Lawrence, Drummond, Jennifer, Wheeler, David, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E, Dhalla, Noreen, Guin, Ranabir, Hirst, Martin, Hirst, Carrie, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan I, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Robertson, A Gordon, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Varhol, Richard J, Beroukhim, Rameen, Bhatt, Ami S, Brooks, Angela N, Cherniack, Andrew D, Freeman, Samuel S, Gabriel, Stacey B, Helman, Elena, Jung, Joonil, Meyerson, Matthew, Ojesina, Akinyemi I, Pedamallu, Chandra Sekhar, Saksena, Gordon, Schumacher, Steven E, Tabak, Barbara, Zack, Travis, Lander, Eric S, Bristow, Christopher A, Hadjipanayis, Angela, Haseley, Psalm, Kucherlapati, Raju, Lee, Semin, Lee, Eunjung, Luquette, Lovelace J, Mahadeshwar, Harshad S, Pantazi, Angeliki, Parfenov, Michael, Park, Peter J, Protopopov, Alexei, Ren, Xiaojia, Santoso, Netty, Seidman, Jonathan, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Xi, Ruibin, Xu, Andrew W, Yang, Lixing, Zeng, Dong, Auman, J Todd, Balu, Saianand, Buda, Elizabeth, Fan, Cheng, Hoadley, Katherine A, Jones, Corbin D, Meng, Shaowu, Mieczkowski, Piotr A, Parker, Joel S, Perou, Charles M, Roach, Jeffrey, Shi, Yan, Silva, Grace O, Tan, Donghui, Veluvolu, Umadevi, Waring, Scot, Wilkerson, Matthew D, Wu, Junyuan, Zhao, Wei, Bodenheimer, Tom, Hayes, D Neil, Hoyle, Alan P, Jeffreys, Stuart R, Mose, Lisle E, Simons, Janae V, Soloway, Mathew G, Baylin, Stephen B, Berman, Benjamin P, Bootwalla, Moiz S, Danilova, Ludmila, and Herman, James G

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Rare Diseases, Good Health and Well Being, Gene Expression Profiling, Genome, Humans, Neoplasms, Cancer Genome Atlas Research Network, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

Published
2013

9. Integrated genomic characterization of endometrial carcinoma

Author

Getz, Gad, Gabriel, Stacey B, Cibulskis, Kristian, Lander, Eric, Sivachenko, Andrey, Sougnez, Carrie, Lawrence, Mike, Kandoth, Cyriac, Dooling, David, Fulton, Robert, Fulton, Lucinda, Kalicki-Veizer, Joelle, McLellan, Michael D, O’Laughlin, Michelle, Schmidt, Heather, Wilson, Richard K, Ye, Kai, Ding, Li, Mardis, Elaine R, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Carlsen, Rebecca, Carter, Candace, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E, Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan I, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Andrew J, Plettner, Patrick, Schein, Jacqueline E, Sipahimalani, Payal, Tam, Angela, Varhol, Richard J, Gordon Robertson, A, Cherniack, Andrew D, Pashtan, Itai, Saksena, Gordon, Onofrio, Robert C, Schumacher, Steven E, Tabak, Barbara, Carter, Scott L, Hernandez, Bryan, Gentry, Jeff, Salvesen, Helga B, Ardlie, Kristin, Winckler, Wendy, Beroukhim, Rameen, Meyerson, Matthew, Hadjipanayis, Angela, Lee, Semin, Mahadeshwar, Harshad S, Park, Peter, Protopopov, Alexei, Ren, Xiaojia, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Xi, Ruibin, Yang, Lixing, Zeng, Dong, Kucherlapati, Raju, Chin, Lynda, Zhang, Jianhua, Todd Auman, J, Balu, Saianand, Bodenheimer, Tom, Buda, Elizabeth, Neil Hayes, D, Hoyle, Alan P, Jefferys, Stuart R, Jones, Corbin D, Meng, Shaowu, Mieczkowski, Piotr A, Mose, Lisle E, Parker, Joel S, Perou, Charles M, Roach, Jeff, Shi, Yan, Simons, Janae V, Soloway, Mathew G, Tan, Donghui, Topal, Michael D, Waring, Scot, Wu, Junyuan, Hoadley, Katherine A, Baylin, Stephen B, and Bootwalla, Moiz S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Reproductive Medicine, Human Genome, Cancer, Uterine Cancer, Biotechnology, Breast Neoplasms, Chromosome Aberrations, DNA Copy Number Variations, DNA Mutational Analysis, DNA Polymerase II, DNA-Binding Proteins, Endometrial Neoplasms, Exome, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Genomics, Humans, Ovarian Neoplasms, Poly-ADP-Ribose Binding Proteins, Signal Transduction, Transcription Factors, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Published
2013

10. Comprehensive genomic characterization of squamous cell lung cancers

Author

Hammerman, Peter S, Lawrence, Michael S, Voet, Douglas, Jing, Rui, Cibulskis, Kristian, Sivachenko, Andrey, Stojanov, Petar, McKenna, Aaron, Lander, Eric S, Gabriel, Stacey, Getz, Gad, Sougnez, Carrie, Imielinski, Marcin, Helman, Elena, Hernandez, Bryan, Pho, Nam H, Meyerson, Matthew, Chu, Andy, Chun, Hye-Jung E, Mungall, Andrew J, Pleasance, Erin, Gordon Robertson, A, Sipahimalani, Payal, Stoll, Dominik, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron SN, Chuah, Eric, Coope, Robin JN, Corbett, Richard, Dhalla, Noreen, Guin, Ranabir, He, An, Hirst, Carrie, Hirst, Martin, Holt, Robert A, Lee, Darlene, Li, Haiyan I, Mayo, Michael, Moore, Richard A, Mungall, Karen, Ming Nip, Ka, Olshen, Adam, Schein, Jacqueline E, Slobodan, Jared R, Tam, Angela, Thiessen, Nina, Varhol, Richard, Zeng, Thomas, Zhao, Yongjun, Jones, Steven JM, Marra, Marco A, Saksena, Gordon, Cherniack, Andrew D, Schumacher, Stephen E, Tabak, Barbara, Carter, Scott L, Nguyen, Huy, Onofrio, Robert C, Crenshaw, Andrew, Ardlie, Kristin, Beroukhim, Rameen, Winckler, Wendy, Protopopov, Alexei, Zhang, Jianhua, Hadjipanayis, Angela, Lee, Semin, Xi, Ruibin, Yang, Lixing, Ren, Xiaojia, Zhang, Hailei, Shukla, Sachet, Chen, Peng-Chieh, Haseley, Psalm, Lee, Eunjung, Chin, Lynda, Park, Peter J, Kucherlapati, Raju, Socci, Nicholas D, Liang, Yupu, Schultz, Nikolaus, Borsu, Laetitia, Lash, Alex E, Viale, Agnes, Sander, Chris, Ladanyi, Marc, Todd Auman, J, Hoadley, Katherine A, Wilkerson, Matthew D, Shi, Yan, Liquori, Christina, Meng, Shaowu, Li, Ling, Turman, Yidi J, Topal, Michael D, and Tan, Donghui

Subjects
Human Genome, Biotechnology, Genetics, Rare Diseases, Cancer, Lung Cancer, Lung, Aetiology, 2.1 Biological and endogenous factors, Adenocarcinoma, Adenocarcinoma of Lung, Carcinoma, Squamous Cell, DNA Mutational Analysis, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, p16, Genes, p53, Genome, Human, Genomics, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Mutation Rate, Phosphatidylinositol 3-Kinases, Signal Transduction, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.

Published
2012

11. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Author

Northcott, Paul, Shih, David, Peacock, John, Garzia, Livia, Morrissy, A, Zichner, Thomas, Stütz, Adrian, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven, Beroukhim, Rameen, Ellison, David, Marshall, Christian, Lionel, Anath, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman, Chu, Andy, Chuah, Eric, Corbett, Richard, Hoad, Gemma, Jackman, Shaun, Li, Yisu, Lo, Allan, Mungall, Karen, Nip, Ka, Qian, Jenny, Raymond, Anthony, Thiessen, Nina, Varhol, Richard, Birol, Inanc, Moore, Richard, Mungall, Andrew, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine, Kool, Marcel, Jones, David, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna, Wechsler-Reya, Robert, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa, Perek-Polnik, Marta, Haberler, Christine, Delattre, Olivier, Reynaud, Stéphanie, Doz, François, Pernet-Fattet, Sarah, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian, Fan, Xing, Muraszko, Karin, Gillespie, G, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna, Kloosterhof, Nanne, French, Pim, Kros, Johan, Olson, James, Ellenbogen, Richard, Zitterbart, Karel, Kren, Leos, Thompson, Reid, Cooper, Michael, Lach, Boleslaw, McLendon, Roger, Bigner, Darell, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet, Bailey, Simon, Van Meir, Erwin, Fouladi, Maryam, Nakamura, Hideo, Cinalli, Giuseppe, Garami, Miklós, Hauser, Peter, Saad, Ali, Iolascon, Achille, Jung, Shin, and Carlotti, Carlos

Subjects
Carrier Proteins, Cerebellar Neoplasms, Child, DNA Copy Number Variations, Gene Duplication, Genes, myc, Genome, Human, Genomic Structural Variation, Genomics, Hedgehog Proteins, Humans, Medulloblastoma, NF-kappa B, Nerve Tissue Proteins, Oncogene Proteins, Fusion, Proteins, RNA, Long Noncoding, Signal Transduction, Transforming Growth Factor beta, Translocation, Genetic
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinsons disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Published
2012

12. The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Author

Shah, Sohrab P, Roth, Andrew, Goya, Rodrigo, Oloumi, Arusha, Ha, Gavin, Zhao, Yongjun, Turashvili, Gulisa, Ding, Jiarui, Tse, Kane, Haffari, Gholamreza, Bashashati, Ali, Prentice, Leah M, Khattra, Jaswinder, Burleigh, Angela, Yap, Damian, Bernard, Virginie, McPherson, Andrew, Shumansky, Karey, Crisan, Anamaria, Giuliany, Ryan, Heravi-Moussavi, Alireza, Rosner, Jamie, Lai, Daniel, Birol, Inanc, Varhol, Richard, Tam, Angela, Dhalla, Noreen, Zeng, Thomas, Ma, Kevin, Chan, Simon K, Griffith, Malachi, Moradian, Annie, Cheng, S-W Grace, Morin, Gregg B, Watson, Peter, Gelmon, Karen, Chia, Stephen, Chin, Suet-Feung, Curtis, Christina, Rueda, Oscar M, Pharoah, Paul D, Damaraju, Sambasivarao, Mackey, John, Hoon, Kelly, Harkins, Timothy, Tadigotla, Vasisht, Sigaroudinia, Mahvash, Gascard, Philippe, Tlsty, Thea, Costello, Joseph F, Meyer, Irmtraud M, Eaves, Connie J, Wasserman, Wyeth W, Jones, Steven, Huntsman, David, Hirst, Martin, Caldas, Carlos, Marra, Marco A, and Aparicio, Samuel

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Alleles, Breast Neoplasms, Clone Cells, DNA Copy Number Variations, DNA Mutational Analysis, Disease Progression, Evolution, Molecular, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genotype, High-Throughput Nucleotide Sequencing, Humans, INDEL Mutation, Mutation, Point Mutation, Precision Medicine, Reproducibility of Results, Sequence Analysis, RNA, General Science & Technology
Abstract

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.

Published
2012

13. Conserved role of intragenic DNA methylation in regulating alternative promoters

Author

Maunakea, Alika K, Nagarajan, Raman P, Bilenky, Mikhail, Ballinger, Tracy J, D’Souza, Cletus, Fouse, Shaun D, Johnson, Brett E, Hong, Chibo, Nielsen, Cydney, Zhao, Yongjun, Turecki, Gustavo, Delaney, Allen, Varhol, Richard, Thiessen, Nina, Shchors, Ksenya, Heine, Vivi M, Rowitch, David H, Xing, Xiaoyun, Fiore, Chris, Schillebeeckx, Maximiliaan, Jones, Steven JM, Haussler, David, Marra, Marco A, Hirst, Martin, Wang, Ting, and Costello, Joseph F

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Brain Disorders, Neurosciences, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Generic health relevance, Good Health and Well Being, Animals, Brain, Carrier Proteins, Cell Line, Conserved Sequence, CpG Islands, DNA Methylation, DNA, Intergenic, Frontal Lobe, Gene Expression Regulation, Histones, Humans, Male, Mice, Mice, Inbred C57BL, Microfilament Proteins, Middle Aged, Nerve Tissue Proteins, Organ Specificity, Promoter Regions, Genetic, Transcription, Genetic, General Science & Technology
Abstract

Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.

Published
2010

15. Supplementary Table S1 from System-Level Analysis of Neuroblastoma Tumor–Initiating Cells Implicates AURKB as a Novel Drug Target for Neuroblastoma

Author

Morozova, Olena, primary, Vojvodic, Milijana, primary, Grinshtein, Natalie, primary, Hansford, Loen M., primary, Blakely, Kim M., primary, Maslova, Alexandra, primary, Hirst, Martin, primary, Cezard, Timothee, primary, Morin, Ryan D., primary, Moore, Richard, primary, Smith, Kristen M., primary, Miller, Freda, primary, Taylor, Paul, primary, Thiessen, Nina, primary, Varhol, Richard, primary, Zhao, Yongjun, primary, Jones, Steven, primary, Moffat, Jason, primary, Kislinger, Thomas, primary, Moran, Michael F., primary, Kaplan, David R., primary, and Marra, Marco A., primary

Published
2023
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16. Supplementary Figures S1-S2 from System-Level Analysis of Neuroblastoma Tumor–Initiating Cells Implicates AURKB as a Novel Drug Target for Neuroblastoma

Author

Morozova, Olena, primary, Vojvodic, Milijana, primary, Grinshtein, Natalie, primary, Hansford, Loen M., primary, Blakely, Kim M., primary, Maslova, Alexandra, primary, Hirst, Martin, primary, Cezard, Timothee, primary, Morin, Ryan D., primary, Moore, Richard, primary, Smith, Kristen M., primary, Miller, Freda, primary, Taylor, Paul, primary, Thiessen, Nina, primary, Varhol, Richard, primary, Zhao, Yongjun, primary, Jones, Steven, primary, Moffat, Jason, primary, Kislinger, Thomas, primary, Moran, Michael F., primary, Kaplan, David R., primary, and Marra, Marco A., primary

Published
2023
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17. A regulatory toolbox of MiniPromoters to drive selective expression in the brain

Author

Portales-Casamar, Elodie, Swanson, Douglas J., Liu, Li, de Leeuw, Charles N., Banks, Kathleen G., Sui, Shannan J. Ho, Fulton, Debra L., Ali, Johar, Amirabbasi, Mahsa, Arenillas, David J., Babyak, Nazar, Black, Sonia F., Bonaguro, Russell J., Brauer, Erich, Candido, Tara R., Castellarin, Mauro, Chen, Jing, Chen, Ying, Cheng, Jason C. Y., Chopra, Vik, Docking, T. Roderick, Dreolini, Lisa, D'Souza, Cletus A., Flynn, Erin K., Glenn, Randy, Hatakka, Kristi, Hearty, Taryn G., Imanian, Behzad, Jiang, Steven, Khorasan-zadeh, Shadi, Komljenovic, Ivana, Laprise, Stéphanie, Liao, Nancy Y., Lim, Jonathan S., Lithwick, Stuart, Liu, Flora, Liu, Jun, Lu, Meifen, McConechy, Melissa, McLeod, Andrea J., Milisavljevic, Marko, Mis, Jacek, O'Connor, Katie, Palma, Betty, Palmquist, Diana L., Schmouth, Jean-François, Swanson, Magdalena I., Tam, Bonny, Ticoll, Amy, Turner, Jenna L., Varhol, Richard, Vermeulen, Jenny, Watkins, Russell F., Wilson, Gary, Wong, Bibiana K. Y., Wong, Siaw H., Wong, Tony Y. T., Yang, George S., Ypsilanti, Athena R., Jones, Steven J. M., Holt, Robert A., Goldowitz, Daniel, Wasserman, Wyeth W., and Simpson, Elizabeth M.

Published
2010

19. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution

Author

Shah, Sohrab P., Morin, Ryan D., Khattra, Jaswinder, Prentice, Leah, Pugh, Trevor, Burleigh, Angela, Delaney, Allen, Gelmon, Karen, Guliany, Ryan, Senz, Janine, Steidl, Christian, Holt, Robert A., Jones, Steven, Sun, Mark, Leung, Gillian, Moore, Richard, Severson, Tesa, Taylor, Greg A., Teschendorff, Andrew E., Tse, Kane, Turashvili, Gulisa, Varhol, Richard, Warren, Rene L., Watson, Peter, Zhao, Yongjun, Caldas, Carlos, Huntsman, David, Hirst, Martin, Marra, Marco A., and Aparicio, Samuel

Subjects
Gene mutations -- Health aspects -- Genetic aspects, Breast tumors -- Genetic aspects -- Development and progression, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Recent advances in next generation sequencing (1-4} have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (>43-fold coverage) and transcriptomes of an oestrogen-receptor-α-positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9years earlier, six (in KIFI C, USP28, MYH8, MORCI, KMA1468 and RNASEH2A) were present at lower frequencies (1-13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneity can be a property of low or intermediate grade primary breast cancers and that significant evolution can occur with disease progression., Lobular breast cancer is an oestrogen-receptor-positive ([ER.sup.+], also known as [ESRl.sup.+]) subtype of breast cancer (approximately 15% of all breast cancers). It is usually of low-intermediate histological grade and can [...]

Published
2009

20. Mutation of FOXL2 in granulosa-cell tumors of the ovary

Author

Shah, Sohrab P., Kobel, Martin, Senz, Janine, Morin, Ryan D., Clarke, Blaise A., Wiegand, Kimberly C., Leung, Gillian, Zayed, Abdalnasser, Mehl, Erika, Kalloger, Steve E., Sun, Mark, Giuliany, Ryan, Yorida, Erika, Jones, Steven, Varhol, Richard, Swenerton, Kenneth D., Miller, Dianne, Clement, Philip B., Crane, Colleen, Madore, Jason, Provencher, Diane, Leung, Peter, DeFazio, Anna, Khattra, Jaswinder, Turashvili, Gulisa, Zhao, Yongjun, Zeng, Thomas, Glover, J.N. Mark, Vanderhyden, Barbara, Zhao, Chengquan, Parkinson, Christine A., Jimenez-Linan, Mercedes, Bowtell, David D.L., Aparicio, Samuel A., Boyd, Niki, Hirst, Martin, Gilks, Blake, Marra, Marco, Mes-Masson, Anne-Marie, and Brenton, James D.

Subjects
Granulosa cell tumor -- Causes of, Granulosa cell tumor -- Research, Granulosa cell tumor -- Genetic aspects
Abstract

The study aims to investigate four adult-type granulosa-cell tumors (GCTs) of the ovary and the role of FOXL2 mutation in the pathogenesis of GCTs. The results indicate that mutant FOXL2 is responsible for adult-type GCTs of the ovary.

Published
2009

21. Using general practice clinical information system data for research: the case in Australia

Author

Youens, David, Moorin, Rachael, Harrison, Amy, Varhol, Richard, Robinson, Suzanne, Brooks, Caroline, Boyd, James, Youens, David, Moorin, Rachael, Harrison, Amy, Varhol, Richard, Robinson, Suzanne, Brooks, Caroline, and Boyd, James

Abstract

General practice is often a patient’s first point of contact with the health system and the gateway to specialist services. In Australia, different aspects of the health system are managed by the Commonwealth Government and individual state / territory governments. Although there is a long history of research using administrative data in Australia, this split in the management and funding of services has hindered whole-system research. Additionally, the administrative data typically available for research are often collected for reimbursement purposes and lack clinical information. General practices collect a range of patient information including diagnoses, medications prescribed, results of pathology tests ordered and so on. Practices are increasingly using clinical information systems and data extraction tools to make use of this information. This paper describes approaches used on several research projects to access clinical, as opposed to administrative, general practice data which to date has seen little use as a resource for research. This information was accessed in three ways. The first was by working directly with practices to access clinical and management data to support research. The second involved accessing general practice data through collaboration with Primary Health Networks, recently established in Australia to increase the efficiency and effectiveness of health services for patients. The third was via NPS MedicineWise’s MedicineInsight program, which collects data from consenting practices across Australia and makes these data available to researchers. We describe each approach including data access requirements and the advantages and challenges of each method. All approaches provide the opportunity to better understand data previously unavailable for research in Australia. The challenge of linking general practice data to other sources, currently being explored for general practice data, is discussed. Finally, we describe some general practice

Published
2020

22. A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells

Author

Siddiqui, Asim S., Khattra, Jaswinder, Delaney, Allen D., Zhao, Yongjun, Astell, Caroline, Asano, Jennifer, Babakaiff, Ryan, Barber, Sarah, Beland, Jaclyn, Bohacec, Slavita, Brown-John, Mabel, Chand, Steve, Charest, David, Charters, Anita M., Cullum, Rebecca, Dhalla, Noreen, Featherstone, Ruth, Gerhard, Daniela S., Hoffman, Brad, Holt, Robert A., Hou, Juan, Kuo, Byron Y.-L., Lee, Lisa L.C., Lee, Stephanie, Leung, Derek, Ma, Kevin, Matsuo, Corey, Mayo, Michael, McDonald, Helen, Prabhu, Anna-Iiisa, Pandoh, Pawan, Riggins, Gregory J., de Algara, Teresa Ruiz, Rupert, James L., Smailus, Duane, Stott, Jeff, Tsai, Miranda, Varhol, Richard, Vrljicak, Pavle, Wong, David, Wu, Mona K., Xie, Yuan-Yun, Yang, George, Zhang, Ida, Hirst, Martin, Jones, Steven J.M., Helgason, Cheryl D., Simpson, Elizabeth M., Hoodless, Pamela A., and Marra, Marco A.

Subjects
Rats -- Genetic aspects, Rats -- Physiological aspects, Rattus -- Genetic aspects, Rattus -- Physiological aspects, Visual cortex -- Research, Pancreas -- Research, Animal development -- Genetic aspects, Science and technology
Abstract

We analyzed 8.55 million LongSAGE tags generated from 72 libraries. Each LongSAGE library was prepared from a different mouse tissue. Analysis of the data revealed extensive overlap with existing gene data sets and evidence for the existence of [approximately equal to] 24,000 previously undescribed genomic loci. The visual cortex, pancreas, mammary gland, preimplantation embryo, and placenta contain the largest number of differentially expressed transcripts, 25% of which are previously undescribed loci. alternative transcripts | development | serial analysis of gene expression

Published
2005

23. Comprehensive molecular characterization of clear cell renal cell carcinoma

Author

Creighton, Chad J., Morgan, Margaret, Gunaratne, Preethi H., Wheeler, David A., Gibbs, Richard A., Robertson, Gordon A., Chu, Andy, Beroukhim, Rameen, Cibulskis, Kristian, Signoretti, Sabina, Hsin-Ta Wu, Fabio Vandin, Raphael, Benjamin J., Verhaak, Roel G. W., Tamboli, Pheroze, Torres-Garcia, Wandaliz, Akbani, Rehan, Weinstein, John N., Reuter, Victor, Hsieh, James J., Brannon, Rose A., Ari Hakimi, A., Jacobsen, Anders, Ciriello, Giovanni, Reva, Boris, Ricketts, Christopher J., Linehan, Marston W., Stuart, Joshua M., Rathmell, Kimryn W., Shen, Hui, Laird, Peter W., Muzny, Donna, Davis, Caleb, Xi, Liu, Chang, Kyle, Kakkar, Nipun, Treviño, Lisa R., Benton, Susan, Reid, Jeffrey G., Morton, Donna, Doddapaneni, Harsha, Han, Yi, Lewis, Lora, Dinh, Huyen, Kovar, Christie, Zhu, Yiming, Santibanez, Jireh, Wang, Min, Hale, Walker, Kalra, Divya, Getz, Gad, Lawrence, Michael S., Sougnez, Carrie, Carter, Scott L., Sivachenko, Andrey, Lichtenstein, Lee, Stewart, Chip, Voet, Doug, Fisher, Sheila, Gabriel, Stacey B., Lander, Eric, Schumacher, Steve E., Tabak, Barbara, Saksena, Gordon, Onofrio, Robert C., Cherniack, Andrew D., Gentry, Jeff, Ardlie, Kristin, Meyerson, Matthew, Chun, Hye-Jung E., Mungall, Andrew J., Sipahimalani, Payal, Stoll, Dominik, Ally, Adrian, Balasundaram, Miruna, Butterfield, Yaron S. N., Carlsen, Rebecca, Carter, Candace, Chuah, Eric, Coope, Robin J. N., Dhalla, Noreen, Gorski, Sharon, Guin, Ranabir, Hirst, Carrie, Hirst, Martin, Holt, Robert A., Lebovitz, Chandra, Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Pleasance, Erin, Plettner, Patrick, Schein, Jacqueline E., Shafiei, Arash, Slobodan, Jared R., Tam, Angela, Thiessen, Nina, Varhol, Richard J., Wye, Natasja, Zhao, Yongjun, Birol, Inanc, Jones, Steven J. M., Marra, Marco A., Auman, Todd J., Tan, Donghui, Jones, Corbin D., Hoadley, Katherine A., Mieczkowski, Piotr A., Mose, Lisle E., Jefferys, Stuart R., Topal, Michael D., Liquori, Christina, Turman, Yidi J., Shi, Yan, Waring, Scot, Buda, Elizabeth, Walsh, Jesse, Wu, Junyuan, Bodenheimer, Tom, Hoyle, Alan P., Simons, Janae V., Soloway, Mathew G., Balu, Saianand, Parker, Joel S., Hayes, Neil D., Perou, Charles M., Kucherlapati, Raju, Park, Peter, Triche, Timothy, Jr, Weisenberger, Daniel J., Lai, Phillip H., Bootwalla, Moiz S., Maglinte, Dennis T., Mahurkar, Swapna, Berman, Benjamin P., Van Den Berg, David J., Cope, Leslie, Baylin, Stephen B., Noble, Michael S., DiCara, Daniel, Zhang, Hailei, Cho, Juok, Heiman, David I., Gehlenborg, Nils, Mallard, William, Lin, Pei, Frazer, Scott, Stojanov, Petar, Liu, Yingchun, Zhou, Lihua, Kim, Jaegil, Chin, Lynda, Vandin, Fabio, Wu, Hsin-Ta, Benz, Christopher, Yau, Christina, Reynolds, Sheila M., Shmulevich, Ilya, Verhaak, Roel G.W., Vegesna, Rahul, Kim, Hoon, Zhang, Wei, Cogdell, David, Jonasch, Eric, Ding, Zhiyong, Lu, Yiling, Zhang, Nianxiang, Unruh, Anna K., Casasent, Tod D., Wakefield, Chris, Tsavachidou, Dimitra, Mills, Gordon B., Schultz, Nikolaus, Antipin, Yevgeniy, Gao, Jianjiong, Cerami, Ethan, Gross, Benjamin, Aksoy, Arman B., Sinha, Rileen, Weinhold, Nils, Sumer, Onur S., Taylor, Barry S., Shen, Ronglai, Ostrovnaya, Irina, Berger, Michael F., Ladanyi, Marc, Sander, Chris, Fei, Suzanne S., Stout, Andrew, Spellman, Paul T., Rubin, Daniel L., Liu, Tiffany T., Ng, Sam, Paull, Evan O., Carlin, Daniel, Goldstein, Theodore, Waltman, Peter, Ellrott, Kyle, Zhu, Jing, Haussler, David, Xiao, Weimin, Shelton, Candace, Gardner, Johanna, Penny, Robert, Sherman, Mark, Mallery, David, Morris, Scott, Paulauskis, Joseph, Burnett, Ken, Shelton, Troy, Kaelin, William G., Choueiri, Toni, Atkins, Michael B., Curley, Erin, Tickoo, Satish, Thorne, Leigh, Boice, Lori, Huang, Mei, Fisher, Jennifer C., Vocke, Cathy D., Peterson, James, Worrell, Robert, Merino, Maria J., Schmidt, Laura S., Czerniak, Bogdan A., Aldape, Kenneth D., Wood, Christopher G., Boyd, Jeff, Weaver, JoEllen, Iacocca, Mary V., Petrelli, Nicholas, Witkin, Gary, Brown, Jennifer, Czerwinski, Christine, Huelsenbeck-Dill, Lori, Rabeno, Brenda, Myers, Jerome, Morrison, Carl, Bergsten, Julie, Eckman, John, Harr, Jodi, Smith, Christine, Tucker, Kelinda, Zach, Leigh Anne, Bshara, Wiam, Gaudioso, Carmelo, Dhir, Rajiv, Maranchie, Jodi, Nelson, Joel, Parwani, Anil, Potapova, Olga, Fedosenko, Konstantin, Cheville, John C., Thompson, Houston R., Mosquera, Juan M., Rubin, Mark A., Blute, Michael L., Pihl, Todd, Jensen, Mark, Sfeir, Robert, Kahn, Ari, Chu, Anna, Kothiyal, Prachi, Snyder, Eric, Pontius, Joan, Ayala, Brenda, Backus, Mark, Walton, Jessica, Baboud, Julien, Berton, Dominique, Nicholls, Matthew, Srinivasan, Deepak, Raman, Rohini, Girshik, Stanley, Kigonya, Peter, Alonso, Shelley, Sanbhadti, Rashmi, Barletta, Sean, Pot, David, Sheth, Margi, Demchok, John A., Davidsen, Tanja, Wang, Zhining, Yang, Liming, Tarnuzzer, Roy W., Zhang, Jiashan, Eley, Greg, Ferguson, Martin L., Mills Shaw, Kenna R., Guyer, Mark S., Ozenberger, Bradley A., and Sofia, Heidi J.

Published
2013
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24. Complete genomic landscape of a recurring sporadic parathyroid carcinoma

Author

Kasaian, Katayoon, Wiseman, Sam M, Thiessen, Nina, Mungall, Karen L, Corbett, Richard D, Qian, Jenny Q, Nip, Ka Ming, He, Ann, Tse, Kane, Chuah, Eric, Varhol, Richard J, Pandoh, Pawan, McDonald, Helen, Zeng, Thomas, Tam, Angela, Schein, Jacquie, Birol, Inanc, Mungall, Andrew J, Moore, Richard A, Zhao, Yongjun, Hirst, Martin, Marra, Marco A, Walker, Blair A, and Jones, Steven JM

Published
2013
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26. Comprehensive molecular portraits of human breast tumours

Author

Koboldt, Daniel C., Fulton, Robert S., McLellan, Michael D., Schmidt, Heather, Kalicki-Veizer, Joelle, McMichael, Joshua F., Fulton, Lucinda L., Dooling, David J., Ding, Li, Mardis, Elaine R., Wilson, Richard K., Ally, Adrian, Balasundaram, Miruna, Butterfield, Yaron S. N., Carlsen, Rebecca, Carter, Candace, Chu, Andy, Chuah, Eric, Chun, Hye-Jung E., Coope, Robin J. N., Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Hirst, Martin, Holt, Robert A., Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Pleasance, Erin, Gordon Robertson, A., Schein, Jacqueline E., Shafiei, Arash, Sipahimalani, Payal, Slobodan, Jared R., Stoll, Dominik, Tam, Angela, Thiessen, Nina, Varhol, Richard J., Wye, Natasja, Zeng, Thomas, Zhao, Yongjun, Birol, Inanc, Jones, Steven J. M., Marra, Marco A., Cherniack, Andrew D., Saksena, Gordon, Onofrio, Robert C., Pho, Nam H., Carter, Scott L., Schumacher, Steven E., Tabak, Barbara, Hernandez, Bryan, Gentry, Jeff, Nguyen, Huy, Crenshaw, Andrew, Ardlie, Kristin, Beroukhim, Rameen, Winckler, Wendy, Getz, Gad, Gabriel, Stacey B., Meyerson, Matthew, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Hoadley, Katherine A., Todd Auman, J., Fan, Cheng, Turman, Yidi J., Shi, Yan, Li, Ling, Topal, Michael D., He, Xiaping, Chao, Hann-Hsiang, Prat, Aleix, Silva, Grace O., Iglesia, Michael D., Zhao, Wei, Usary, Jerry, Berg, Jonathan S., Adams, Michael, Booker, Jessica, Wu, Junyuan, Gulabani, Anisha, Bodenheimer, Tom, Hoyle, Alan P., Simons, Janae V., Soloway, Matthew G., Mose, Lisle E., Jefferys, Stuart R., Balu, Saianand, Parker, Joel S., Neil Hayes, D., Perou, Charles M., Malik, Simeen, Mahurkar, Swapna, Shen, Hui, Weisenberger, Daniel J., Triche, Timothy, Jr, Lai, Phillip H., Bootwalla, Moiz S., Maglinte, Dennis T., Berman, Benjamin P., Van Den Berg, David J., Baylin, Stephen B., Laird, Peter W., Creighton, Chad J., Donehower, Lawrence A., Noble, Michael, Voet, Doug, Gehlenborg, Nils, DiCara, Daniel, Zhang, Juinhua, Zhang, Hailei, Wu, Chang-Jiun, Liu, Spring Yingchun, Lawrence, Michael S., Zou, Lihua, Sivachenko, Andrey, Lin, Pei, Stojanov, Petar, Jing, Rui, Cho, Juok, Sinha, Raktim, Park, Richard W., Nazaire, Marc-Danie, Robinson, Jim, Thorvaldsdottir, Helga, Mesirov, Jill, Reynolds, Sheila, Kreisberg, Richard B., Bernard, Brady, Bressler, Ryan, Erkkila, Timo, Lin, Jake, Thorsson, Vesteinn, Zhang, Wei, Shmulevich, Ilya, Ciriello, Giovanni, Weinhold, Nils, Schultz, Nikolaus, Gao, Jianjiong, Cerami, Ethan, Gross, Benjamin, Jacobsen, Anders, Sinha, Rileen, Arman Aksoy, B., Antipin, Yevgeniy, Reva, Boris, Shen, Ronglai, Taylor, Barry S., Ladanyi, Marc, Sander, Chris, Anur, Pavana, Spellman, Paul T., Lu, Yiling, Liu, Wenbin, Verhaak, Roel R. G., Mills, Gordon B., Akbani, Rehan, Zhang, Nianxiang, Broom, Bradley M., Casasent, Tod D., Wakefield, Chris, Unruh, Anna K., Baggerly, Keith, Coombes, Kevin, Weinstein, John N., Haussler, David, Benz, Christopher C., Stuart, Joshua M., Benz, Stephen C., Zhu, Jingchun, Szeto, Christopher C., Scott, Gary K., Yau, Christina, Paull, Evan O., Carlin, Daniel, Wong, Christopher, Sokolov, Artem, Thusberg, Janita, Mooney, Sean, Ng, Sam, Goldstein, Theodore C., Ellrott, Kyle, Grifford, Mia, Wilks, Christopher, Ma, Singer, Craft, Brian, Yan, Chunhua, Hu, Ying, Meerzaman, Daoud, Gastier-Foster, Julie M., Bowen, Jay, Ramirez, Nilsa C., Black, Aaron D., Pyatt, Robert E., White, Peter, Zmuda, Erik J., Frick, Jessica, Lichtenberg, Tara M., Brookens, Robin, George, Myra M., Gerken, Mark A., Harper, Hollie A., Leraas, Kristen M., Wise, Lisa J., Tabler, Teresa R., McAllister, Cynthia, Barr, Thomas, Hart-Kothari, Melissa, Tarvin, Katie, Saller, Charles, Sandusky, George, Mitchell, Colleen, Iacocca, Mary V., Brown, Jennifer, Rabeno, Brenda, Czerwinski, Christine, Petrelli, Nicholas, Dolzhansky, Oleg, Abramov, Mikhail, Voronina, Olga, Potapova, Olga, Marks, Jeffrey R., Suchorska, Wiktoria M., Murawa, Dawid, Kycler, Witold, Ibbs, Matthew, Korski, Konstanty, Spychała, Arkadiusz, Murawa, Paweł, Brzeziński, Jacek J., Perz, Hanna, Łaźniak, Radosław, Teresiak, Marek, Tatka, Honorata, Leporowska, Ewa, Bogusz-Czerniewicz, Marta, Malicki, Julian, Mackiewicz, Andrzej, Wiznerowicz, Maciej, Van Le, Xuan, Kohl, Bernard, Viet Tien, Nguyen, Thorp, Richard, Van Bang, Nguyen, Sussman, Howard, Duc Phu, Bui, Hajek, Richard, Phi Hung, Nguyen, Viet The Phuong, Tran, Quyet Thang, Huynh, Zaki Khan, Khurram, Penny, Robert, Mallery, David, Curley, Erin, Shelton, Candace, Yena, Peggy, Ingle, James N., Couch, Fergus J., Lingle, Wilma L., King, Tari A., Maria Gonzalez-Angulo, Ana, Dyer, Mary D., Liu, Shuying, Meng, Xiaolong, Patangan, Modesto, Waldman, Frederic, Stöppler, Hubert, Kimryn Rathmell, W., Thorne, Leigh, Huang, Mei, Boice, Lori, Hill, Ashley, Morrison, Carl, Gaudioso, Carmelo, Bshara, Wiam, Daily, Kelly, Egea, Sophie C., Pegram, Mark D., Gomez-Fernandez, Carmen, Dhir, Rajiv, Bhargava, Rohit, Brufsky, Adam, Shriver, Craig D., Hooke, Jeffrey A., Leigh Campbell, Jamie, Mural, Richard J., Hu, Hai, Somiari, Stella, Larson, Caroline, Deyarmin, Brenda, Kvecher, Leonid, Kovatich, Albert J., Ellis, Matthew J., Stricker, Thomas, White, Kevin, Olopade, Olufunmilayo, Luo, Chunqing, Chen, Yaqin, Bose, Ron, Chang, Li-Wei, Beck, Andrew H., Pihl, Todd, Jensen, Mark, Sfeir, Robert, Kahn, Ari, Chu, Anna, Kothiyal, Prachi, Wang, Zhining, Snyder, Eric, Pontius, Joan, Ayala, Brenda, Backus, Mark, Walton, Jessica, Baboud, Julien, Berton, Dominique, Nicholls, Matthew, Srinivasan, Deepak, Raman, Rohini, Girshik, Stanley, Kigonya, Peter, Alonso, Shelley, Sanbhadti, Rashmi, Barletta, Sean, Pot, David, Sheth, Margi, Demchok, John A., Mills Shaw, Kenna R., Yang, Liming, Eley, Greg, Ferguson, Martin L., Tarnuzzer, Roy W., Zhang, Jiashan, Dillon, Laura A. L., Buetow, Kenneth, Fielding, Peter, Ozenberger, Bradley A., Guyer, Mark S., Sofia, Heidi J., and Palchik, Jacqueline D.

Published
2012
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27. Comprehensive molecular characterization of human colon and rectal cancer

Author

Muzny, Donna M., Bainbridge, Matthew N., Chang, Kyle, Dinh, Huyen H., Drummond, Jennifer A., Fowler, Gerald, Kovar, Christie L., Lewis, Lora R., Morgan, Margaret B., Newsham, Irene F., Reid, Jeffrey G., Santibanez, Jireh, Shinbrot, Eve, Trevino, Lisa R., Wu, Yuan-Qing, Wang, Min, Gunaratne, Preethi, Donehower, Lawrence A., Creighton, Chad J., Wheeler, David A., Gibbs, Richard A., Lawrence, Michael S., Voet, Douglas, Jing, Rui, Cibulskis, Kristian, Sivachenko, Andrey, Stojanov, Petar, McKenna, Aaron, Lander, Eric S., Gabriel, Stacey, Getz, Gad, Ding, Li, Fulton, Robert S., Koboldt, Daniel C., Wylie, Todd, Walker, Jason, Dooling, David J., Fulton, Lucinda, Delehaunty, Kim D., Fronick, Catrina C., Demeter, Ryan, Mardis, Elaine R., Wilson, Richard K., Chu, Andy, Chun, Hye-Jung E., Mungall, Andrew J., Pleasance, Erin, Robertson, Gordon A., Stoll, Dominik, Balasundaram, Miruna, Birol, Inanc, Butterfield, Yaron S. N., Chuah, Eric, Coope, Robin J. N., Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Hirst, Martin, Holt, Robert A., Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Schein, Jacqueline E., Slobodan, Jared R., Tam, Angela, Thiessen, Nina, Varhol, Richard, Zeng, Thomas, Zhao, Yongjun, Jones, Steven J. M., Marra, Marco A., Bass, Adam J., Ramos, Alex H., Saksena, Gordon, Cherniack, Andrew D., Schumacher, Stephen E., Tabak, Barbara, Carter, Scott L., Pho, Nam H., Nguyen, Huy, Onofrio, Robert C., Crenshaw, Andrew, Ardlie, Kristin, Beroukhim, Rameen, Winckler, Wendy, Meyerson, Matthew, Protopopov, Alexei, Zhang, Juinhua, Hadjipanayis, Angela, Lee, Eunjung, Xi, Ruibin, Yang, Lixing, Ren, Xiaojia, Zhang, Hailei, Sathiamoorthy, Narayanan, Shukla, Sachet, Chen, Peng-Chieh, Haseley, Psalm, Xiao, Yonghong, Lee, Semin, Seidman, Jonathan, Chin, Lynda, Park, Peter J., Kucherlapati, Raju, Auman, Todd J., Hoadley, Katherine A., Du, Ying, Wilkerson, Matthew D., Shi, Yan, Liquori, Christina, Meng, Shaowu, Li, Ling, Turman, Yidi J., Topal, Michael D., Tan, Donghui, Waring, Scot, Buda, Elizabeth, Walsh, Jesse, Jones, Corbin D., Mieczkowski, Piotr A., Singh, Darshan, Wu, Junyuan, Gulabani, Anisha, Dolina, Peter, Bodenheimer, Tom, Hoyle, Alan P., Simons, Janae V., Soloway, Matthew, Mose, Lisle E., Jefferys, Stuart R., Balu, Saianand, O’Connor, Brian D., Prins, Jan F., Chiang, Derek Y., Hayes, Neil D., Perou, Charles M., Hinoue, Toshinori, Weisenberger, Daniel J., Maglinte, Dennis T., Pan, Fei, Berman, Benjamin P., Van Den Berg, David J., Shen, Hui, Triche, Timothy, Jr, Baylin, Stephen B., Laird, Peter W., Noble, Michael, Voet, Doug, Gehlenborg, Nils, DiCara, Daniel, Wu, Chang-Jiun, Yingchun Liu, Spring, Zhou, Lihua, Lin, Pei, Park, Richard W., Nazaire, Marc-Danie, Robinson, Jim, Thorvaldsdottir, Helga, Mesirov, Jill, Thorsson, Vesteinn, Reynolds, Sheila M., Bernard, Brady, Kreisberg, Richard, Lin, Jake, Iype, Lisa, Bressler, Ryan, Erkkilä, Timo, Gundapuneni, Madhumati, Liu, Yuexin, Norberg, Adam, Robinson, Tom, Yang, Da, Zhang, Wei, Shmulevich, Ilya, de Ronde, Jorma J., Schultz, Nikolaus, Cerami, Ethan, Ciriello, Giovanni, Goldberg, Arthur P., Gross, Benjamin, Jacobsen, Anders, Gao, Jianjiong, Kaczkowski, Bogumil, Sinha, Rileen, Aksoy, Arman B., Antipin, Yevgeniy, Reva, Boris, Shen, Ronglai, Taylor, Barry S., Chan, Timothy A., Ladanyi, Marc, Sander, Chris, Akbani, Rehan, Zhang, Nianxiang, Broom, Bradley M., Casasent, Tod, Unruh, Anna, Wakefield, Chris, Hamilton, Stanley R., Cason, Craig R., Baggerly, Keith A., Weinstein, John N., Haussler, David, Benz, Christopher C., Stuart, Joshua M., Benz, Stephen C., Sanborn, Zachary J., Vaske, Charles J., Zhu, Jingchun, Szeto, Christopher, Scott, Gary K., Yau, Christina, Ng, Sam, Goldstein, Ted, Ellrott, Kyle, Collisson, Eric, Cozen, Aaron E., Zerbino, Daniel, Wilks, Christopher, Craft, Brian, Spellman, Paul, Penny, Robert, Shelton, Troy, Hatfield, Martha, Morris, Scott, Yena, Peggy, Shelton, Candace, Sherman, Mark, Paulauskis, Joseph, Gastier-Foster, Julie M., Bowen, Jay, Ramirez, Nilsa C., Black, Aaron, Pyatt, Robert, Wise, Lisa, White, Peter, Bertagnolli, Monica, Brown, Jen, Chu, Gerald C., Czerwinski, Christine, Denstman, Fred, Dhir, Rajiv, Dörner, Arnulf, Fuchs, Charles S., Guillem, Jose G., Iacocca, Mary, Juhl, Hartmut, Kaufman, Andrew, Kohl, Bernard, III, Van Le, Xuan, Mariano, Maria C., Medina, Elizabeth N., Meyers, Michael, Nash, Garrett M., Paty, Phillip B., Petrelli, Nicholas, Rabeno, Brenda, Richards, William G., Solit, David, Swanson, Pat, Temple, Larissa, Tepper, Joel E., Thorp, Richard, Vakiani, Efsevia, Weiser, Martin R., Willis, Joseph E., Witkin, Gary, Zeng, Zhaoshi, Zinner, Michael J., Zornig, Carsten, Jensen, Mark A., Sfeir, Robert, Kahn, Ari B., Chu, Anna L., Kothiyal, Prachi, Wang, Zhining, Snyder, Eric E., Pontius, Joan, Pihl, Todd D., Ayala, Brenda, Backus, Mark, Walton, Jessica, Whitmore, Jon, Baboud, Julien, Berton, Dominique L., Nicholls, Matthew C., Srinivasan, Deepak, Raman, Rohini, Girshik, Stanley, Kigonya, Peter A., Alonso, Shelley, Sanbhadti, Rashmi N., Barletta, Sean P., Greene, John M., Pot, David A., Mills Shaw, Kenna R., Dillon, Laura A. L., Buetow, Ken, Davidsen, Tanja, Demchok, John A., Eley, Greg, Ferguson, Martin, Fielding, Peter, Schaefer, Carl, Sheth, Margi, Yang, Liming, Guyer, Mark S., Ozenberger, Bradley A., Palchik, Jacqueline D., Peterson, Jane, Sofia, Heidi J., and Thomson, Elizabeth

Published
2012
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28. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers

Author

Yip, Stephen, Butterfield, Yaron S, Morozova, Olena, Chittaranjan, Suganthi, Blough, Michael D, An, Jianghong, Birol, Inanc, Chesnelong, Charles, Chiu, Readman, Chuah, Eric, Corbett, Richard, Docking, Rod, Firme, Marlo, Hirst, Martin, Jackman, Shaun, Karsan, Aly, Li, Haiyan, Louis, David N, Maslova, Alexandra, Moore, Richard, Moradian, Annie, Mungall, Karen L, Perizzolo, Marco, Qian, Jenny, Roldan, Gloria, Smith, Eric E, Tamura-Wells, Jessica, Thiessen, Nina, Varhol, Richard, Weiss, Samuel, Wu, Wei, Young, Sean, Zhao, Yongjun, Mungall, Andrew J, Jones, Steven JM, Morin, Gregg B, Chan, Jennifer A, Cairncross, Gregory J, and Marra, Marco A

Published
2012
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29. Whole-Genome Sequencing and Social-Network Analysis of a Tuberculosis Outbreak

Author

Gardy, Jennifer L., Johnston, James C., Sui, Shannan J. Ho, Cook, Victoria J., Shah, Lena, Brodkin, Elizabeth, Rempel, Shirley, Moore, Richard, Zhao, Yongjun, Holt, Robert, Varhol, Richard, Birol, Inanc, Lem, Marcus, Sharma, Meenu K., Elwood, Kevin, Jones, Steven J.M., Brinkman, Fiona S.L., Brunham, Robert C., and Tang, Patrick

Published
2011

32. De novo transcriptome assembly with ABySS

Author

Birol, Inanç, Jackman, Shaun D., Nielsen, Cydney B., Qian, Jenny Q., Varhol, Richard, Stazyk, Greg, Morin, Ryan D., Zhao, Yongjun, Hirst, Martin, Schein, Jacqueline E., Horsman, Doug E., Connors, Joseph M., Gascoyne, Randy D., Marra, Marco A., and Jones, Steven J. M.

Published
2009

35. Identification of a set of genes showing regionally enriched expression in the mouse brain

Author

Marra Marco A, Goldowitz Daniel, He An, Wasserman Wyeth W, Portales-Casamar Elodie, Bilenky Mikhail, Lee Lisa LC, Zhao Yongjun, Bohacec Slavita, Xie Yuan-Yun, Varhol Richard, Chopra Vikramjit, D'Souza Cletus A, Holt Robert A, Simpson Elizabeth M, and Jones Steven JM

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters (< 4 kb) that drive gene expression in specific brain regions or cell-types of therapeutic interest. Our goal was to first identify genes displaying regionally enriched expression in the mouse brain so that promoters designed from orthologous human genes can then be tested to drive reporter expression in a similar pattern in the mouse brain. Results We have utilized LongSAGE to identify regionally enriched transcripts in the adult mouse brain. As supplemental strategies, we also performed a meta-analysis of published literature and inspected the Allen Brain Atlas in situ hybridization data. From a set of approximately 30,000 mouse genes, 237 were identified as showing specific or enriched expression in 30 target regions of the mouse brain. GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology. Conclusion Using a multi-faceted expression validation approach, we have identified mouse genes whose human orthologs are good candidates for design of mini-promoters. These mouse genes represent molecular markers in several discrete brain regions/cell-types, which could potentially provide a mechanistic explanation of unique functions performed by each region. This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression.

Published
2008
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36. Exploring geospatial variation in diabetes-related primary health care service utilisation and potentially preventable hospitalisations in Western Australia

Author

Veenendaal, Bert, Koh, C., Saleem, Ashty, Varhol, Richard, Xiao, J., Mai, B., Liu, Y., Veenendaal, Bert, Koh, C., Saleem, Ashty, Varhol, Richard, Xiao, J., Mai, B., and Liu, Y.

Abstract

© Authors 2018. Greater investments and improvements in primary health care (PHC) can provide benefits in reducing the high costs of hospital admissions. Potentially preventable hospitalisations (PPH) are a health system performance indicator used to evaluate access to and effectiveness of community-based health services. The Western Australia Department of Health obtained detailed primary health care data, for the first time at the postcode level scale, and analysed its associations with PPH information for selected conditions. PHC data obtained from the Commonwealth Department of Health for the financial year 2013/14 was Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) records at postcode level. In this paper we explore the sensitivity of various benchmarks of spatial zonings for comparison of diabetes-related primary health care utilisation and potentially preventable hospitalisations and then examine the relationship between them among the various spatial zonings. From the geospatial visualisation and analysis undertaken, conclusions are drawn about the patterns and relationships between diabetes-related primary health care utilisation and potentially preventable hospitalisations. The scale of spatial zonings used for comparison is important as too large or too small areas may mask out the relative geospatial variation of diabetes-related PHC utilisation and PPH evident among postcode areas.

Published
2018

38. Investigating articulated heavy-vehicle crashes in western Australia using a spatial approach

Author

Gudes, O., Varhol, Richard, Sun, Q., Meuleners, Lynn, Gudes, O., Varhol, Richard, Sun, Q., and Meuleners, Lynn

Abstract

Recent developments in Western Australia's economy including widespread traffic congestion as well as road safety issues are increasingly becoming prominent. Previous studies relied on traditional statistical methods to investigate patterns and characteristics of motor vehicle crashes. Although useful, statistical analysis alone is incapable of providing a spatial context and is therefore unable to associate existing crash characteristics with a spatial distribution. Aims To identify concentrations or “hotspots” of articulated heavy vehicle crashes in WA between the years 2001–2013, by using a spatial analysis approach. Methods Spatial modelling and spatio-temporal analytical methods such as Emerging Hotspots were used to identify emerging hotspots on specific roads in Western Australia using the Integrated Road Information System (IRIS). Results The results suggest that the majority of articulated heavy vehicles crashes occurred in the vicinity or within the Perth metropolitan area. Based on spatial-temporal trend analyses, our findings highlight some regions that are emerging as areas of interest. Discussion This study was one of the first attempts to adopt a spatial analysis approach in studying heavy-vehicle crashes in Western Australia. Applying spatial methodologies to road safety data has the potential of obtaining previously undiscovered insights, which can be extended further, and provide future avenues to research in this field.

Published
2017

39. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

Author

Hoadley, Katherine A., Yau, Christina, Wolf, Denise M., Cherniack, Andrew D., Tamborero, David, Sam, Ng, Leiserson, Max D. M., Niu, Beifang, Mclellan, Michael D., Uzunangelov, Vladislav, Zhang, Jiashan, Kandoth, Cyriac, Akbani, Rehan, Shen, Hui, Omberg, Larsson, Chu, Andy, Margolin, Adam A., Van'T Veer, Laura J., Lopez Bigas, Nuria, Laird, Peter W., Raphael, Benjamin J., Ding, Li, Robertson, A. Gordon, Byers, Lauren A., Mills, Gordon B., Weinstein, John N., Van Waes, Carter, Chen, Zhong, Collisson, Eric A., Benz, Christopher C, Perou, Charles M., Stuart, Joshua M., Rachel, Abbott, Scott, Abbott, Arman Aksoy, B., Kenneth, Aldape, Adrian, Ally, Samirku mar Amin, Dimitris, Anastassiou, Todd Auman, J., Baggerly, Keith A., Miruna, Balasundaram, Saianand, Balu, Baylin, Stephen B., Benz, Stephen C., Berman, Benjamin P., Brady, Bernard, Bhatt, Ami S., Inanc, Birol, Black, Aaron D., Tom, Bodenheimer, Bootwalla, Moiz S., Jay, Bowen, Ryan, Bressler, Bristow, Christopher A., Brooks, Angela N., Bradley, Broom, Elizabeth, Buda, Robert, Burton, Butterfield, Yaron S. N., Daniel, Carlin, Carter, Scott L., Casasent, Tod D., Kyle, Chang, Stephen, Chanock, Lynda, Chin, Dong Yeon Cho, Juok, Cho, Eric, Chuah, Chun, Hye Jung E., Kristian, Cibulskis, Giovanni, Ciriello, James Cle land, Melisssa, Cline, Brian, Craft, Creighton, Chad J., Ludmila, Danilova, Tanja, Davidsen, Caleb, Davis, Dees, Nathan D., Kim, Delehaunty, Demchok, John A., Noreen, Dhalla, Daniel, Dicara, Huyen, Dinh, Dobson, Jason R., Deepti, Dodda, Harshavardhan, Doddapaneni, Lawrence, Donehower, Dooling, David J., Gideon, Dresdner, Jennifer, Drummond, Andrea, Eakin, Mary, Edgerton, Eldred, Jim M., Greg, Eley, Kyle, Ellrott, Cheng, Fan, Suzanne, Fei, Ina, Felau, Scott, Frazer, Freeman, Samuel S., Jessica, Frick, Fronick, Catrina C., Ful ton, Lucinda L., Robert, Fulton, Gabriel, Stacey B., Jianjiong, Gao, Gastier Foster, Julie M., Nils, Gehlenborg, Myra, George, Gad, Getz, Richard, Gibbs, Mary, Goldman, Abel Gonzalez Perez, Benjamin, Gross, Ranabir, Guin, Preethi, Gunaratne, Angela, Hadjipanayis, Hamilton, Mark P., Hamilton, Stanley R., Leng, Han, Han, Yi, Harper, Hollie A., Psalm, Haseley, David, Haussler, Neil Hayes, D., Heiman, David I., Elena, Helman, Carmen, Helsel, Herbrich, Shelley M., Her man, James G., Toshinori, Hinoue, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Hoyle, Alan P., Lisa, Iype, Anders, Jacobsen, Jeffreys, Stuart R., Jensen, Mark A., Jones, Corbin D., Jones, Steven J. M., Zhenlin, Ju, Joonil, Jung, Andre, Kahles, Ari, Kahn, Joelle Kalicki Veizer, Divya, Kalra, Krishna Latha Kanchi, Kane, David W., Hoon, Kim, Jaegil, Kim, Theo, Knijnenburg, Koboldt, Daniel C., Christie, Kovar, Roger, Kramer, Richard, Kreisberg, Raju, Kucherlapati, Marc, Ladanyi, Lander, Eric S., Larson, David E., Lawrence, Michael S., Darlene, Lee, Eunjung, Lee, Semin, Lee, William, Lee, Kjong Van Lehmann, Kalle, Leinonen, Ler aas, Kristen M., Seth, Lerner, Levine, Douglas A., Lora, Lewis, Ley, Timothy J., Haiyan I., Li, Jun, Li, Wei, Li, Han, Liang, Lichtenberg, Tara M., Jake, Lin, Ling, Lin, Pei, Lin, Wen bin Liu, Yingchun, Liu, Yuexin, Liu, Lorenzi, Philip L., Charles, Lu, Yiling, Lu, Luquette, Love lace J., Singer, Ma, Magrini, Vincent J., Mahadeshwar, Harshad S., Mardis, Elaine R., Adam, Margolin, Marra, Marco A., Michael, Mayo, Cynthia, Mcallister, Mcguire, Sean E., Mcmichael, Joshua F., James, Melott, Shaowu, Meng, Matthew, Meyerson, Mieczkowski, Piotr A., Miller, Christopher A., Miller, Martin L., Michael, Miller, Moore, Richard A., Margaret, Morgan, Donna, Morton, Mose, Lisle E., Mungall, Andrew J., Donna, Muzny, Lam, Nguyen, Noble, Michael S., Houtan, Noushmehr, Michelle, O’Laughlin, Ojesina, Akinyemi I., Tai Hsien Ou Yang, Brad, Ozenberger, Angeliki, Pantazi, Michael, Parfenov, Park, Peter J., Parker, Joel S., Evan, Paull, Chandra Sekhar Pedamallu, Todd, Pihl, Craig, Pohl, David, Pot, Alexei, Protopopov, Teresa, Przytycka, Amie Raden baugh, Ramirez, Nilsa C., Ricardo, Ramirez, Gunnar Ra, ̈ tsch, Jeffrey, Reid, Xiao jia Ren, Boris, Reva, Reynolds, Sheila M., Rhie, Suhn K., Jeffrey, Roach, Hector, Rovira, Michael, Ryan, Gordon, Saksena, Sofie, Salama, Chris, Sander, Netty, Santoso, Schein, Jacqueline E., Heather, Schmidt, Nikolaus, Schultz, Schumacher, Steven E., Jonathan, Seidman, Yasin, Senbabaoglu, Sahil, Seth, Saman tha Sharpe, Ronglai, Shen, Margi, Sheth, Yan, Shi, Ilya, Shmulevich, Silva, Grace O., Simons, Janae V., Rileen, Sinha, Payal, Sipahimalani, Smith, Scott M., Sofia, Heidi J., Artem, Sokolov, Soloway, Mathew G., Xingzhi, Song, Carrie Soug nez, Paul, Spellman, Louis, Staudt, Chip, Stewart, Petar, Stojanov, Xiaoping, Su, Onur Sumer, S., Yichao, Sun, Teresa, Swatloski, Barbara, Tabak, Angela, Tam, Donghui, Tan, Jiabin, Tang, Roy, Tarnuzzer, Taylor, Barry S., Nina, Thiessen, Ves teinn Thorsson, Timothy Triche, J. r., Van Den Berg, David J., Vandin, Fabio, Varhol, Richard J., Vaske, Charles J., Umadevi, Veluvolu, Roeland, Verhaak, Doug, Voet, Jason, Walker, Wallis, John W., Peter, Waltman, Yunhu, Wan, Min, Wang, Wenyi, Wang, Zhining, Wang, Scot, Waring, Nils, Weinhold, Weisenberger, Daniel J., Wendl, Michael C., David, Wheeler, Wilkerson, Matthew D., Wilson, Richard K., Lisa, Wise, Andrew, Wong, Chang Jiun Wu, Chia Chin Wu, Hsin Ta Wu, Junyuan, Wu, Todd, Wylie, Liu, Xi, Ruibin, Xi, Zheng, Xia, Andrew W., Xu, Yang, Da, Liming, Yang, Lixing, Yang, Yang, Yang, Jun, Yao, Rong, Yao, Kai, Ye, Ko suke Yoshihara, Yuan, Yuan, Yung, Alfred K., Travis, Zack, Dong, Zeng, Jean Claude Zenklusen, Hailei, Zhang, Jianhua, Zhang, Nianxiang, Zhang, Qunyuan, Zhang, Wei, Zhang, Wei, Zhao, Siyuan, Zheng, Jing, Zhu, Erik, Zmuda, and Lihua, Zou

Subjects
Genetics and Molecular Biology (all), Cluster Analysis, Humans, Neoplasms, Transcriptome, Biochemistry, Genetics and Molecular Biology (all), Extramural, Biochemistry, Genetics and Molecular Biology(all), Cancer, Computational biology, Disease, Biology, medicine.disease, Bioinformatics, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, 3. Good health, Molecular classification, TP63, CLUSTERS (ANÁLISE), medicine, Head and neck, Gene
Abstract

Summary Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014
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40. Large-scale production of SAGE libraries from microdissected tissues, flow-sorted cells, and cell lines

Author

Khattra, Jaswinder, Delaney, Allen D., Yongjun Zhao, Siddiqui, Asim, Asano, Jennifer, McDonald, Helen, Pandoh, Pawan, Dhalla, Noreen, Prabhu; Anna-Iiisa, Ma, Kevin, Lee, Stephanie, Ally, Adrian, Tam, Angela, Sa, Danne, Rogers, Sean, Charest, David, Stott, Jeff, Zuyderdyun, Scott, Varhol, Richard, Eaves, Connie, Jones, Steven, Holt, Robert, Hirst, Martin, Hoodless, Pamela A., and Marra, Marco A.

Subjects
Eukaryotes -- Genetic aspects, Eukaryotes -- Research, Gene expression -- Analysis, Nucleotide sequencing -- Analysis, Polymerase chain reaction -- Analysis, Health
Abstract

A serial analysis of gene expression (SAGE) library construction pipeline that is devised and implemented to generate high-quality digital gene expression profiling data is described. The pipeline comprises of several previous published improvements with the modification in the SAGE protocol resulting in improved cloning and DNA sequencing efficiencies.

Published
2007

41. The Australian primary healthcare experiment: a national survey of Medicare Locals

Author

Robinson, Suzanne, Varhol, Richard, Ramamurthy, Vijaya, Denehy, M., Hendrie, Delia, O'Leary, Peter, Selvey, Linda, Robinson, Suzanne, Varhol, Richard, Ramamurthy, Vijaya, Denehy, M., Hendrie, Delia, O'Leary, Peter, and Selvey, Linda

Abstract

Objective - The objectives of this study are to evaluate the development and implementation of Medicare Locals as new primary care organisations and consider the implications of these findings for the wider challenge of strengthening primary healthcare in Australia and internationally. Design - National survey of Medicare Locals which involved the use of content analysis and a descriptive survey tool. Setting - 61 Medicare Locals in Australia. Participants - The survey was distributed electronically to all 61 Medicare Local Chief Executive Officers (CEOs) between October and December 2013. Main outcome measures - The research was interested in exploring the following areas; the form and function of Medicare Locals; the confidence and capacity of Medicare Locals to perform against their objectives around population planning and system integration; their ability to engage relevant stakeholder groups; and the barriers and facilitators to reform. Results - A total of 43 (70%) of Medicare Locals completed the survey with representation from six of the eight Australian states and Territories. Results suggest differences in the form and function of the Medicare Local organisations and considerable diversity in the implementation of Medicare Local organisations across Australia. This diversity and lack of guidance from government impacted on the overall success of the reform. Other barriers to reform included difficulties in stakeholder relationships and limited incentives (financial and other) to drive and influence change. Conclusions - Findings from this study produce important insights for primary care reform in Australia; and internationally it adds to the growing body of knowledge around primary care reform.

Published
2015

42. HealthPathways: creating a pathway for health systems reform

Author

Robinson, Suzanne, Varhol, Richard, Bell, C., Quirk, F., Durrington, L., Robinson, Suzanne, Varhol, Richard, Bell, C., Quirk, F., and Durrington, L.

Abstract

Inefficiencies in the co-ordination and integration of primary and secondary care services in Australia, have led to increases in waiting times, unnecessary presentations to emergency departments and issues around poor discharge of patients. HealthPathways is a program developed in Canterbury, New Zealand, that builds relationships between General Practitioners and Specialists and uses information technology so that efficiency is maximised and the right patient is given the right care at the right time. Healthpathways is being implemented by a number of Medicare Locals across Australia however, little is known about the impact HealthPathways may have in Australia. This article provides a short description of HealthPathways and considers what it may offer in the Australian context and some of the barriers and facilitators to implementation.

Published
2015

43. Barnacle: Detecting and Characterizing Tandem Duplications and Fusions in Transcriptome Assemblies

Author

Swanson, Lucas, Robertson, Gordon, Mungall, Karen, Butterfield, Yaron, Chiu, Readman, Corbett, Richard, Docking, T., Hogge, Donna, Jackman, Shaun, Moore, Richard, Mungall, Andrew, Nip, Ka, Parker, Jeremy, Qian, Jenny, Raymond, Anthony, Sung, Sandy, Tam, Angela, Thiessen, Nina, Varhol, Richard, Yorukoglu, Deniz, Zhao, YongJun, Hoodless, Pamela, Sahinalp, S., Karsan, Aly, and Birol, Inanc

Abstract

Background Chimeric transcripts, including partial and internal tandem duplications (PTDs, ITDs) and gene fusions, are important in the detection, prognosis, and treatment of human cancers. Results We describe Barnacle, a production-grade analysis tool that detects such chimeras in de novo assemblies of RNA-seq data, and supports prioritizing them for review and validation by reporting the relative coverage of co-occurring chimeric and wild-type transcripts. We demonstrate applications in large-scale disease studies, by identifying PTDs in MLL, ITDs in FLT3, and reciprocal fusions between PML and RARA, in two deeply sequenced acute myeloid leukemia (AML) RNA-seq datasets. Conclusions Our analyses of real and simulated data sets show that, with appropriate filter settings, Barnacle makes highly specific predictions for three types of chimeric transcripts that are important in a range of cancers: PTDs, ITDs, and fusions. High specificity makes manual review and validation efficient, which is necessary in large-scale disease studies. Characterizing an extended range of chimera types will help generate insights into progression, treatment, and outcomes for complex diseases.

Published
2013

44. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Northcott, Paul A, Shih, David JH, Peacock, John, Garzia, Livia, Morrissy, A Sorana, Zichner, Thomas, Stütz, Adrian M, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven E, Beroukhim, Rameen, Ellison, David W, Marshall, Christian R, Lionel, Anath C, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence MG, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman YB, Chu, Andy, Chuah, Eric, Corbett, Richard D, Hoad, Gemma R, Jackman, Shaun D, Li, Yisu, Lo, Allan, Mungall, Karen L, Nip, Ka Ming, Qian, Jenny Q, Raymond, Anthony GJ, Thiessen, Nina T, Varhol, Richard J, Birol, Inanc, Moore, Richard A, Mungall, Andrew J, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F, Kool, Marcel, Jones, David TW, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna M, Wechsler-Reya, Robert J, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Haberler, Christine C, Delattre, Olivier, Reynaud, Stéphanie S, Doz, François F, Pernet-Fattet, Sarah S, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F, Fan, Xing, Muraszko, Karin M, Gillespie, G Yancey, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Kloosterhof, Nanne K, French, Pim J, Kros, Johan M, Olson, James M, Ellenbogen, Richard G, Zitterbart, Karel, Kren, Leos, Thompson, Reid C, Cooper, Michael K, Lach, Boleslaw, McLendon, Roger E, Bigner, Darell D, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet C, Bailey, Simon, Gupta, Nalin, Weiss, William A, Bognár, László, Klekner, Almos, Van Meter, Timothy E, Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K, Leonard, Jeffrey R, and Rubin, Joshua B

Subjects
Pediatric Research Initiative, DNA Copy Number Variations, Pediatric Cancer, General Science & Technology, Translocation, Nerve Tissue Proteins, Rare Diseases, Genetic, Transforming Growth Factor beta, Gene Duplication, Genetics, Humans, Hedgehog Proteins, Cerebellar Neoplasms, Fusion, Child, Cancer, Oncogene Proteins, Pediatric, Genome, NF-kappa B, Neurosciences, Proteins, Genomics, myc, Brain Disorders, Brain Cancer, Genes, 5.1 Pharmaceuticals, Genomic Structural Variation, RNA, Long Noncoding, Development of treatments and therapeutic interventions, Carrier Proteins, Medulloblastoma, Signal Transduction, Human
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Published
2012

47. Comprehensive molecular profiling of lung adenocarcinoma

Author

Collisson, Eric A., Campbell, Joshua D., Brooks, Angela N., Berger, Alice H., Lee, William, Chmielecki, Juliann, Beer, David G., Cope, Leslie, Creighton, Chad J., Danilova, Ludmila, Ding, Li, Getz, Gad, Hammerman, Peter S., Hayes, D. Neil, Hernandez, Bryan, Herman, James G., Heymach, John V., Jurisica, Igor, Kucherlapati, Raju, Kwiatkowski, David, Ladanyi, Marc, Robertson, Gordon, Schultz, Nikolaus, Shen, Ronglai, Sinha, Rileen, Sougnez, Carrie, Tsao, Ming-Sound, Travis, William D., Weinstein, John N., Wigle, Dennis A., Wilkerson, Matthew D., Chu, Andy, Cherniack, Andrew D., Hadjipanayis, Angela, Rosenberg, Mara, Weisenberger, Daniel J., Laird, Peter W., Radenbaugh, Amie, Ma, Singer, Stuart, Joshua M., Byers, Lauren Averett, Baylin, Stephen B., Govindan, Ramaswamy, Meyerson, Matthew, Gabriel, Stacey B., Cibulskis, Kristian, Kim, Jaegil, Stewart, Chip, Lichtenstein, Lee, Lander, Eric S., Lawrence, Michael S., Kandoth, Cyriac, Fulton, Robert, Fulton, Lucinda L., McLellan, Michael D., Wilson, Richard K., Ye, Kai, Fronick, Catrina C., Maher, Christopher A., Miller, Christopher A., Wendl, Michael C., Cabanski, Christopher, Mardis, Elaine, Wheeler, David, Balasundaram, Miruna, Butterfield, Yaron S. N., Carlsen, Rebecca, Chuah, Eric, Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Varhol, Richard, Robertson, A. Gordon, Wye, Natasja, Thiessen, Nina, Holt, Robert A., Jones, Steven J. M., Marra, Marco A., Imielinski, Marcin, Onofrio, Robert C., Hodis, Eran, Zack, Travis, Helman, Elena, Pedamallu, Chandra Sekhar, Mesirov, Jill, Saksena, Gordon, Schumacher, Steven E., Carter, Scott L., Garraway, Levi, Beroukhim, Rameen, Lee, Semin, Mahadeshwar, Harshad S., Pantazi, Angeliki, Protopopov, Alexei, Ren, Xiaojia, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Yang, Lixing, Zhang, Jianhua, Chen, Peng-Chieh, Parfenov, Michael, Xu, Andrew Wei, Santoso, Netty, Chin, Lynda, Park, Peter J., Hoadley, Katherine A., Auman, J. Todd, Meng, Shaowu, Shi, Yan, Buda, Elizabeth, Waring, Scot, Veluvolu, Umadevi, Tan, Donghui, Mieczkowski, Piotr A., Jones, Corbin D., Simons, Janae V., Soloway, Matthew G., Bodenheimer, Tom, Jefferys, Stuart R., Roach, Jeffrey, Hoyle, Alan P., Wu, Junyuan, Balu, Saianand, Singh, Darshan, Prins, Jan F., Marron, J. S., Parker, Joel S., Perou, Charles M., Liu, Jinze, Maglinte, Dennis T., Lai, Philip H., Bootwalla, Moiz S., Van Den Berg, David J., Triche, Timothy, Jr., Cho, Juok, DiCara, Daniel, Heiman, David, Lin, Pei, Mallard, William, Voet, Douglas, Zhang, Hailei, Zou, Lihua, Noble, Michael S., Gehlenborg, Nils, Thorvaldsdottir, Helga, Nazaire, Marc-Danie, Robinson, Jim, Aksoy, B. Arman, Ciriello, Giovanni, Taylor, Barry S., Dresdner, Gideon, Gao, Jianjiong, Gross, Benjamin, Seshan, Venkatraman E., Reva, Boris, Sumer, S. Onur, Weinhold, Nils, Sander, Chris, Zhu, Jingchun, Benz, Christopher C., Yau, Christina, Haussler, David, Spellman, Paul T., Kimes, Patrick K., Broom, Bradley M., Wang, Jing, Lu, Yiling, Diao, Lixia, Liu, Wenbin, Amos, Christopher I., Akbani, Rehan, Mills, Gordon B., Curley, Erin, Paulauskis, Joseph, Lau, Kevin, Morris, Scott, Shelton, Troy, Mallery, David, Gardner, Johanna, Penny, Robert, Saller, Charles, Tarvin, Katherine, Richards, William G., Cerfolio, Robert, Bryant, Ayesha, Raymond, Daniel P., Pennell, Nathan A., Farver, Carol, Czerwinski, Christine, Huelsenbeck-Dill, Lori, Iacocca, Mary, Petrelli, Nicholas, Rabeno, Brenda, Brown, Jennifer, Bauer, Thomas, Dolzhanskiy, Oleg, Potapova, Olga, Rotin, Daniil, Voronina, Olga, Nemirovich-Danchenko, Elena, Fedosenko, Konstantin V., Gal, Anthony, Behera, Madhusmita, Ramalingam, Suresh S., Sica, Gabriel, Flieder, Douglas, Boyd, Jeff, Weaver, JoEllen, Kohl, Bernard, Sandusky, George, Juhl, Hartmut, Duhig, Edwina, Illei, Peter, Gabrielson, Edward, Shin, James, Lee, Beverly, Rogers, Kristen, Trusty, Dante, Brock, Malcolm V., Williamson, Christina, Burks, Eric, Rieger-Christ, Kimberly, Holway, Antonia, Sullivan, Travis, Asiedu, Michael K., Kosari, Farhad, Rekhtman, Natasha, Zakowski, Maureen, Rusch, Valerie W., Zippile, Paul, Suh, James, Pass, Harvey, Goparaju, Chandra, Owusu-Sarpong, Yvonne, Bartlett, John M. S., Kodeeswaran, Sugy, Parfitt, Jeremy, Sekhon, Harmanjatinder, Albert, Monique, Eckman, John, Myers, Jerome B., Cheney, Richard, Morrison, Carl, Gaudioso, Carmelo, Borgia, Jeffrey A., Bonomi, Philip, Pool, Mark, Liptay, Michael J., Moiseenko, Fedor, Zaytseva, Irina, Dienemann, Hendrik, Meister, Michael, Schnabel, Philipp A., Muley, Thomas R., Peifer, Martin, Gomez-Fernandez, Carmen, Herbert, Lynn, Egea, Sophie, Huang, Mei, Thorne, Leigh B., Boice, Lori, Salazar, Ashley Hill, Funkhouser, William K., Rathmell, W. Kimryn, Dhir, Rajiv, Yousem, Samuel A., Dacic, Sanja, Schneider, Frank, Siegfried, Jill M., Hajek, Richard, Watson, Mark A., McDonald, Sandra, Meyers, Bryan, Clarke, Belinda, Yang, Ian A., Fong, Kwun M., Hunter, Lindy, Windsor, Morgan, Bowman, Rayleen V., Peters, Solange, Letovanec, Igor, Khan, Khurram Z., Jensen, Mark A., Snyder, Eric E., Srinivasan, Deepak, Kahn, Ari B., Baboud, Julien, Pot, David A., Shaw, Kenna R. Mills, Sheth, Margi, Davidsen, Tanja, Demchok, John A., Yang, Liming, Wang, Zhining, Tarnuzzer, Roy, Zenklusen, Jean Claude, Ozenberger, Bradley A., Sofia, Heidi J., Collisson, Eric A., Campbell, Joshua D., Brooks, Angela N., Berger, Alice H., Lee, William, Chmielecki, Juliann, Beer, David G., Cope, Leslie, Creighton, Chad J., Danilova, Ludmila, Ding, Li, Getz, Gad, Hammerman, Peter S., Hayes, D. Neil, Hernandez, Bryan, Herman, James G., Heymach, John V., Jurisica, Igor, Kucherlapati, Raju, Kwiatkowski, David, Ladanyi, Marc, Robertson, Gordon, Schultz, Nikolaus, Shen, Ronglai, Sinha, Rileen, Sougnez, Carrie, Tsao, Ming-Sound, Travis, William D., Weinstein, John N., Wigle, Dennis A., Wilkerson, Matthew D., Chu, Andy, Cherniack, Andrew D., Hadjipanayis, Angela, Rosenberg, Mara, Weisenberger, Daniel J., Laird, Peter W., Radenbaugh, Amie, Ma, Singer, Stuart, Joshua M., Byers, Lauren Averett, Baylin, Stephen B., Govindan, Ramaswamy, Meyerson, Matthew, Gabriel, Stacey B., Cibulskis, Kristian, Kim, Jaegil, Stewart, Chip, Lichtenstein, Lee, Lander, Eric S., Lawrence, Michael S., Kandoth, Cyriac, Fulton, Robert, Fulton, Lucinda L., McLellan, Michael D., Wilson, Richard K., Ye, Kai, Fronick, Catrina C., Maher, Christopher A., Miller, Christopher A., Wendl, Michael C., Cabanski, Christopher, Mardis, Elaine, Wheeler, David, Balasundaram, Miruna, Butterfield, Yaron S. N., Carlsen, Rebecca, Chuah, Eric, Dhalla, Noreen, Guin, Ranabir, Hirst, Carrie, Lee, Darlene, Li, Haiyan I., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Varhol, Richard, Robertson, A. Gordon, Wye, Natasja, Thiessen, Nina, Holt, Robert A., Jones, Steven J. M., Marra, Marco A., Imielinski, Marcin, Onofrio, Robert C., Hodis, Eran, Zack, Travis, Helman, Elena, Pedamallu, Chandra Sekhar, Mesirov, Jill, Saksena, Gordon, Schumacher, Steven E., Carter, Scott L., Garraway, Levi, Beroukhim, Rameen, Lee, Semin, Mahadeshwar, Harshad S., Pantazi, Angeliki, Protopopov, Alexei, Ren, Xiaojia, Seth, Sahil, Song, Xingzhi, Tang, Jiabin, Yang, Lixing, Zhang, Jianhua, Chen, Peng-Chieh, Parfenov, Michael, Xu, Andrew Wei, Santoso, Netty, Chin, Lynda, Park, Peter J., Hoadley, Katherine A., Auman, J. Todd, Meng, Shaowu, Shi, Yan, Buda, Elizabeth, Waring, Scot, Veluvolu, Umadevi, Tan, Donghui, Mieczkowski, Piotr A., Jones, Corbin D., Simons, Janae V., Soloway, Matthew G., Bodenheimer, Tom, Jefferys, Stuart R., Roach, Jeffrey, Hoyle, Alan P., Wu, Junyuan, Balu, Saianand, Singh, Darshan, Prins, Jan F., Marron, J. S., Parker, Joel S., Perou, Charles M., Liu, Jinze, Maglinte, Dennis T., Lai, Philip H., Bootwalla, Moiz S., Van Den Berg, David J., Triche, Timothy, Jr., Cho, Juok, DiCara, Daniel, Heiman, David, Lin, Pei, Mallard, William, Voet, Douglas, Zhang, Hailei, Zou, Lihua, Noble, Michael S., Gehlenborg, Nils, Thorvaldsdottir, Helga, Nazaire, Marc-Danie, Robinson, Jim, Aksoy, B. Arman, Ciriello, Giovanni, Taylor, Barry S., Dresdner, Gideon, Gao, Jianjiong, Gross, Benjamin, Seshan, Venkatraman E., Reva, Boris, Sumer, S. Onur, Weinhold, Nils, Sander, Chris, Zhu, Jingchun, Benz, Christopher C., Yau, Christina, Haussler, David, Spellman, Paul T., Kimes, Patrick K., Broom, Bradley M., Wang, Jing, Lu, Yiling, Diao, Lixia, Liu, Wenbin, Amos, Christopher I., Akbani, Rehan, Mills, Gordon B., Curley, Erin, Paulauskis, Joseph, Lau, Kevin, Morris, Scott, Shelton, Troy, Mallery, David, Gardner, Johanna, Penny, Robert, Saller, Charles, Tarvin, Katherine, Richards, William G., Cerfolio, Robert, Bryant, Ayesha, Raymond, Daniel P., Pennell, Nathan A., Farver, Carol, Czerwinski, Christine, Huelsenbeck-Dill, Lori, Iacocca, Mary, Petrelli, Nicholas, Rabeno, Brenda, Brown, Jennifer, Bauer, Thomas, Dolzhanskiy, Oleg, Potapova, Olga, Rotin, Daniil, Voronina, Olga, Nemirovich-Danchenko, Elena, Fedosenko, Konstantin V., Gal, Anthony, Behera, Madhusmita, Ramalingam, Suresh S., Sica, Gabriel, Flieder, Douglas, Boyd, Jeff, Weaver, JoEllen, Kohl, Bernard, Sandusky, George, Juhl, Hartmut, Duhig, Edwina, Illei, Peter, Gabrielson, Edward, Shin, James, Lee, Beverly, Rogers, Kristen, Trusty, Dante, Brock, Malcolm V., Williamson, Christina, Burks, Eric, Rieger-Christ, Kimberly, Holway, Antonia, Sullivan, Travis, Asiedu, Michael K., Kosari, Farhad, Rekhtman, Natasha, Zakowski, Maureen, Rusch, Valerie W., Zippile, Paul, Suh, James, Pass, Harvey, Goparaju, Chandra, Owusu-Sarpong, Yvonne, Bartlett, John M. S., Kodeeswaran, Sugy, Parfitt, Jeremy, Sekhon, Harmanjatinder, Albert, Monique, Eckman, John, Myers, Jerome B., Cheney, Richard, Morrison, Carl, Gaudioso, Carmelo, Borgia, Jeffrey A., Bonomi, Philip, Pool, Mark, Liptay, Michael J., Moiseenko, Fedor, Zaytseva, Irina, Dienemann, Hendrik, Meister, Michael, Schnabel, Philipp A., Muley, Thomas R., Peifer, Martin, Gomez-Fernandez, Carmen, Herbert, Lynn, Egea, Sophie, Huang, Mei, Thorne, Leigh B., Boice, Lori, Salazar, Ashley Hill, Funkhouser, William K., Rathmell, W. Kimryn, Dhir, Rajiv, Yousem, Samuel A., Dacic, Sanja, Schneider, Frank, Siegfried, Jill M., Hajek, Richard, Watson, Mark A., McDonald, Sandra, Meyers, Bryan, Clarke, Belinda, Yang, Ian A., Fong, Kwun M., Hunter, Lindy, Windsor, Morgan, Bowman, Rayleen V., Peters, Solange, Letovanec, Igor, Khan, Khurram Z., Jensen, Mark A., Snyder, Eric E., Srinivasan, Deepak, Kahn, Ari B., Baboud, Julien, Pot, David A., Shaw, Kenna R. Mills, Sheth, Margi, Davidsen, Tanja, Demchok, John A., Yang, Liming, Wang, Zhining, Tarnuzzer, Roy, Zenklusen, Jean Claude, Ozenberger, Bradley A., and Sofia, Heidi J.

Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen(mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2014

48. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

Author

Hoadley, K., Yau, C., Wolf, D., Cherniack, A., Tamborero, D., Ng, S., Leiserson, M., Niu, B., McLellan, M., Uzunangelov, V., Zhang, J., Kandoth, C., Akbani, R., Shen, H., Omberg, L., Chu, A., Margolin, A., van't Veer, L., Lopez-Bigas, N., Laird, P., Raphael, B., Ding, L., Robertson, A., Byers, L., Mills, G., Weinstein, J., Van Waes, C., Chen, Z., Collisson, E., Benz, C., Perou, C., Stuart, J., Abbott, R., Abbott, S., Aksoy, B., Aldape, K., Ally, A., Amin, S., Anastassiou, D., Auman, J., Baggerly, K., Balasundaram, M., Balu, S., Baylin, S., Benz, S., Berman, B., Bernard, B., Bhatt, A., Birol, I., Black, A., Bodenheimer, T., Bootwalla, M., Bowen, J., Bressler, R., Bristow, C., Brooks, A., Broom, B., Buda, E., Burton, R., Butterfield, Y., Carlin, D., Carter, S., Casasent, T., Chang, K., Chanock, S., Chin, L., Cho, D., Cho, J., Chuah, E., Chun, H., Cibulskis, K., Ciriello, G., Cleland, J., Cline, M., Craft, B., Creighton, C., Danilova, L., Davidsen, T., Davis, C., Dees, N., Delehaunty, K., Demchok, J., Dhalla, N., DiCara, D., Dinh, H., Dobson, J., Dodda, D., Doddapaneni, H., Donehower, L., Dooling, D., Dresdner, G., Drummond, J., Eakin, A., Edgerton, M., Eldred, J., Eley, G., Ellrott, K., Fan, C., Fei, S., Felau, I., Frazer, S., Freeman, S., Frick, J., Fronick, C., Fulton, L., Fulton, R., Gabriel, S., Gao, J., Gastier-Foster, J., Gehlenborg, N., George, M., Getz, G., Gibbs, R., Goldman, M., Gonzalez-Perez, A., Gross, B., Guin, R., Gunaratne, P., Hadjipanayis, A., Hamilton, M., Hamilton, S., Han, L., Han, Y., Harper, H., Haseley, P., Haussler, D., Hayes, D., Heiman, D., Helman, E., Helsel, C., Herbrich, S., Herman, J., Hinoue, T., Hirst, C., Hirst, M., Holt, R., Hoyle, A., Iype, L., Jacobsen, A., Jeffreys, S., Jensen, M., Jones, C., Jones, S., Ju, Z., Jung, J., Kahles, A., Kahn, A., Kalicki-Veizer, J., Kalra, D., Kanchi, K., Kane, D., Kim, H., Kim, J., Knijnenburg, T., Koboldt, D., Kovar, C., Kramer, R., Kreisberg, R., Kucherlapati, R., Ladanyi, M., Lander, E., Larson, D., Lawrence, M., Lee, D., Lee, E., Lee, S., Lee, W., Lehmann, K., Leinonen, K., Leraas, K., Lerner, S., Levine, D., Lewis, L., Ley, T., Li, H., Li, J., Li, W., Liang, H., Lichtenberg, T., Lin, J., Lin, L., Lin, P., Liu, W., Liu, Y., Lorenzi, P., Lu, C., Lu, Y., Luquette, L., Ma, S., Magrini, V., Mahadeshwar, H., Mardis, E., Marra, M., Mayo, M., McAllister, C., McGuire, S., McMichael, J., Melott, J., Meng, S., Meyerson, M., Mieczkowski, P., Miller, C., Miller, M., Moore, R., Morgan, M., Morton, D., Mose, L., Mungall, A., Muzny, D., Nguyen, L., Noble, M., Noushmehr, H., O'Laughlin, M., Ojesina, A., Yang, T., Ozenberger, B., Pantazi, A., Parfenov, M., Park, P., Parker, J., Paull, E., Pedamallu, C., Pihl, T., Pohl, C., Pot, D., Protopopov, A., Przytycka, T., Radenbaugh, A., Ramirez, N., Ramirez, R., Ratsch, G., Reid, J., Ren, X., Reva, B., Reynolds, S., Rhie, S., Roach, J., Rovira, H., Ryan, M., Saksena, G., Salama, S., Sander, C., Santoso, N., Schein, J., Schmidt, H., Schultz, N., Schumacher, S., Seidman, J., Senbabaoglu, Y., Seth, S., Sharpe, S., Shen, R., Sheth, M., Shi, Y., Shmulevich, I., Silva, G., Simons, J., Sinha, R., Sipahimalani, P., Smith, S., Sofia, H., Sokolov, A., Soloway, M., Song, X., Sougnez, C., Spellman, P., Staudt, L., Stewart, C., Stojanov, P., Su, X., Sumer, S., Sun, Y., Swatloski, T., Tabak, B., Tam, A., Tan, D., Tang, J., Tarnuzzer, R., Taylor, B., Thiessen, N., Thorsson, V., Triche, T., Van Den Berg, D., Vandin, F., Varhol, Richard, Vaske, C., Veluvolu, U., Verhaak, R., Voet, D., Walker, J., Wallis, J., Waltman, P., Wan, Y., Wang, M., Wang, W., Wang, Z., Waring, S., Weinhold, N., Weisenberger, D., Wendl, M., Wheeler, D., Wilkerson, M., Wilson, R., Wise, L., Wong, A., Wu, C., Wu, H., Wu, J., Wylie, T., Xi, L., Xi, R., Xia, Z., Xu, A., Yang, D., Yang, L., Yang, Y., Yao, J., Yao, R., Ye, K., Yoshihara, K., Yuan, Y., Yung, A., Zack, T., Zeng, D., Zenklusen, J., Zhang, H., Zhang, N., Zhang, Q., Zhang, W., Zhao, W., Zheng, S., Zhu, J., Zmuda, E., Zou, L., Hoadley, K., Yau, C., Wolf, D., Cherniack, A., Tamborero, D., Ng, S., Leiserson, M., Niu, B., McLellan, M., Uzunangelov, V., Zhang, J., Kandoth, C., Akbani, R., Shen, H., Omberg, L., Chu, A., Margolin, A., van't Veer, L., Lopez-Bigas, N., Laird, P., Raphael, B., Ding, L., Robertson, A., Byers, L., Mills, G., Weinstein, J., Van Waes, C., Chen, Z., Collisson, E., Benz, C., Perou, C., Stuart, J., Abbott, R., Abbott, S., Aksoy, B., Aldape, K., Ally, A., Amin, S., Anastassiou, D., Auman, J., Baggerly, K., Balasundaram, M., Balu, S., Baylin, S., Benz, S., Berman, B., Bernard, B., Bhatt, A., Birol, I., Black, A., Bodenheimer, T., Bootwalla, M., Bowen, J., Bressler, R., Bristow, C., Brooks, A., Broom, B., Buda, E., Burton, R., Butterfield, Y., Carlin, D., Carter, S., Casasent, T., Chang, K., Chanock, S., Chin, L., Cho, D., Cho, J., Chuah, E., Chun, H., Cibulskis, K., Ciriello, G., Cleland, J., Cline, M., Craft, B., Creighton, C., Danilova, L., Davidsen, T., Davis, C., Dees, N., Delehaunty, K., Demchok, J., Dhalla, N., DiCara, D., Dinh, H., Dobson, J., Dodda, D., Doddapaneni, H., Donehower, L., Dooling, D., Dresdner, G., Drummond, J., Eakin, A., Edgerton, M., Eldred, J., Eley, G., Ellrott, K., Fan, C., Fei, S., Felau, I., Frazer, S., Freeman, S., Frick, J., Fronick, C., Fulton, L., Fulton, R., Gabriel, S., Gao, J., Gastier-Foster, J., Gehlenborg, N., George, M., Getz, G., Gibbs, R., Goldman, M., Gonzalez-Perez, A., Gross, B., Guin, R., Gunaratne, P., Hadjipanayis, A., Hamilton, M., Hamilton, S., Han, L., Han, Y., Harper, H., Haseley, P., Haussler, D., Hayes, D., Heiman, D., Helman, E., Helsel, C., Herbrich, S., Herman, J., Hinoue, T., Hirst, C., Hirst, M., Holt, R., Hoyle, A., Iype, L., Jacobsen, A., Jeffreys, S., Jensen, M., Jones, C., Jones, S., Ju, Z., Jung, J., Kahles, A., Kahn, A., Kalicki-Veizer, J., Kalra, D., Kanchi, K., Kane, D., Kim, H., Kim, J., Knijnenburg, T., Koboldt, D., Kovar, C., Kramer, R., Kreisberg, R., Kucherlapati, R., Ladanyi, M., Lander, E., Larson, D., Lawrence, M., Lee, D., Lee, E., Lee, S., Lee, W., Lehmann, K., Leinonen, K., Leraas, K., Lerner, S., Levine, D., Lewis, L., Ley, T., Li, H., Li, J., Li, W., Liang, H., Lichtenberg, T., Lin, J., Lin, L., Lin, P., Liu, W., Liu, Y., Lorenzi, P., Lu, C., Lu, Y., Luquette, L., Ma, S., Magrini, V., Mahadeshwar, H., Mardis, E., Marra, M., Mayo, M., McAllister, C., McGuire, S., McMichael, J., Melott, J., Meng, S., Meyerson, M., Mieczkowski, P., Miller, C., Miller, M., Moore, R., Morgan, M., Morton, D., Mose, L., Mungall, A., Muzny, D., Nguyen, L., Noble, M., Noushmehr, H., O'Laughlin, M., Ojesina, A., Yang, T., Ozenberger, B., Pantazi, A., Parfenov, M., Park, P., Parker, J., Paull, E., Pedamallu, C., Pihl, T., Pohl, C., Pot, D., Protopopov, A., Przytycka, T., Radenbaugh, A., Ramirez, N., Ramirez, R., Ratsch, G., Reid, J., Ren, X., Reva, B., Reynolds, S., Rhie, S., Roach, J., Rovira, H., Ryan, M., Saksena, G., Salama, S., Sander, C., Santoso, N., Schein, J., Schmidt, H., Schultz, N., Schumacher, S., Seidman, J., Senbabaoglu, Y., Seth, S., Sharpe, S., Shen, R., Sheth, M., Shi, Y., Shmulevich, I., Silva, G., Simons, J., Sinha, R., Sipahimalani, P., Smith, S., Sofia, H., Sokolov, A., Soloway, M., Song, X., Sougnez, C., Spellman, P., Staudt, L., Stewart, C., Stojanov, P., Su, X., Sumer, S., Sun, Y., Swatloski, T., Tabak, B., Tam, A., Tan, D., Tang, J., Tarnuzzer, R., Taylor, B., Thiessen, N., Thorsson, V., Triche, T., Van Den Berg, D., Vandin, F., Varhol, Richard, Vaske, C., Veluvolu, U., Verhaak, R., Voet, D., Walker, J., Wallis, J., Waltman, P., Wan, Y., Wang, M., Wang, W., Wang, Z., Waring, S., Weinhold, N., Weisenberger, D., Wendl, M., Wheeler, D., Wilkerson, M., Wilson, R., Wise, L., Wong, A., Wu, C., Wu, H., Wu, J., Wylie, T., Xi, L., Xi, R., Xia, Z., Xu, A., Yang, D., Yang, L., Yang, Y., Yao, J., Yao, R., Ye, K., Yoshihara, K., Yuan, Y., Yung, A., Zack, T., Zeng, D., Zenklusen, J., Zhang, H., Zhang, N., Zhang, Q., Zhang, W., Zhao, W., Zheng, S., Zhu, J., Zmuda, E., and Zou, L.

Abstract

© 2014 Elsevier Inc. Recent genomic analyses of pathologically defined tumor types identify 'within-a-tissue' disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-oforigin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pancancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014

49. The expression level of small non-coding RNAs derived from the first exon of protein-coding genes is predictive of cancer status

Author

Zovoilis, A., Mungall, A., Moore, R., Varhol, Richard, Chu, A., Wong, T., Marra, M., Jones, S., Zovoilis, A., Mungall, A., Moore, R., Varhol, Richard, Chu, A., Wong, T., Marra, M., and Jones, S.

Abstract

Small non-coding RNAs (smRNAs) are known to be significantly enriched near the transcriptional start sites of genes. However, the functional relevance of these smRNAs remains unclear, and they have not been associated with human disease. Within the cancer genome atlas project (TCGA), we have generated small RNA datasets for many tumor types. In prior cancer studies, these RNAs have been regarded as transcriptional "noise," due to their apparent chaotic distribution. In contrast, we demonstrate their striking potential to distinguish efficiently between cancer and normal tissues and classify patients with cancer to subgroups of distinct survival outcomes. This potential to predict cancer status is restricted to a subset of these smRNAs, which is encoded within the first exon of genes, highly enriched within CpG islands and negatively correlated with DNA methylation levels. Thus, our data show that genome-wide changes in the expression levels of small non-coding RNAs within first exons are associated with cancer. Synopsis The expression of small non-coding RNAs encoded within the first exon of genes can be used to efficiently identify cancer samples and classify patients into subgroups of different survival. Such pan-cancer association is the first link between these RNAs and disease. Exon 1 small non-coding RNAs (smRNAs) can distinguish between cancer and normal tissues. The prediction potential of exon 1 smRNAs differs from that of other smRNAs around transcriptional start sites (TSS). smRNA locations around TSS are conserved between different individuals. smRNA locations are enriched within CpG islands and their levels negatively correlated with DNA methylation. The expression of small non-coding RNAs encoded within the first exon of genes can be used to efficiently identify cancer samples and classify patients into subgroups of different survival. Such pan-cancer association is the first link between these RNAs and disease. © 2014 The Authors.

Published
2014

50. Comprehensive molecular profiling of lung adenocarcinoma: The cancer genome atlas research network

Author

Collisson, E., Campbell, J., Brooks, A., Berger, A., Lee, W., Chmielecki, J., Beer, D., Cope, L., Creighton, C., Danilova, L., Ding, L., Getz, G., Hammerman, P., Hayes, D., Hernandez, B., Herman, J., Heymach, J., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M., Travis, W., Weinstein, J., Wigle, D., Wilkerson, M., Chu, A., Cherniack, A., Hadjipanayis, A., Rosenberg, M., Weisenberger, D., Laird, P., Radenbaugh, A., Ma, S., Stuart, J., Byers, L., Baylin, S., Govindan, R., Meyerson, M., Gabriel, S., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E., Lawrence, M., Getz, E., Fulton, R., Fulton, L., McLellan, M., Wilson, R., Ye, K., Fronick, C., Maher, C., Miller, C., Wendl, M., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H., Mayo, M., Moore, R., Mungall, A., Schein, J., Sipahimalani, P., Tam, A., Varhol, Richard, Robertson, A., Wye, N., Thiessen, N., Holt, R., Jones, S., Marra, M., Imielinski, M., Onofrio, R., Hodis, E., Zack, T., Helman, E., Collisson, E., Campbell, J., Brooks, A., Berger, A., Lee, W., Chmielecki, J., Beer, D., Cope, L., Creighton, C., Danilova, L., Ding, L., Getz, G., Hammerman, P., Hayes, D., Hernandez, B., Herman, J., Heymach, J., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M., Travis, W., Weinstein, J., Wigle, D., Wilkerson, M., Chu, A., Cherniack, A., Hadjipanayis, A., Rosenberg, M., Weisenberger, D., Laird, P., Radenbaugh, A., Ma, S., Stuart, J., Byers, L., Baylin, S., Govindan, R., Meyerson, M., Gabriel, S., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E., Lawrence, M., Getz, E., Fulton, R., Fulton, L., McLellan, M., Wilson, R., Ye, K., Fronick, C., Maher, C., Miller, C., Wendl, M., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H., Mayo, M., Moore, R., Mungall, A., Schein, J., Sipahimalani, P., Tam, A., Varhol, Richard, Robertson, A., Wye, N., Thiessen, N., Holt, R., Jones, S., Marra, M., Imielinski, M., Onofrio, R., Hodis, E., Zack, T., and Helman, E.

Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2014

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