Genomics

Dataset Information

49

Affymetrix 250K StyI SNP array data across multiple human cancer types


ABSTRACT: A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. We have reported high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several candidate genes and families are enriched among these regions of focal SCNA, including members of the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types. Overall design: Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from 3,131 cancer DNAs derived from primary tissues or cell line material, as well as from DNA obtained from 1,480 normal DNA samples. Signal intensities were normalized to raw copy number estimates using the tangent normalization method, as described in Beroukhim et al., In Press and Mermel et al., In preparation. Data analysis across samples was performed using this GISTIC algorithm (Beroukhim R et al, PNAS 2007). The 250K SNP array data used in this study were obtained from several sources, including 2,327 previously or concurrently published data from our laboratory and other groups and 804 previously unpublished data from cancer and normal specimens (included in this submission). The 2,327 published cancer copy-number profiles not included in our submission consist of data from the following publications (see below for full references): - 510 non-small cell lung cancers (Ramos et al 2009; GlaxoSmithKline; Bass et al; Weir et al; and Sos et al) - 388 acute lymphoblastic leukemias (GlaxoSmithKline; Mullighan et al 2007; Mullighan et al 2008) - 215 myeloproliferative disorders (Kilpivaara et al) - 130 breast cancers (GlaxoSmithKline; Haverty et al; Nikolsky et al) - 151 colorectal cancers (GlaxoSmithKline; Firestein et al) - 115 miscellaneous other types of cancer (GlaxoSmithKline) - 111 renal cancers (GlaxoSmithKline; Beroukhim et al) - 106 hepatocellular cancers (GlaxoSmithKline; Chiang et al) - 77 melanomas (GlaxoSmithKline; Lin et al) - 54 prostate cancers (GlaxoSmithKline; Demichelis et al) - 40 esophageal squamous cell carcinomas (GlaxoSmithKline; Bass et al) - 31 neuroblastomas (GlaxoSmithKline; George et al) - 21 non-Hodkgin's lymphomas (GlaxoSmithKline) - 21 small cell lung cancers (GlaxoSmithKline) - 10 gliomas (GlaxoSmithKline) - 4 thyroid cancers (GlaxoSmithKline) - 2 medulloblastomas (GlaxoSmithKline) - 7 ovarian cancers (GlaxoSmithKline) - 212 sarcoma samples of various subtypes (Barretina et al, in review) - 73 esophageal adenocarcinoma samples (Ramos et al, in Preparation) - 26 mesotheliomas (Barchmann et al, in preparation) - 23 gastric cancer samples (GlaxoSmithKline; Ramos et al, in preparation). Full references: Bass, A., Watanabe, H., Mermel, C. & al, e. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinoma. Nat Genet 41, 1238-42 (2009). Beroukhim, R. et al. Patterns of gene expression and copy-number alterations in VHL disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res 69, 4674-4681 (2009). Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 68, 6779-6788 (2008). Demichelis, F. et al. Distinct genomic aberrations associated with ERG rearranged prostate cancer. Genes Chromosomes Cancer 48, 366-380 (2009). Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates [bgr]-catenin activity. Nature 455, 547-551 (2008). George, R. E. et al. Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays. PLoS ONE 2, e255 (2007). GlaxoSmithKline. GSK Cancer Cell Line Genomic Profiling Data, https://cabig.nci.nih.gov/tools/caArray_GSKdata (2008). Haverty, P. M. et al. High-resolution genomic and expression analyses of copy number alterations in breast tumors. Genes Chromosomes Cancer 47, 530-542 (2008). Kilpivaara, O. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet 41, 455-459 (2009). Lin, W. M. et al. Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res 68, 664-673 (2008). Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758-764 (2007). Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110-114 (2008). Nikolsky, Y. et al. Genome-wide functional synergy between amplified and mutated genes in human breast cancer. Cancer Res 68, 9532-9540 (2008). Ramos, A. et al. Amplification of PDGFRA and KIT in Non-small Cell Lung Cancer. Cancer Biology and Therapy 8, 2051-3 (2009). Sos, M. L. et al. Predicting drug activity in non-small cell lung cancer based on genetic lesions. JCI 119, 1727-1740 (2009). Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 450, 893-898 (2007).

INSTRUMENT(S): [Mapping250K_Sty] Affymetrix Mapping 250K Sty2 SNP Array

SUBMITTER: Craig Mermel  

PROVIDER: GSE19399 | GEO | 2010-02-18

SECONDARY ACCESSION(S): PRJNA121763

REPOSITORIES: GEO

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Publications

The landscape of somatic copy-number alteration across human cancers.

Beroukhim Rameen R   Mermel Craig H CH   Porter Dale D   Wei Guo G   Raychaudhuri Soumya S   Donovan Jerry J   Barretina Jordi J   Boehm Jesse S JS   Dobson Jennifer J   Urashima Mitsuyoshi M   Mc Henry Kevin T KT   Pinchback Reid M RM   Ligon Azra H AH   Cho Yoon-Jae YJ   Haery Leila L   Greulich Heidi H   Reich Michael M   Winckler Wendy W   Lawrence Michael S MS   Weir Barbara A BA   Tanaka Kumiko E KE   Chiang Derek Y DY   Bass Adam J AJ   Loo Alice A   Hoffman Carter C   Prensner John J   Liefeld Ted T   Gao Qing Q   Yecies Derek D   Signoretti Sabina S   Maher Elizabeth E   Kaye Frederic J FJ   Sasaki Hidefumi H   Tepper Joel E JE   Fletcher Jonathan A JA   Tabernero Josep J   Baselga José J   Tsao Ming-Sound MS   Demichelis Francesca F   Rubin Mark A MA   Janne Pasi A PA   Daly Mark J MJ   Nucera Carmelo C   Levine Ross L RL   Ebert Benjamin L BL   Gabriel Stacey S   Rustgi Anil K AK   Antonescu Cristina R CR   Ladanyi Marc M   Letai Anthony A   Garraway Levi A LA   Loda Massimo M   Beer David G DG   True Lawrence D LD   Okamoto Aikou A   Pomeroy Scott L SL   Singer Samuel S   Golub Todd R TR   Lander Eric S ES   Getz Gad G   Sellers William R WR   Meyerson Matthew M  

Nature 20100201 7283


A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene loc  ...[more]

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