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 located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.
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Gene Expression Omnibus
The SNP array data have been deposited to the Gene Expression Omnibus (GEO) under accession number GSE19399.
This work was supported by grants from the National Institutes of Health (NIH) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578, R01CA109038, R01CA109467, P01CA085859, P01CA 098101 and K08CA122833), the Doris Duke Charitable Foundation, the Sarah Thomas Monopoli Lung Cancer Research Fund, the Seaman Corporation Fund for Lung Cancer Research, and the Lucas Foundation. Medulloblastoma samples were obtained in collaboration with the Children’s Oncology Group. N. Vena provided technical assistance with FISH, and I. Mellinghoff, P. S. Mischel, L. Liau and T. F. Cloughesy provided DNA samples. We thank T. Ried, R. Weinberg and B. Vogelstein for critical review of the manuscript and for comments about its context in the field of cancer genetics.
Author Contributions R.B., C.H.M., E.S.L., G.G., W.R.S. and M.M. conceived and designed the study; R.B., J.B., M.U., A.H.L., Y.-J.C., W.W., B.A.W., D.Y.C., A.J.B., J.P., S.S., E.M., F.J.K., H.S., J.E.T., J.A.F., J.T., J.B., M.-S.T., F.D., M.A.R., P.A.J., C.N., R.L.L., B.L.E., S.G., A.K.R., C.R.A., M.L., L.A.G., M.L., D.G.B., L.D.T., A.O., S.L.P., S.S. and M.M. contributed primary samples and/or assisted in the generation of the data; R.B., C.H.M., S.R., J.Dob., M.S.L., B.A.W., M.J.D. and G.G. performed the data analysis; R.B., D.P., G.W., J.Don., J.S.B., K.T.M., L.H., H.G., K.E.T., A.L., C.H., D.Y., A.L., L.A.G., T.R.G. and M.M. designed and performed the functional experiments on BCL2 family member genes; R.B., C.H.M., R.M.P., M.R., T.L. and Q.G. designed and built the cancer copy-number portal; R.B., C.H.M., E.S.L. and M.M. wrote, and all other authors have critically read and commented on, the manuscript.
This table presents the breakdown of our sample set according to tissue type, origin, and publication status.
This table reports the significant peak regions of amplification and deletion identified in the pooled analysis of all samples.
This table reports the results of the comparison of the significant peak regions of amplification and deletion identified in this study with those reported in 18 prior publications.
This table reports the literature terms identified by GRAIL as being most significantly reached in the significant peak regions of amplifications and deletion identified in this study.
This table reports the 199 peak regions of amplification and deletion identified to be significant in analysis of individual tumor types but not in the analysis of the pooled dataset.
This table reports the significant arm-level SCNAs that distinguish the major developmental clusters displayed in Supplementary Figure 7, as determined by comparative marker selection.
This table reports a comparison of the peak regions of deletion identified using the marker-based (SNP-GISTIC) rather than the gene-based (GENE-GISTIC) scoring function (described in the Supplementary Methods).
This table lists the tumor types in which significant levels of gains or losses are observed for each of the 39 chromosome arms probed by the 250K StyI SNP Array.