Journal Article

The landscape of somatic copy-number alteration across human cancers

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

2010

Overview

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. Cancer genomics refined Two Articles in this issue add major data sets to the growing picture of the cancer genome. Bignell et al . analysed a large number of homozygous gene deletions in a collection of 746 publicly available cancer cell lines. Combined with information about hemizygous deletions of the same genes, the data suggest that many deletions found in cancer reflect the position of a gene at a fragile site in the genome, rather than as a recessive cancer gene whose loss confers a selective growth advantage. Beroukhim et al . present the largest data set to date on somatic copy-number variations across more than 3,000 specimens of human primary cancers. Many alterations are shared between multiple tumour types. Functional experiments demonstrate an oncogenic role for the apoptosis genes MCL1 and BCL2L1 that are associated with amplifications found in many cancers. One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1 , which reside in amplified genome regions in many cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/68 / 631/208/737 / 692/699/67 / Apoptosis - genetics / bcl-X Protein - genetics / Biological and medical sciences / Cancer / Carcinogenesis / Carcinogenesis, carcinogens and anticarcinogens / Cell Line, Tumor / Cell Survival - genetics / DNA Copy Number Variations - genetics / Gene Amplification - genetics / Gene Dosage - genetics / General aspects / Genes / Genetic aspects / Genetic variation / Genetics / Genomics / Health aspects / Humanities and Social Sciences / Humans / Medical sciences / multidisciplinary / Multigene Family - genetics / Myeloid Cell Leukemia Sequence 1 Protein / Neoplasms - classification / Neoplasms - genetics / Neoplasms - pathology / Proto-Oncogene Proteins c-bcl-2 - genetics / Risk factors / Science / Science (multidisciplinary) / Signal Transduction / Tumors