The landscape of somatic copy-number alteration across human cancers

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. Here, we report 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 gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB 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.

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…Applied to study colon cancer, the first step employs a straightforward genomic analysis of the Cancer Genome Atlas (TCGA) database (Beroukhim et al , 2010; Barretina et al , 2012) to identify metabolic genes that are downregulated in colorectal cancer (Fig 1A). Subsequently, we performed a novel metabolic modeling analysis to identify, among the genes identified as associated with tumorigenesis in the first step, those whose downregulation is indeed most likely to result in the metabolic alterations observed in colorectal tumors and thus are more likely to play an actual causal role in the transformation of normal to cancerous tissues (Fig 1B).…”

“…This step consists of three sub‐steps that are applied sequentially, analyzing gene expression, copy number (CN), and survival data from 272 colorectal cancer samples and 42 matching healthy colon tissues samples in the TCGA (Beroukhim et al , 2010; Barretina et al , 2012): (i) First, analyzing the transcriptomic data of these samples, we identified 4593 genes that are significantly downregulated in colon cancer (one‐sided Wilcoxon rank‐sum test with multiple hypothesis correction (α = 0.001), Table EV1). (ii) Second, 328 of these downregulated genes have significantly lower copy number in the tumors compared to the healthy samples ( Q ‐values < 0.25, Table EV2).…”

Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

“…One of the important genetic lesions that plays a pivotal role in tumorigenesis is the somatic copy number alterations (SCNAs). SCNAs encompass sequences that have different copy numbers in an individual's germline DNA and in the DNA of a clonal subpopulation of cells, which happen to be malignant (Beroukhim et al ., 2010). In other words, the SCNAs involve genomic gains (amplifications, duplications) or losses (deletions) that alter the diploid status of a particular locus, thereby disrupting the balanced genome.…”

“…SCNAs in particular are the most intriguing form of genetic variations to study in cancer, as they alter the dosage of a gene product independent of the transcription factors and other controls. Analyses of cancer genome by cytogenetic studies and more recently by array hybridization profiling‐based methodologies have assisted in the identification of recurrent alterations unique to various cancers as well as some common alterations (Beroukhim et al ., 2010; Zack et al ., 2013). In understanding the role of CNAs, it becomes imperative to characterize the CNAs as the driver events in a particular malignancy and distinguish them from the passenger CNAs that would have been imbued into the genome during cancer evolution and possibly do not contribute towards it (Zack et al ., 2013).…”

Characterization of aberrant pathways across human cancers

“…Cancers can also be divided into clinically meaningful subtypes based on their gene expression patterns that may be indicative of response to a treatment, like Her2 positive breast cancers [4] or KIT positive gastro-intestinal tumours [5], for example. Many cancers have characteristic sets of somatic mutations that can be used to identify and classify the tumours [6]; few studies have even compared these across cancer types [7]. However, cancers are not commonly classified or studied based on the acquired traits or alterations to the pathways because of the added complexity.…”