Network-Guided Analysis of Genes with Altered Somatic Copy Number and Gene Expression Reveals Pathways Commonly Perturbed in Metastatic Melanoma

Abstract

Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression (‘SCNA-genes’) in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

“…Although Wnt is one of the main signaling pathways commonly perturbed in metastatic melanomas (47), its role in oncogenesis is paradoxical. Canonical Wnt signaling and β-catenin activation seem to be a key step in the initiation of melanoma (34).…”

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…However, it is clear that combining RNA-Seq with other NGS applications -as well as other platforms (ie, SNP and CGH arrays) -will help to detect somatic CNV affecting gene expression and potentially new candidate genes involved in tumorigenesis. 65 eQTL, EPIGENETICS AND RNA-SEQ The spectrum of nucleotide variations predisposing to, or responsible for, human genetic diseases ranges from very rare mutations (MAF, minor allele frequency oo0.01) -in Mendelian disorders -and rare variants (MAF o0.01) to very common SNPs (MAF 0.01-0.05) with weak effects on complex traits and common diseases. In the latter case, a small fraction of them falls in the coding regions and affecting the protein.…”

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

“…Putative CNVs were called as chromosomal segments with unusually high or low log 2 ratios of fluorescent intensity between the test DNA (DS with or without CHD) and reference DNA (a DS individual without CHD) using the genome alteration detection analysis (GADA) algorithm (Pique-Regi et al 2008) using the options ''-M 10 -T 12 -a 0.2.'' CNVs calling by GADA were followed by intersection across all the individuals to obtain CNV intersected regions (CNV tests) (Valsesia et al 2011). A total of 4401 intersected CNV tests spanning the entire chromosome 21 were identified according to three classes (deletion, duplication, and copy neutral).…”