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

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

TRANSLOCATION-(6-10)(P21-Q22) IN UTERINE LEIOMYOMAS

A translocation between chromosomes 6 and 10 was observed in two uterine leiomyomas. Translocation (6;10) may be important in the pathogenesis of a subgroup of uterine leiomyomas

CYTOGENETIC FINDINGS IN 21 MALIGNANT MELANOMAS

Cytogenetic analysis was performed on 21 tumor samples of malignant melanoma to identify the presence of consistent chromosome abnormalities. Four cases had a normal karyotype, and 17 were cytogenetically abnormal. Numerical chromosome alterations were observed in 15 tumors: 12 were hyperdiploid and three were hypodiploid. The most frequent losses consisted of chromosomes 5, 9, 17 and Y. The structural abnormalities were usually complex, consisting mainly of nonreciprocal translocations and deletions affecting 1p, 1q, 3p, and 9p. This study adds further data to previously reported melanoma cases, confirming that chromosomes 1, 3, 6, and 9 are nonrandomly affected

CYTOGENETIC FINDINGS IN 19 MALIGNANT BONE TUMORS

Background. The majority of karyotypes observed in osteosarcomas (OS) and chondrosarcomas (CS) are complex. Specific chromosomal abnormalities have not yet been characterized in either tumor except for a ring chromosome in parosteal OS. The purpose of this study was to determine recurrent chromosomal abnormalities and establish a possible correlation between the cytogenetic changes and the pathologic findings