Integrative Copy Number Analysis of Uveal Melanoma Reveals Novel Candidate Genes Involved in Tumorigenesis Including a Tumor Suppressor Role for .

Purpose: Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in , and additional mutations in (usually associated with LOH of Chr 3), , or . There are other characteristic chromosomal alterations, but their significance is not clear.

Experimental Design: To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings.

Results: We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of and one with a frameshift mutation with concomitant loss of the wild-type allele. Downregulation of in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for as a novel tumor suppressor at Chr 6q27.

Conclusions: Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for .