Role of Elevated <i>PHIP</i> Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma.

Abstract

<b>Purpose:</b> Previous studies have indicated an important role for pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Here we aimed to confirm the role of <i>PHIP</i> copy number in successive stages of melanoma progression.<b>Experimental Design:</b><i>PHIP</i> copy number was examined using FISH in three independent cohorts by recording the percentage of cells harboring ≥3 copies of <i>PHIP</i> The impact of <i>PHIP</i> copy number on survival was assessed using Cox regression analysis. The enrichment of <i>PHIP</i> was assessed in various molecular melanoma subtypes. <i>PHIP</i> expression was analyzed in The Cancer Genome Atlas (TCGA) melanoma cohort.<b>Results:</b> Elevated <i>PHIP</i> copy number was significantly predictive of reduced distant metastasis-free survival (DMFS) and disease-specific survival (DSS), and increased prevalence of ulceration in primary melanoma (cohort No. 1). By multivariate analysis, <i>PHIP</i> FISH scores were independently predictive of DMFS and DSS. <i>PHIP</i> copy number was enriched in metastatic melanomas harboring mutant <i>NRAS</i> or expressing PTEN protein (cohort No. 2). <i>PHIP</i> copy number was significantly elevated in metastatic melanomas when compared with matched primary tumors from the same patient (cohort No. 3). Several of these associations were replicated using TCGA cohort analysis.<b>Conclusions:</b> These results underscore the important role of <i>PHIP</i> copy-number elevation in melanoma progression, and identify molecular subtypes of melanoma in which <i>PHIP</i> is enriched. Finally, as elevated <i>PHIP</i> copy number appears to be selected for during the progression of primary to metastatic melanoma, these results confirm PHIP as a promising therapeutic target for melanoma. <i>Clin Cancer Res; 24(17); 4119-25. ©2018 AACR</i>.