Prognostic Impact of PHIP Copy Number in Melanoma: Linkage to Ulceration

• Published in: Journal of investigative dermatology Vol. 134; no. 3; pp. 783 - 790
• Main Authors: Bezrookove, Vladimir, De Semir, David, Nosrati, Mehdi, Tong, Schuyler, Wu, Clayton, Thummala, Suresh, Dar, Altaf A., Leong, Stanley P.L., Cleaver, James E., Sagebiel, Richard W., Miller, James R., Kashani-Sabet, Mohammed
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2014; Elsevier Limited
• Subjects: Adult; Aged; Animals; Biomarkers, Tumor - genetics; Cell Line, Tumor; Female; Gene Dosage - genetics; Humans; Intracellular Signaling Peptides and Proteins - genetics; Kaplan-Meier Estimate; Male; Melanoma - genetics; Melanoma - mortality; Melanoma - pathology; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Prognosis; Skin Neoplasms - genetics; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Ulcer - genetics; Skin Ulcer - mortality; Skin Ulcer - pathology
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2013.369

Ulceration is an important prognostic factor in melanoma whose biologic basis is poorly understood. Here we assessed the prognostic impact of pleckstrin homology domain-interacting protein (PHIP) copy number and its relationship to ulceration. PHIP copy number was determined using fluorescence in situ hybridization (FISH) in a tissue microarray cohort of 238 melanomas. Elevated PHIP copy number was associated with significantly reduced distant metastasis-free survival (DMFS; P=0.01) and disease-specific survival (DSS; P=0.009) by Kaplan–Meier analyses. PHIP FISH scores were independently predictive of DMFS (P=0.03) and DSS (P=0.03). Increased PHIP copy number was an independent predictor of ulceration status (P=0.04). The combined impact of increased PHIP copy number and tumor vascularity on ulceration status was highly significant (P<0.0001). Stable suppression of PHIP in human melanoma cells resulted in significantly reduced glycolytic activity in vitro, with lower expression of lactate dehydrogenase 5, hypoxia-inducible factor 1 alpha subunit, and vascular endothelial growth factor, and was accompanied by reduced microvessel density in vivo. These results provide further support for PHIP as a molecular prognostic marker of melanoma, and reveal a significant linkage between PHIP levels and ulceration. Moreover, they suggest that ulceration may be driven by increased glycolysis and angiogenesis.