Prognostic impact of PHIP copy number in melanoma: linkage to ulceration

J Invest Dermatol. 2014 Mar;134(3):783-790. doi: 10.1038/jid.2013.369. Epub 2013 Sep 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
  • PHIP protein, human