title: Prognostic impact of PHIP copy number in melanoma: linkage to ulceration.
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.
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: De Semir
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nosrati
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Schuyler
authors.initials: S
authors.lastname: Tong
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Clayton
authors.initials: C
authors.lastname: Wu
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Suresh
authors.initials: S
authors.lastname: Thummala
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Stanley P L
authors.initials: SPL
authors.lastname: Leong
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: James E
authors.initials: JE
authors.lastname: Cleaver
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Sagebiel
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: James R
authors.initials: JR
authors.lastname: Miller
authors.affiliation: Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, San Francisco, California.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashani-Sabet
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012883:Skin Ulcer / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C418612:PHIP protein, human