title: Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis.
abstract: Prognosis of primary melanoma is presently based on morphological parameters, mainly tumor thickness. However, more reliable prognostic markers are needed that allow a better stratification of patients, especially with regard to therapeutic options. Here, a retrospective study was performed on patients with primary superficial-spreading melanoma (SSM, n=44) or nodular melanoma (n=16) of 1.5-4 mm thickness. Thirty patients had survived the follow-up of 10 years, whereas the other 30 patients developed metastases. Tumor sections were analyzed by immunohistochemistry for the expression of regulators of the cell cycle (p21; retinoblastoma protein (pRb)), of the intrinsic or extrinsic proapoptotic pathways (p53; murine double minute gene 2 protein; tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-R1/DR4; TRAIL-R2/DR5) and of Bcl-2-related proteins (Bcl-2, Mcl-1, Bax, Bak, Bok), which regulate the common mitochondrial apoptotic pathway. In SSM, decrease of Bax and Bak was significantly correlated with a poor prognosis: high Bax was associated with 10-year survival rates of 68%, whereas low Bax resulted in only 26% survival, and high Bak was associated with 10-year survival rates of 62%, whereas low Bak resulted in only 10% survival. Regulators of apoptosis may therefore candidate for independent prognostic markers for primary melanomas. The study underlines the particular role of the mitochondrial apoptosis pathway and of proapoptotic Bcl-2-related proteins for melanoma progression.
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Lothar F
authors.initials: LF
authors.lastname: Fecker
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Geilen
authors.forename: Georgi
authors.initials: G
authors.lastname: Tchernev
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
authors.forename: Chalid
authors.initials: C
authors.lastname: Assaf
authors.forename: Bachtier M
authors.initials: BM
authors.lastname: Kurbanov
authors.forename: Constanze
authors.initials: C
authors.lastname: Schwarz
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eberle
mesh_terms: D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000032:analysis*; D051028:bcl-2-Associated X Protein / Q000032:analysis*
chemical_list: D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; D014408:Biomarkers, Tumor; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein