title: c-FLIPL expression defines two ovarian cancer patient subsets and is a prognostic factor of adverse outcome.
abstract: The impairment of apoptotic pathways represents an efficient mechanism to promote chemoresistance in cancer cells. We previously showed that in epithelial ovarian cancer (EOC) cells, long isoform of cellular FLICE-inhibitory protein (c-FLIP(L)) accounts for apoptosis resistance in a context of functional p53 and resistance could be overcome by c-FLIP(L) downmodulation. Here, we studied the association between c-FLIP(L) and p53 expressions and their prognostic impact in EOC patients. Tumor tissue from 207 patients diagnosed with primary EOC was analyzed by immunohistochemistry (IHC) for c-FLIP(L) and p53 expressions, and multiple correspondence analysis (MCA) was used to evaluate the multivariable pattern of association among patients' clinical-pathological characteristics and biological determinants. IHC revealed c-FLIP(L) expression and p53 nuclear accumulation inversely related (P = 0.0001; odds ratio = 0.29, confidence interval (CI) = 0.15-0.055). MCA indicated that p53 accumulation was associated to clinical-pathological variables, while c-FLIP(L) expression contributed to the overall association pattern independently from other's clinical characteristics and complementary to p53. Kaplan-Meier curves showed a reduced survival time according to c-FLIP(L) expression in concert with p53 accumulation (median overall survival (OS): 35 months) compared with lack of expression of both markers (median OS: 110 months; log-rank test, P value = 0.024). The multivariable Cox regression model, adjusted for known prognostic factors, identified c-FLIP(L) expression, but not p53 nuclear accumulation, as an independent prognostic factor for adverse outcome (hazard ratio = 1.82, 95% CI = 1.17-2.82; P = 0.008). Altogether these data support the independent contribution of c-FLIP(L) in refining the prognostic information obtained from standard clinical-pathological indicators, confirming its pivotal role in promoting cell survival.
authors.affiliation: Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bagnoli
authors.forename: Federico
authors.initials: F
authors.lastname: Ambrogi
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Paola
authors.initials: P
authors.lastname: Alberti
authors.forename: Antonino
authors.initials: A
authors.lastname: Ditto
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.forename: Enzo
authors.initials: E
authors.lastname: Galligioni
authors.forename: Elia
authors.initials: E
authors.lastname: Biganzoli
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica