title: Poly(adenosine diphosphate-ribose) polymerase expression in BRCA-proficient ovarian high-grade serous carcinoma; association with patient survival.
abstract: Ovarian cancers with BRCA mutations rely on the alternative DNA repair mechanism of the poly(adenosine diphosphate-ribose) polymerases (PARP)-dependent base excision repair pathway, with a better overall survival and response to chemotherapy, than BRCA1-proficient cases. This can be enhanced further by using PARP inhibitors. Rate of PARP cleavage may have an independent role from BRCA in contributing to response to chemotherapy. We hypothesize that, regardless of BRCA profile, high expression of PARP1 is associated with poor disease outcome and could be used as a biomarker to identify cases that may have a better response to PARP inhibitors. The expressions of BRCA1, PARP1 in its intact and cleaved (C-PARP1) forms were immunohistochemically semiquantified in 174 sporadic high-grade serous carcinoma patients. Association with clinicopathologic variables and survival was analyzed. PARP1 expression was negatively associated with overall survival and progression-free survival in those patients with low BRCA1 profile (P = .04). Analysis of the combined expression of PARP1 and BRCA1 revealed that high expression of PARP1 is associated with poor survival when combined with either high or low BRCA expression. This was reinforced by multivariate analysis showing PARP1 (P = .034) as an independent prognostic factor. A trend toward worse survival was noted with low levels of C-PARP. PARP1 may have an independent role in response to chemotherapy separate from BRCA gene mutation and partly due to reduced PARP cleavage. An approach to exploit PARP expression as a beneficial biomarker to identify patients suitable for PARP inhibitor therapy is suggested.
authors.affiliation: Department of Histopathology, Nottingham University Hospitals NHS Trust, Queen's Medical Centre Campus, Nottingham, NG7 2UH, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Gan
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nolan
authors.forename: Stewart
authors.initials: S
authors.lastname: Martin
authors.forename: Suha
authors.initials: S
authors.lastname: Deen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis*; D011379:Prognosis; D016016:Proportional Hazards Models; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D011065:Poly(ADP-ribose) Polymerases
keywords: BRCA; Ovarian cancer; PARP; Serous carcinoma