title: The impact of DNA damage response gene polymorphisms on therapeutic outcomes in late stage ovarian cancer.
abstract: Late stage epithelial ovarian cancer has a dismal prognosis. Identification of pharmacogenomic markers (i.e. polymorphisms) to stratify patients to optimize individual therapy is of paramount importance. We here report the retrospective analysis of polymorphisms in 5 genes (ATM, ATR, Chk1, Chk2 and CDK12) involved in the cellular response to platinum in a cohort of 240 cancer patients with late stage ovarian cancer. The aim of the present study was to evaluate associations between the above mentioned SNPs and patients' clinical outcomes: overall survival (OS) and progression free survival (PFS). None of the ATM, ATR, Chk1 and Chk2 polymorphisms was found to significantly affect OS nor PFS in this cohort of patients. Genotype G/G of CDK12 polymorphism (rs1054488) predicted worse OS and PFS than the genotype A/A-A/G in univariate analysis. The predictive value was lost in the multivariate analysis. The positive correlation observed between this polymorphism and age, grade and residual tumor may explain why the CDK12 variant was not confirmed as an independent prognostic factor in multivariate analysis.The importance of CDK12 polymorphism as possible prognostic biomarker need to be confirmed in larger ovarian cancer cohorts, and possibly in other cancer population responsive to platinum agents.
authors.affiliation: Department of Oncology, Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Guffanti
authors.affiliation: Clinc of Obstetrics and Gynecology, San Gerardo Hospital, Department of Medicine and Surgery, University of Milan-Bicocca, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Fruscio
authors.affiliation: Department of Oncology, Laboratory of Methodology for Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rulli
authors.affiliation: Department of Oncology, Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Damia
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D000071877:Checkpoint Kinase 1 / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics; D015331:Cohort Studies; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000628:therapy*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases