title: DNA Damage and Repair Biomarkers in Cervical Cancer Patients Treated with Neoadjuvant Chemotherapy: An Exploratory Analysis.
abstract: Cervical cancer cells commonly harbour a defective G1/S checkpoint owing to the interaction of viral oncoproteins with p53 and retinoblastoma protein. The activation of the G2/M checkpoint may thus become essential for protecting cancer cells from genotoxic insults, such as chemotherapy. In 52 cervical cancer patients treated with neoadjuvant chemotherapy, we investigated whether the levels of phosphorylated Wee1 (pWee1), a key G2/M checkpoint kinase, and γ-H2AX, a marker of DNA double-strand breaks, discriminated between patients with a pathological complete response (pCR) and those with residual disease. We also tested the association between pWee1 and phosphorylated Chk1 (pChk1), a kinase acting upstream Wee1 in the G2/M checkpoint pathway. pWee1, γ-H2AX and pChk1 were retrospectively assessed in diagnostic biopsies by immunohistochemistry. The degrees of pWee1 and pChk1 expression were defined using three different classification methods, i.e., staining intensity, Allred score, and a multiplicative score. γ-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and γ-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and γ-H2AX were both associated with reduced pCR. Internal validation conducted through a re-sampling without replacement procedure confirmed the robustness of the multivariate model. Finally, we found a significant association between pWee1 and pChk1. The message conveyed by the present analysis is that biomarkers of DNA damage and repair may predict the efficacy of neoadjuvant chemotherapy in cervical cancer. Further studies are warranted to prospectively validate these encouraging findings.
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Buglioni
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Sergi
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Antoniani
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Carosi
authors.affiliation: Medical Oncology Unit, ASL Frosinone, Frosinone, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gamucci
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dattilo
authors.affiliation: Drug Discovery Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Bartucci
authors.affiliation: Department of Surgery, Gynecologic Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vincenzoni
authors.affiliation: Department of Surgery, Gynecologic Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy.|HPV-UNIT, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Department of Surgery, Gynecologic Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Vizza
authors.affiliation: Department of Radiotherapy, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sanguineti
authors.affiliation: Department of Experimental and Clinical Medicine, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy.
authors.forename: Angiolo
authors.initials: A
authors.lastname: Gadducci
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maugeri-Saccà
mesh_terms: D015415:Biomarkers / Q000032:analysis; D018797:Cell Cycle Proteins / Q000032:analysis*; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D006657:Histones / Q000032:analysis*; D006801:Humans; D020360:Neoadjuvant Therapy; D009687:Nuclear Proteins / Q000032:analysis*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human