TY - JOUR
T1 - DNA damage and repair biomarkers in cervical cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis
AU - Vici, Patrizia
AU - Buglioni, Simonetta
AU - Sergi, Domenico
AU - Pizzuti, Laura
AU - Di Lauro, Luigi
AU - Antoniani, Barbara
AU - Sperati, Francesca
AU - Terrenato, Irene
AU - Carosi, Mariantonia
AU - Gamucci, Teresa
AU - Dattilo, Rosanna
AU - Bartucci, Monica
AU - Vincenzoni, Cristina
AU - Mariani, Luciano
AU - Vizza, Enrico
AU - Sanguineti, Giuseppe
AU - Gadducci, Angiolo
AU - Vitale, Ilio
AU - Barba, Maddalena
AU - De Maria Marchiano, Ruggero
AU - Mottolese, Marcella
AU - Maugeri-Saccà, Marcello
PY - 2016
Y1 - 2016
N2 - 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 y-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, y-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. y-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and y-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and y-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.
AB - 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 y-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, y-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. y-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and y-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and y-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.
KW - Agricultural and Biological Sciences (all)
KW - Biochemistry, Genetics and Molecular Biology (all)
KW - Biomarkers
KW - Cell Cycle Proteins
KW - Cervix Uteri
KW - DNA Damage
KW - DNA Repair
KW - Female
KW - G2 Phase Cell Cycle Checkpoints
KW - Histones
KW - Humans
KW - Medicine (all)
KW - Neoadjuvant Therapy
KW - Nuclear Proteins
KW - Phosphorylation
KW - Protein-Tyrosine Kinases
KW - Treatment Outcome
KW - Uterine Cervical Neoplasms
KW - Agricultural and Biological Sciences (all)
KW - Biochemistry, Genetics and Molecular Biology (all)
KW - Biomarkers
KW - Cell Cycle Proteins
KW - Cervix Uteri
KW - DNA Damage
KW - DNA Repair
KW - Female
KW - G2 Phase Cell Cycle Checkpoints
KW - Histones
KW - Humans
KW - Medicine (all)
KW - Neoadjuvant Therapy
KW - Nuclear Proteins
KW - Phosphorylation
KW - Protein-Tyrosine Kinases
KW - Treatment Outcome
KW - Uterine Cervical Neoplasms
UR - http://hdl.handle.net/10807/94018
UR - http://www.plosone.org/article/fetchobject.action?uri=info:doi/10.1371/journal.pone.0149872&representation=pdf
U2 - 10.1371/journal.pone.0149872
DO - 10.1371/journal.pone.0149872
M3 - Article
SN - 1932-6203
VL - 11
SP - e0149872-N/A
JO - PLoS One
JF - PLoS One
ER -