DNA damage and repair biomarkers in cervical cancer patients treated with neoadjuvant chemotherapy

An exploratory analysis

Patrizia Vici, Simonetta Buglioni, Domenico Sergi, Laura Pizzuti, Luigi Di Lauro, Barbara Antoniani, Francesca Sperati, Irene Terrenato, Mariantonia Carosi, Teresa Gamucci, Rosanna Dattilo, Monica Bartucci, Cristina Vincenzoni, Luciano Mariani, Enrico Vizza, Giuseppe Sanguineti, Angiolo Gadducci, Ilio Vitale, Maddalena Barba, Ruggero De Maria & 2 others Marcella Mottolese, Marcello Maugeri-Saccà

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 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.

Original languageEnglish
Article numbere149872
JournalPLoS One
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

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uterine cervical neoplasms
Chemotherapy
Biomarkers
DNA repair
DNA Repair
Uterine Cervical Neoplasms
DNA damage
DNA Damage
drug therapy
biomarkers
Repair
Drug Therapy
DNA
phosphotransferases (kinases)
Phosphotransferases
Cells
Association reactions
Tumor Suppressor Protein p53
Retinoblastoma Protein
Double-Stranded DNA Breaks

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

DNA damage and repair biomarkers in cervical cancer patients treated with neoadjuvant chemotherapy : An exploratory analysis. / Vici, Patrizia; Buglioni, Simonetta; Sergi, Domenico; Pizzuti, Laura; Di Lauro, Luigi; Antoniani, Barbara; Sperati, Francesca; Terrenato, Irene; Carosi, Mariantonia; Gamucci, Teresa; Dattilo, Rosanna; Bartucci, Monica; Vincenzoni, Cristina; Mariani, Luciano; Vizza, Enrico; Sanguineti, Giuseppe; Gadducci, Angiolo; Vitale, Ilio; Barba, Maddalena; De Maria, Ruggero; Mottolese, Marcella; Maugeri-Saccà, Marcello.

In: PLoS One, Vol. 11, No. 3, e149872, 01.03.2016.

Research output: Contribution to journalArticle

Vici, Patrizia ; Buglioni, Simonetta ; Sergi, Domenico ; Pizzuti, Laura ; Di Lauro, Luigi ; Antoniani, Barbara ; Sperati, Francesca ; Terrenato, Irene ; Carosi, Mariantonia ; Gamucci, Teresa ; Dattilo, Rosanna ; Bartucci, Monica ; Vincenzoni, Cristina ; Mariani, Luciano ; Vizza, Enrico ; Sanguineti, Giuseppe ; Gadducci, Angiolo ; Vitale, Ilio ; Barba, Maddalena ; De Maria, Ruggero ; Mottolese, Marcella ; Maugeri-Saccà, Marcello. / DNA damage and repair biomarkers in cervical cancer patients treated with neoadjuvant chemotherapy : An exploratory analysis. In: PLoS One. 2016 ; Vol. 11, No. 3.
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AU - Buglioni, Simonetta

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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, Ruggero

AU - Mottolese, Marcella

AU - Maugeri-Saccà, Marcello

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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.

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