A functional biological network centered on XRCC3: A new possible marker of chemoradiotherapy resistance in rectal cancer patients

Marco Agostini, Andrea Zangrando, Chiara Pastrello, Edoardo D’Angelo, Gabriele Romano, Roberto Giovannoni, Marco Giordan, Isacco Maretto, Chiara Bedin, Carlo Zanon, Maura Digito, Giovanni Esposito, Claudia Mescoli, Marialuisa Lavitrano, Flavio Rizzolio, Igor Jurisica, Antonio Giordano, Salvatore Pucciarelli, Donato Nitti

Research output: Contribution to journalArticlepeer-review

Abstract

Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard’s Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy D 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer.

Original languageEnglish
Pages (from-to)1160-1171
Number of pages12
JournalCancer Biology and Therapy
Volume16
Issue number8
DOIs
Publication statusPublished - 2015

Keywords

  • Biological network
  • Integrated approach
  • Microarray
  • Preoperative chemoradiotherapy
  • Rectal cancer
  • Treatment response
  • XRCC3

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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