title: A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients.
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 = 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.
authors.affiliation: a Department of Surgical , Oncological and Gastroenterological Sciences ; Section of Surgery ; University of Padova ; Padua , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Agostini
authors.forename: Andrea
authors.initials: A
authors.lastname: Zangrando
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastrello
authors.forename: Edoardo
authors.initials: E
authors.lastname: D'Angelo
authors.forename: Gabriele
authors.initials: G
authors.lastname: Romano
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
authors.forename: Marco
authors.initials: M
authors.lastname: Giordan
authors.forename: Isacco
authors.initials: I
authors.lastname: Maretto
authors.forename: Chiara
authors.initials: C
authors.lastname: Bedin
authors.forename: Carlo
authors.initials: C
authors.lastname: Zanon
authors.forename: Maura
authors.initials: M
authors.lastname: Digito
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Claudia
authors.initials: C
authors.lastname: Mescoli
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Lavitrano
authors.forename: Flavio
authors.initials: F
authors.lastname: Rizzolio
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pucciarelli
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D059248:Chemoradiotherapy; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C110901:X-ray repair cross complementing protein 3
keywords: CEA, carcinoembryonic antigen; CRT, Chemoradiotherapy; DSB, Double-strand breaks; Gy, Gray; HT, High throughput; PPI, Protein-protein interaction; RC, Rectal cancer; RIN, RNA integrity number; SNP, Single nucleotide polymorphism; SSB, Single-strand breaks; XRCC3; biological network; integrated approach; mRNA, mRNA; microarray; pCRT, Preoperative chemoradiotherapy; preoperative chemoradiotherapy; rectal cancer; siRNA, Small interfering RNA; treatment response