title: Gene expression profile is associated with chemoradiation resistance in rectal cancer.
abstract: OBJECTIVE
  Patients with rectal cancer who achieve a complete pathological response after preoperative chemoradiation (CRT) have an improved oncological outcome. Identifying factors associated with a lack of response could help our understanding of the underlying biology of treatment resistance. This study aimed to develop a gene expression signature for CRT-resistant rectal cancer using high-throughput nucleotide microarrays.
  
  
  METHODS
  Pretreatment biopsies of rectal adenocarcinomas were prospectively collected and freshly frozen according to an institutional review board-approved protocol. Total tumour mRNA was extracted and gene expression levels were measured using microarrays. Patients underwent proctectomy after completing standard long-course CRT and the resected specimens were graded for treatment response. Gene expression profiles for nonresponders were compared with those of responders. Differentially expressed genes were analyzed for functional significance using the Ingenuity Pathway Analysis (IPA) software.
  
  
  RESULTS
  Thirty-three patients treated between 2006 and 2009 were included. We derived 812-gene and 183-gene signatures separating nonresponders from responders. The classifiers were able to identify nonresponders with a sensitivity and specificity of 100% using the 812-gene signature, and sensitivity and specificity of 33% and 100% using the 183-gene signature. IPA canonical pathway analysis revealed a significant ratio of differentially expressed genes in the 'DNA double-strand break repair by homologous recombination' pathway.
  
  
  CONCLUSIONS
  Certain rectal cancer gene profiles are associated with poor response to CRT. Alterations in the DNA double-strand break repair pathway could contribute to treatment resistance and provides an opportunity for further studies.
authors.affiliation: Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Gantt
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Dejulius
authors.forename: A G
authors.initials: AG
authors.lastname: Mace
authors.forename: J
authors.initials: J
authors.lastname: Barnholtz-Sloan
authors.forename: M F
authors.initials: MF
authors.lastname: Kalady
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000628:therapy; D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis*; D011836:Radiation Tolerance / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics* / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D004273:DNA, Neoplasm; D012333:RNA, Messenger
keywords: Gene Expression Profile; Microarray; Neoadjuvant Chemoradiation; Rectal Cancer; Response to Therapy