title: A Predictive Genetic Signature for Response to Fluoropyrimidine-Based Neoadjuvant Chemoradiation in Clinical Stage II and III Rectal Cancer.
abstract: OBJECTIVE
  Pre-operative chemoradiation (CRT) is currently the standard of care for patients with clinical stage II and III rectal cancer but only about 45% of patients achieve tumor downstaging and <20% of patients achieve a pathologic complete response. Better methods to stratify patients according to potential neoadjuvant treatment response are needed. We used microarray analysis to identify a genetic signature that correlates with a pathological complete response (pCR) to neoadjuvant CRT. We performed a gene network analysis to identify potential signaling pathways involved in determining response to neoadjuvant treatment.
  
  
  METHODS
  We identified 31 T3-4 N0-1 rectal cancer patients who were treated with neoadjuvant fluorouracil-based CRT. Eight patients were identified to have achieved a pCR to treatment while 23 patients did not. mRNA expression was analyzed using cDNA microarrays. The correlation between mRNA expression and pCR from pre-treatment tumor biopsies was determined. Gene network analysis was performed for the genes represented by the predictive signature.
  
  
  RESULTS
  A genetic signature represented by expression levels of the three genes EHBP1, STAT1, and GAPDH was found to correlate with a pCR to neoadjuvant treatment. The difference in expression levels between patients who achieved a pCR and those who did not was greatest for EHBP1. Gene network analysis showed that the three genes can be connected by the gene ubiquitin C (UBC).
  
  
  CONCLUSIONS
  This study identifies a 3-gene signature expressed in pre-treatment tumor biopsies that correlates with a pCR to neoadjuvant CRT in patients with clinical stage II and III rectal cancer. These three genes can be connected by the gene UBC, suggesting that ubiquitination is a molecular mechanism involved in determining response to treatment. Validating this genetic signature in a larger number of patients is proposed.
authors: Department of Radiation Oncology, Brown University , Providence, RI , USA.
authors: Jason
authors: J
authors: Chan
authors: Michael T
authors: MT
authors: Kinsella
authors: Joseph E
authors: JE
authors: Willis
authors: Huankai
authors: H
authors: Hu
authors: Harry
authors: H
authors: Reynolds
authors: Conor
authors: C
authors: Delaney
authors: Andrea
authors: A
authors: McCulla
authors: Steve
authors: S
authors: Deharo
authors: Miika
authors: M
authors: Ahdesmäki
authors: Wendy Louise
authors: WL
authors: Allen
authors: Patrick G
authors: PG
authors: Johnston
authors: Timothy J
authors: TJ
authors: Kinsella
keywords: EHBP1; UBC; gene array; rectal neoplasms; ubiquitination