DNA microarray analysis of locally advanced rectaladenocarcinomas: prediction of sensitivity to neoadjuvantchemoradiotherapy

PURPOSE: Rectal cancer prognosis is favorable for surgically cured patients. To allow radical surgery removal of locally advanced rectal adenocarcinomas (LARA), neoadjuvant chemoradiotherapy is performed to reduce of tumor volume. This practice also increase a feasibility of sphincter sparing surgery. Unfortunately, not all patients, who underwent neoadjuvant chemoradiotherapy gain its benefits. Molecular characterization of sensitive or resistant patients should assist to oncologists in treatment decision by selecting those patients who will respond to neoadjuvant chemoradiotherapy, and who not. Patients who do not respond can be spared from toxicity, time, and expense associated with the treatment. The aim of our study was to identify differences in gene expression profiles of LARA treated with neoadjuvant chemoradiotherapy. METHODS: Eleven patients (pts) with LARA treated with neoadjuvant chemoradiotherapy based on fluoropyrimidines (fluorouracil or capecitabine) were included in our pilot study. Response to the therapy was determined on both level, 1. clinically (TNM) by transrectal ultrasonography and CT or MRI before and after therapy, and 2. histopathologically by TRG scoring system (tumor regression grade from 1 to 5) according to Mandard (Cancer 1994). Analyzed patients were divided into two groups: 1. Responders R (TRG 1 or 2 and clinical downstaging), and 2. Non-Responders NR (TRG 4 or 5, no-minimal downstaging). Tumor biopsies were obtained before initiation the therapy and stored in RNA later. RNA was extracted from each specimen and relative gene expression levels of 440 genes known to be involved in cancer biology were obtained by low density oligonucleotide microarrays. RESULTS: Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t test methods identified 7 genes (lipocalin 2, oncogene JUNB, cell cycle regulator RB1, p53 binding protein MDM4, calnexin, peroxisome proliferator activated receptor delta PPARD, mucin-like adhesion molecule CD24) with significantly up regulated expression in primary tumors of NR. In subsequent cluster analysis this group of genes was able to discriminate R and NR.CONCLUSION: Our preliminary data suggest that lowdensity oligonucleotide microarray technology should contribute to a better understanding of rectal cancer resistance at molecular level and facilitate prediction of tumor response to neoadjuvant chemoradiotherapy. IGA MZ CR NR/9076.