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Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer

Departments of ¹ Medicine, ² Genetics, ³ Pathology, and ⁴ Molecular Biology and Pharmacology and ⁵ Division of Biostatistics, Washington University School of Medicine and ⁶ Siteman Cancer Center, Saint Louis, Missouri

Requests for reprints: Howard L. McLeod, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8069, Saint Louis, MO 63110-1093. Phone: 314-747-5183; Fax: 314-362-3764; E-mail: hmcleod{at}im.wustl.edu.

The exact mechanism responsible for large variation of response to chemotherapy remains unclear. This study profiled the gene expression for the entire irinotecan pathway to provide insights into individualized cancer therapy. The RNA expressions of 24 irinotecan pathway genes were measured in paired tumor and normal tissues from 52 patients with Dukes' C colorectal cancer using a real-time quantitative reverse transcription-PCR assay. The relative expression levels across the 24 pathway genes varied considerably, with a 441-fold range from highest to lowest expression levels for the tumor tissues and a 934-fold range for the normal tissues. Interpatient variability was also quite large, with a 33.6 median fold change in the tumor tissue genes and a 30.1 median fold change in the normal tissue genes. Six of the 24 irinotecan pathway genes had dramatically lower expression levels in the tumor samples than did the genes in the normal tissues (median range, 1.28-4.39 folds; P = 0.001-0.029). Eight genes had significantly higher levels (median range, 1.35-2.42 folds; P = 0.001-0.011). Using hierarchical clustering, three gene clusters and three patient groups were observed with high similarity indices by the RNA expressions in colorectal tumors. The three patient groups had no unique clinical pathologic features but could be differentiated by the statistically significant differences in RNA expression level of seven genes. Our study indicates that gene expression profiling could be valuable for predicting tumor response to chemotherapy and for tailoring therapy to individual cancer patients.

Key Words: irinotecan pathway • colorectal cancer • gene expression profiling • pharmacogenomics • real-time PCR

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