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Published on: July 25, 2020
Expression microarray analysis and oligo array comparative genomic hybridization of acquired gemcitabine resistance
Mark A van de Wiel1, Jose L Costa, Kees Smid
1Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, the Netherlands.
Abstract:
Gemcitabine is a commonly used therapy for many solid tumors. Acquired resistance to this nucleoside analogue, however, diminishes the long-term effectiveness in a majority of patients. To better define the molecular background of gemcitabine resistance, a mouse colon tumor was selected during successive rounds of transplantation with continued treatment of gemcitabine. Expression microarray analysis was applied to determine which genes are consistently and highly overexpressed or underexpressed in the resistant versus the nonresistant tumor. For the statistical interpretation of the microarray data, a parametric model was implemented, which returns model-based differential gene expression (log-) ratios and their uncertainties. This defined a set of 13 genes, putatively responsible for the gemcitabine resistance in solid tumors. One of these, RRM1, was previously identified as an important marker for gemcitabine resistance in human cell lines. Five of the 13 genes, including RRM1, are located within a 3 Mb region at chromosome 7E1 of which four are highly overexpressed, suggesting a chromosomal amplification. Therefore, chromosomal copy number changes were measured, using oligo array comparative genomic hybridization. A narrow and high amplification area was identified on 7E1 that encompassed all five genes. In addition, reduced RNA expression of two other genes at 8E1 encoding COX4I1 and RPL13 could be explained by a decrease in chromosomal copy number on chromosome 8. In conclusion, the array comparative genomic hybridization biologically validates our statistical approach and shows that gemcitabine is capable to select for chromosomally aberrant tumor cells, where changed gene expression levels lead to drug resistance.
Insights
Gemcitabine resistance in solid tumors can arise from chromosomal abnormalities. This study identified specific gene amplifications on chromosome 7 that drive gemcitabine resistance by altering gene expression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gemcitabine is a vital chemotherapy for solid tumors, but acquired resistance limits its efficacy.
- Understanding the molecular mechanisms of gemcitabine resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To identify genes and chromosomal alterations associated with gemcitabine resistance in solid tumors.
- To investigate the role of chromosomal copy number changes in acquired drug resistance.
Main Methods:
- Utilized expression microarray analysis to compare gene expression in gemcitabine-resistant and non-resistant mouse colon tumors.
- Applied a parametric model for statistical interpretation of microarray data to identify differentially expressed genes.
- Employed oligo array comparative genomic hybridization (aCGH) to detect chromosomal copy number variations.
Main Results:
- Identified 13 genes potentially responsible for gemcitabine resistance, including RRM1.
- Discovered a high amplification on chromosome 7E1 encompassing five overexpressed genes, including RRM1.
- Observed decreased copy number and expression for COX4I1 and RPL13 on chromosome 8.
Conclusions:
- Gemcitabine treatment can select for chromosomally aberrant tumor cells.
- Chromosomal amplifications and deletions significantly contribute to gemcitabine resistance by altering gene expression.
- Array comparative genomic hybridization validates the statistical approach and highlights the role of genomic instability in drug resistance.
