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Updated: Aug 4, 2026
Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing
Published on: October 18, 2013
Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced
Wesley S van de Geer1, Ron H J Mathijssen2, Job van Riet1
1Dept. of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Cancer Computational Biology Center, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands; Dept. of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.
Abstract:
Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.
Insights
Cancer drug resistance is linked to transporter gene mutations. Tumors treated with protein kinase inhibitors showed more deletions in copper and nucleoside transporter genes, suggesting primary resistance mechanisms.
Area of Science:
- Genomics and Cancer Biology
- Molecular Oncology
- Drug Resistance Mechanisms
Background:
- Drug resistance remains a significant challenge in cancer therapy.
- Altered drug transport across cancer cell membranes impacts drug exposure and resistance.
- Understanding the genetic basis of transporter function is crucial for overcoming resistance.
Purpose of the Study:
- To investigate the somatic mutational landscape of transporter genes in advanced cancer.
- To identify potential drug resistance mechanisms related to transporter gene alterations.
- To explore the impact of previous systemic therapies on transporter gene mutations.
Main Methods:
- Whole genome and transcriptome sequencing of 3290 advanced cancer patients (CPCT-02 cohort).
- Analysis of 48 ATP-binding cassette and 416 solute carrier transporter genes.
- Stratification of patients based on prior treatment with protein kinase inhibitors (PKIs) versus chemotherapy.
Main Results:
- Significant deletions in copper transporter genes (SLC31A1, SLC31A2) and nucleoside transporter genes (SLC28A2, SLC28A3) were observed in patients pretreated with PKIs compared to chemotherapy.
- 16 transporters showed differential RNA expression between the treatment groups.
- These findings suggest transporter alterations may arise independently of selective pressure from chemotherapy.
Conclusions:
- The observed transporter gene alterations in PKI-treated patients may represent primary drug resistance mechanisms.
- These findings warrant further investigation into the role of transporters in cancer drug resistance.
- Targeting specific transporters could offer new therapeutic strategies to overcome resistance.
