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Updated: Nov 22, 2025
Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing
Published on: October 18, 2013
Decoding variants in drug-metabolizing enzymes and transporters in solid tumor patients by whole-exome sequencing
Mourad A M Aboul-Soud1, Alhussain J Alzahrani2, Amer Mahmoud3
1Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia.
Background:
Pharmacogenetics is involved in customizing therapy according to the genetic makeup of an individual, and is applicable for chemotherapy, radiotherapy as well as targeted therapy. Drug metabolizing enzymes (DMEs) involving both phase I, and phase II reactions are widely studied. Our study was involved in whole exome sequencing (WES) of cancer patients, followed by analysis for identifying key variations in DMEs, and associated transporters that have a potential impact on treatment outcome.
Methodology:
A total of 181 solid tumor patients at stage >/= III were subjected to WES by the SureSelectXT Human All Exon V6 + UTR library preparation kit, and sequencing in the Illumina NextSeq 550 system. Bioinformatics analysis involved use of GATK pipeline, and the variants were further assessed for population frequency, functional impact with annovar insilico algorithms. Further variant information from significant DMEs, and transporters were extracted and analyzed with PharmGKB to assess level of evidence and infer their impact on the pathways involved in drug response.
Results:
The total study cohort of 181 solid tumor patients included 60 males, and 121 females respectively. Among DMEs, deleterious mutation in dihydropyrimidine dehydrogenase (DPYD; rs67376798), solute carrier organic anion transporter family member 1B1 (SLCO1B1*5), and cytochrome P450 2D6 (CYP2D6*10) associated with metabolism of anticancer drugs was detected to be in high frequency of 26%, 21% and 25% respectively.
Conclusion:
Our analysis detected variations in both phase I and phase II DMEs, as well as associated transporter genes which has been documented to reduce drug efficacy, as well as cause grade 3 and 4 toxicity. Our study reiterates the significance of pharmacogenomics in stratifying patients for appropriate therapy regimen focused at better treatment outcome and quality of life.
Insights
Pharmacogenomic analysis of cancer patients reveals high-frequency mutations in key drug metabolizing enzymes (DMEs) and transporters. These genetic variations impact anticancer drug efficacy and toxicity, highlighting the need for personalized treatment strategies.
Area of Science:
- Pharmacogenomics
- Cancer Therapeutics
- Drug Metabolism
Background:
- Pharmacogenetics enables personalized therapy by considering individual genetic makeup for chemotherapy, radiotherapy, and targeted therapy.
- Drug metabolizing enzymes (DMEs) and transporters play a crucial role in drug response and are key targets for pharmacogenomic studies.
- Understanding genetic variations in DMEs and transporters is essential for optimizing cancer treatment outcomes.
Purpose of the Study:
- To identify key genetic variations in drug metabolizing enzymes (DMEs) and associated transporters in cancer patients using whole exome sequencing (WES).
- To analyze the potential impact of identified genetic variations on the efficacy and toxicity of anticancer treatments.
- To underscore the importance of pharmacogenomic profiling for personalized cancer therapy.
Main Methods:
- Whole exome sequencing (WES) was performed on 181 solid tumor patients (Stage III or higher).
- Bioinformatics analysis utilized the GATK pipeline for variant calling, followed by functional impact assessment using annovar.
- Variants in significant DMEs and transporters were cross-referenced with PharmGKB to evaluate evidence and infer impact on drug response pathways.
Main Results:
- High-frequency deleterious mutations were detected in key DMEs and transporters: 26% in dihydropyrimidine dehydrogenase (DPYD), 21% in SLCO1B1 (*5), and 25% in cytochrome P450 2D6 (CYP2D6 *10).
- These identified genetic variations are associated with the metabolism of commonly used anticancer drugs.
- The study cohort comprised 181 patients, with 60 males and 121 females.
Conclusions:
- Genetic variations in both phase I and phase II DMEs, along with transporter genes, can significantly reduce drug efficacy and increase severe toxicity (Grade 3-4).
- Pharmacogenomic profiling is crucial for stratifying cancer patients.
- Personalized therapy regimens based on pharmacogenomic data can lead to improved treatment outcomes and enhanced quality of life.
