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Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine
E W Chua1,2, S Cree1, M L Barclay3,4
1Carney Centre for Pharmacogenomics and Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
The Pharmacogenomics Journal
|March 11, 2015
Summary
Genetic variations may cause thiopurine hypermethylation, leading to drug resistance. Researchers investigated whole-exome sequencing in patients with extreme resistance, identifying potential gene candidates but no clear Mendelian cause.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Clinical Genetics
Background:
- Thiopurine S-methyltransferase (TPMT) is crucial for thiopurine drug metabolism.
- Aberrant methylation of azathioprine (AZA) and 6-mercaptopurine (6-MP) leads to thiopurine resistance.
- Mendelian causes for thiopurine hypermethylation remain largely unexplored.
Purpose of the Study:
- To identify genetic factors contributing to thiopurine hypermethylation and subsequent drug resistance.
- To investigate potential Mendelian causes for extreme therapeutic resistance to thiopurine drugs.
Main Methods:
- Whole-exome sequencing (WES) was performed on 12 individuals with extreme thiopurine resistance.
- Array-based comparative genomic hybridization (aCGH) was used for copy-number variant analysis.
- Exome-wide variant filtering was applied to identify candidate genes.
Main Results:
- Four genes (ENOSF1, NFS1, SLC17A4, RCC2) were highlighted for potential roles in thiopurine metabolism, transport, or action.
- Variants in these candidate genes were found in only a small subset of patients (2-3 individuals each).
- No pathogenic copy-number variants were identified through aCGH analysis.
Conclusions:
- The genetic basis for thiopurine hypermethylation appears heterogeneous, potentially involving multiple genes with small effects or regulatory regions not assessed by WES.
- Further investigation with large patient cohorts and genome-wide association studies is needed to elucidate the genetic architecture of thiopurine hypermethylation.
- Current findings suggest complex genetic underpinnings for thiopurine resistance beyond single Mendelian inheritance patterns.
