Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers

Eng Wee Chua, S. Cree, M. L. Barclay, K. Doudney, K. Lehnert, A. Aitchison, M. A. Kennedy

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome sequencing (WES) and copy-number variant analysis by array-based comparative genomic hybridisation (aCGH). Exome-wide variant filtering highlighted four genes potentially associated with thiopurine metabolism (ENOSF1 and NFS1), transport (SLC17A4) or therapeutic action (RCC2). However, variants of each gene were found only in two or three patients, and it is unclear whether these genes could influence thiopurine hypermethylation. Analysis by aCGH did not identify any unusual or pathogenic copy-number variants. This suggests that if causative mutations for the hypermethylation phenotype exist they may be heterogeneous, occurring in several different genes, or they may lie within regulatory regions not captured by WES. Alternatively, hypermethylation may arise from the involvement of multiple genes with small effects. To test this hypothesis would require recruitment of large patient samples and application of genome-wide association studies.

Original languageEnglish
Pages (from-to)414-421
Number of pages8
JournalPharmacogenomics Journal
Volume15
Issue number5
DOIs
Publication statusPublished - 24 Oct 2015

Fingerprint

Exome
Comparative Genomic Hybridization
6-Mercaptopurine
Genes
Azathioprine
Nucleic Acid Regulatory Sequences
Genome-Wide Association Study
Patient Selection
6-methylthiopurine
Phenotype
Mutation
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Genetics

Cite this

Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers. / Chua, Eng Wee; Cree, S.; Barclay, M. L.; Doudney, K.; Lehnert, K.; Aitchison, A.; Kennedy, M. A.

In: Pharmacogenomics Journal, Vol. 15, No. 5, 24.10.2015, p. 414-421.

Research output: Contribution to journalArticle

Chua, Eng Wee ; Cree, S. ; Barclay, M. L. ; Doudney, K. ; Lehnert, K. ; Aitchison, A. ; Kennedy, M. A. / Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers. In: Pharmacogenomics Journal. 2015 ; Vol. 15, No. 5. pp. 414-421.
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