Last year we saw many developmental activities through geneOmbio’s R&D effort that are now getting translated into active business through new cases being prescribed for testing in pharmacogenomics domain. We have recently come up analysis of a different gene in TPMT therapy that is found to contribute in toxicity due to treatment with thiopurine drugs. The gene named NUDT15 is found to have a nonsynonymous SNP in encoding p.Arg139Cys that is strongly associated with thiopurine-induced early leukopenia. Moreover the frequency of this mutation is higher in Asian population. Hence while assessing therapeutic dosage and toxicity due to TPMT treatment, it has become a necessity to perform genetic test to identify whether this mutation is present in an individual along with his status with TPMT alleles.

Acute lymphoblastic leukemia (ALL) is a cancer that affects the white blood cells. These cells fight infection and help protect the body against disease. Patients with ALL have too many immature white blood cells in their bone marrow. ALL is model disease for pharmacogenomics research. Thiopurine drug adjustment is one of the first example of implementation of pharmacogenetics in clinical practice. Inherited deficiency of thiopurine methytransferase (TPMT) resulting nonsynonymous germline polymorphisms leads to higher level of active metabolites of thiopurine and excess hematologic toxicities during ALL therapy. Thiopurines are also commonly prescribed in patients with inflammatory bowel diseases (IBD, e.g., Crohn’s disease and ulcerative colitis), especially for their steroid-sparing potential and efficacy in remission maintenance. Thiopurine treatment for IBD is associated with substantial hematopoietic toxicity, leading to discontinuation of therapy in up to 40% of patients and subsequent disease recurrence. Therefore, the narrow therapeutic indices of Thiopurine point to a strong need for applying evidence-based precision medicine approaches to the use of this class of medications.

Nudix hydrolase 15 is a protein in human encoded by NUDT15 gene, the gene encodes an enzyme that belongs to nudix hydrolase superfamily, that catalyze the hydrolysis of nucleoside diphosphates including substrates like 8-oxo-dGTPP which results oxidative damage and can induce base mispairing DNA replication causing transversion. Mutation in this gene results in poor metabolism of thiopurine and are associated with thiopurine induced early leukopenia. Recent genome-wide association studies described a missense variant in the NUDT15 gene p.Arg139Cys variant hereafter) that is strongly associated with thiopurine-related myelosuppression in patients with IBD. NUDT15 is hypothesized to dephosphorylate the thiopurine active metabolites TGTP and TdGTP, thus preventing their incorporation into DNA and negatively affecting the desired cytotoxic effects of thiopurines. A critical barrier to integrating NUDT15 genotypes into thiopurine dosing algorithm has been the paucity of data to establish the pharmacologic basis for dose reduction for patients with NUDT15 risk alleles.

NUDT15 deficiency directly resulted in excessive levels of thiopurine active metabolites (TGTP and DNA-TG) and increased host toxicity. Therefore, reducing thiopurine doses for patients who carry the mutant missense variant allele. NUDT15 variants would likely tailor their exposure to a level of TGTP and DNA-TG that is similar to wildtype patients receiving standard thiopurine doses. This is a highly plausible strategy for utilizing NUDT15 genotype to individualize thiopurine therapy to mitigate toxicity, as it is the same principle used for TPMT-based dose adjustments. NUDT15 variants are highly penetrant and confer exquisite sensitivity to thiopurines (homozygous carriers can tolerate < 10% of standard dosage), with effect sizes comparable to TPMT variants that are clinically implemented to guide thiopurine dose reduction.

In contrast, NUDT15 genetic variation is substantially over-represented in Asians and is their predominant genetic cause for thiopurine toxicity.

Based on this research background and data available, geneOmbio has come up with this additional gene testing for thiopurine toxicity assessment through pharmacogenomics services. We would continue our thrust of new developmental activities and promotion of these services on wider scale in this year as our prime focus will be the pharmacogenomics market.

– Dr. Parag Purohit

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