NUDT15 variant and thiopurine-induced leukopenia in Hong Kong

Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose

“…AZA and 6-MP can convert to active metabolites 6-thioguanine nucleotides (6-TGNs) via multiple sequential anabolic reactions [3, 4], which (e.g., deoxythioguanosine triphosphate) can incorporate into double-stranded DNA to trigger futile mismatch repair and lead multiple types of cells (e.g., T lymphocytes) to apoptosis and subsequent resolution of inflammation [5–8]. Meanwhile, 6-MP and its metabolites can be methylated by thiopurine methyltransferase (TPMT) and interrupt intervening DNA synthesis [9, 10].…”

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C)

“…In 2003, the USA Food and Drug Administration decided to change the drug label to include information about inherited TPMT deficiency [3] and later recommended TPMT genotyping or genotypic testing to be performed before initiating treatment with azathioprine [4]. This was due to the finding that individuals homozygous for an inherited defect in the TPMT gene displayed increased sensitivity to myelosuppression, the dose-limiting toxicity of the thiopurines [5].…”

“…Arguably, an assay with rapid turnaround time is advantageous since it will not delay the sometimes life-saving treatment [19]. On the other hand, to promote adoption of the test, the assay should be simple, objectively interpreted and have low consumable costs compared to traditional sequencing [4], with differentiation based on relative amplification efficiency [20] or by probe-based tests [21,22,23]. Additionally, the assay should be robust to variations caused by pre-analytical variables [24].…”

NUDT15 and TPMT genetic polymorphisms are related to 6‐mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon

“…normal) for TPMT still develop toxicity that necessitates MP dose reduction or protocol interruption . Recently, several studies reported on an inherited nucleoside diphosphate‐linked moiety X motif 15 ( NUDT15 ) c.415C>T (rs116855232) nonsynonymous (R139C) low‐function variant that is associated with decreased thiopurine metabolism and leukopenia in ALL and other diseases . This allele and a few others in the same gene are most common among individuals of Asian ancestry, with the initial susceptibility to thiopurine‐related leucopenia being reported in a cohort of Korean subjects with Crohn disease .…”

“…9 Recently, several studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T (rs116855232) nonsynonymous (R139C) low-function variant that is associated with decreased thiopurine metabolism 10 and leukopenia in ALL 9-15 and other diseases. [16][17][18][19] This allele and a few others in the same gene are most common among individuals of Asian ancestry, with the initial susceptibility to thiopurine-related leucopenia being reported in a cohort of Korean subjects with Crohn disease. 13 Interestingly, the CPIC is considering incorporating NUDT15 preemptive genotyping in the current thiopurine dosing recommendations.…”