Agnes (not her real name) is a typical 7-year-old in Primary 1, except for one thing: she has acute lymphoblastic leukaemia (ALL). She is also extremely sensitive to the common ALL drug 6-mercaptopurine (6-MP) and its toxic side effects. Shortly after starting treatment with 6-MP, Agnes’ blood cell levels plunged, making her susceptible to repeated infections.
Approximately 1 out of 80 ALL patients are hypersensitive to 6-MP like Agnes. For many years, doctors have known that sensitivity to 6-MP and other thiopurine drugs are linked to variations in the TPMT gene in Caucasians. However, Asians appeared to be more sensitive than Caucasians to the drug, and this difference could not be explained by differences in the frequency of TPMT variants.
Now, a study of children with ALL has shown that another gene, NUDT15, is likely to be responsible for the greater sensitivity in Asians than in Caucasians. Published online in Nature Genetics in February, the study was led by Dr Takaya Moriyama and Dr Jun J. Yang, both of St Jude Children’s Research Hospital in Memphis, Tennessee in the U.S. The researchers examined variants in the NUDT15 gene in 270 children with ALL in three countries, Guatemala, Singapore, and Japan. The Guatemalan patients were descended from Native Americans, who are genetically related to East Asians. The Singaporean arm, which comprised 69 ALL paediatric patients at NUH, was led by Associate Professor Allen Yeoh of the Department of Paediatrics. Assoc Prof Yeoh is also Agnes’ doctor.
The NUDT15 gene normally produces an enzyme that breaks down toxic metabolites of the 6-MP drug into less harmful substances, thus neutralising the drug’s toxicity. The study showed that, in all three groups, several variants of the NUDT15 gene made the enzyme less active. Patients with one variant gene had intermediate enzyme activity and were more susceptible to 6-MP toxicity than patients with no variant genes. Two variant NUDT15 genes multiplied the effect. These patients had low enzyme activity and were extremely sensitive to 6-MP toxicity (see Facts Box).
Based on the findings, NUDT15 gene testing will soon be offered at St Jude Children’s Research Hospital and at the new NUS-Viva Centre for Translational Research in Acute Leukaemia (CenTRAL), a $10-million laboratory funded by the Viva Foundation for Children with Cancer.
NUDT15 is one more gene in the expanding arsenal of genes that have been linked to specific functions. For example, in ALL, Assoc Prof Yeoh has characterised other genes that help to predict treatment response and outcome.
After close monitoring and multiple dosage adjustments, accompanied by bouts of infection, Assoc Prof Yeoh was able to find a dose that controlled Agnes’ cancer without causing severe side effects. NUDT15 gene testing could reduce or even eliminate this difficult period of adjustment. Since 6-MP is prescribed for the second phase of treatment (5 weeks after initial treatment with another drug), patients can be tested to determine an appropriate 6-MP dose before even starting the drug. As Dr Yang sees it, NUDT15 gene testing represents a step towards “turning imprecision medicine into precision medicine.”
How NUDT15 Gene Testing Can Help to Determine 6-MP Dosage
(No. of NUDT15 Variants)
|NUDT15 Activity||6-MP Dosage Adjustment|
|0||Normal||None (normal does)|
|1||Intermediate||Lower dose (eg, half-dose)|
|2||Low||Much lower dose (eg, 10% of normal dose)|
- Moriyama T, Perez-Andreu V, Nishii R, et al. NUDT15 polymorphisms and individualization of thiopurine therapy. Nat Genet. 2016 Feb 15. [Epub ahead of print]
- Lu Y, Kham SK, Ariffin H, et al. Host genetic variants of ABCB1 and IL15 influence treatment outcome in paediatric acute lymphoblastic leukaemia. Br J Cancer. 2014;110:1673-1680.