Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia.
OBJECTIVE
To explore the role of genetic variants of thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) in 6-mercaptopurine (6-MP)-induced toxicity in Indian children with acute lymphoblastic leukemia (ALL).


METHODS
Children with ALL receiving 6-MP in maintenance phase of treatment (n = 90) were enrolled in the study. Bidirectional sequencing of TPMT (whole gene) and ITPA (exon 2, exon 3, and intron 2) was undertaken, and correlation between genotype and 6-MP toxicity was assessed.


RESULTS
Five variations were observed in TPMT, including two exonic variations, TPMT*12 (374 C > T) and TPMT*3C (719A > G), and three intronic, intron 3 (12356 C > T), intron 4 (16638 C > T), and TPMT rs2842949. Two exonic, ITPA exon -2 (94 C → A) and exon 3 of ITPA (138 G > A), and one intronic, ITPA intron 2 (A→C), variations were observed in ITPA. Multifactor dimensionality reduction analysis of all the genetic variants showed independent association of ITPA 94 C→A as well as synergic epistatic interactions, i.e., TPMT*12 × ITPA ex3, ITPA ex2 × TPMT*12 × ITPA ex3, and TPMT*3C × ITPA ex2 × TPMT*12 × ITPA ex3, in determining hematological toxicity. This is further substantiated by a multiple linear regression model, which showed moderate predictability of toxicity with these variants (area under the curve = 0.70, p = 0.004).


CONCLUSIONS
Our results suggest that apart from the individual effect of ITPA 94 C→A, epistatic interactions between the variations of TPMT (*3C, *12) and ITPA (ex2, ex3) are associated with the 6-MP toxicity. Testing these variants facilitates tailoring of the 6-MP therapy in children with ALL.
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh, India.
Patchva
P
Dorababu
Narayana
N
Nagesh
Vijay Gandhi
VG
Linga
Sadashivudu
S
Gundeti
Vijay Kumar
VK
Kutala
Pallu
P
Reddanna
Raghunadharao
R
Digumarti
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007194:India; D007958:Leukocyte Count; D008297:Male; D015122:Mercaptopurine / Q000633:toxicity*; D008780:Methyltransferases / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase