Prominence of NUDT15 genetic variation associated with 6‐mercaptopurine tolerance in a genome‐wide association study of Japanese children with acute lymphoblastic leukaemia. (12th August 2022)

• Record Type: Journal Article
• Authors: Tanaka, Yoichi; Urayama, Kevin Y.; Mori, Makiko; Arakawa, Yuki; Hasegawa, Daisuke; Noguchi, Yasushi; Yanagimachi, Masakatsu; Keino, Dai; Ota, Setsuo; Akahane, Koshi; Inukai, Takeshi; Hangai, Mayumi; Kawaguchi, Takahisa; Takagi, Masatoshi; Koh, Katsuyoshi; Matsuda, Fumihiko; Manabe, Atsushi
• Is Part Of: British journal of haematology. Volume 199:Number 2(2022)
• Page Start: 260
• Page End: 269
• Publication Date: 2022-08-12
• Subjects: 6‐mercaptopurine -- genetic variant -- genome‐wide association study -- Japanese children -- tolerance; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.18405
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: Inherited genetic variation is associated with 6‐mercaptopurine (6‐MP) dose reduction and frequent toxicities induced by 6‐MP. However, the tolerable dose for 6‐MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome‐wide association study (GWAS) related to 6‐MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome‐wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6‐MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene‐coding regions, among which only variants at 13q14.2 were significant and replicated genome‐wide (rs116855232, NUDT15, β = −10.99, p = 3.7 × 10 −13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10 −6 ) and CHST11 (rs1148407, p = 2.09 × 10 −6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6‐MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions ( p adjust = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6‐MP tolerable dose in children in Japan.