Analysis of the IDH1G105 (SNPrs11554137) Polymorphism in 961 AML Patients and in a Large Cohort of 475 Healthy Controls

Mutations in IDH1 and IHD2 at arginines 132 and 140 or 172, respectively, have recently been shown to play an important role in AML. Also the IDH1105GGT minor allele of the IDH1G105 (SNPrs11554137) polymorphism that is localized in the same exon as the IDH1R132 mutation has recently been reported to be an adverse prognostic factor in AML (JCO: 14, 2356–2364, 2010). Aim: We aimed at further delineating the frequency and impact of the IDH1105GGT minor allele in AML and also analyzed a healthy control cohort. Methods:IDH1G105 (SNPrs11554137) was analyzed in 961 AML patients by a LightCycler-based melting curve assay. Female/male ratio was 433/528 and age ranged from 13.1–100.4 years (median, 66.7 years). The results were compared to a healthy control cohort from the KORA (Cooperative Health Research in the Region of Augsburg) survey S4, which consists of 475 cases who where matched to the leukemia samples with respect to sex (193f/282m) and age (median: 67, range 32–81 years). Informed consent for participation in anonymized genetic studies was obtained from all individuals. IDH1G105 in the healthy cohort was analyzed by Sanger sequencing. Further mutation analyses were available in subsets of the AML patients, respectively, as follows: (IDH1R132 n=625, IDH2R140 n=587, IDH2R172 n=590, FLT3-ITD n=629, FLT3-TKD n=503, NPM1 n=628, CEBPA n=587, RUNX1 n=231, MLL-PTD n=629, NRAS n=273, KRAS n=133, ASXL1 n=470) and were analyzed as described previously. A subcohort of 634 AML with intermediate risk karyotype was analyzed for survival. Female/male ratio of this subcohort was 280/354 and age ranged from 15.7–86.6 years (median, 66.9 years). The adverse impact of IDH1R132, IDH2R140 and IDH2R172 on the NPM1+/FLT3-ITD- group has been shown previously for this group (Blood 2010 116: Abstract 102). Results: The IDH1105GGT minor allele was detected in 11.2% (108/961) in AML and in 8.8% (42/475) of the KORA control. This slight difference does not reach statistical significance (p=0.17) and thus there is no indication that this variance is a predisposing factor for leukemia. Also the frequency of a homozygous IDH1105GGT minor allele was not different between the AML cohort (3/108, 2.8%) and the KORA cohort (2/42, 4.8%, n.s.). In the AML cohort there was no association of the IDH1105GGT minor allele with age, WBC, platelet count or any of the above mentioned molecular mutations. In contrast, some differences in survival were observed: patients with the IDH1105GGT minor allele had a longer event free survival (EFS) than those with the IDH1105GGC major allele (median: 30.1 vs. 21.6 months, p=0.052) in the intermediate risk cohort. This prognostically favourable effect of the IDH1105GGT minor allele was most prominent in the NPM1+/FLT3- group with a median EFS of 45.1 vs 23.5 months as compared to those with the IDH1105GGC major allele (p=0.015). Conclusions: 1) The polymorphic IDH1105GGT minor allele was not found to be a marker predisposing for AML. 2) No association of the IDH1105GGT minor allele to any mutation or other biological parameters was detected. 3) We were not able to reproduce the previously published adverse impact of the IDH1105GGT minor allele on survival in AML. In contrast, in our cohort of 475 patients with intermediate risk AML the EFS was even better in patients carrying the IDH1105GGT minor allele, especially in the subcohort with NPM1+/FLT3−ITD−. Thus, we would suppose that the IDH1105GGT minor allele is a favorable molecular marker in intermediate risk AML. However, as these findings are in contrast to previously published data, further confirmation in additional studies is necessary to draw firm conclusions on the utility of the IDH1105 polymorphism as a marker for diagnostics and prognosis in AML.

Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.