Temozolomide-induced myelotoxicity and single nucleotide polymorphisms in the MGMT gene in patients with adult diffuse glioma: a single-institutional pharmacogenetic study

• Published in: Journal of neuro-oncology Vol. 156; no. 3; pp. 625 - 634
• Main Authors: Moitra, Prithwijit, Chatterjee, Abhishek, Kota, Priti Khatri, Epari, Sridhar, Patil, Vijay, Dasgupta, Archya, Kowtal, Pradnya, Sarin, Rajiv, Gupta, Tejpal
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2022; Springer Nature B.V
• Subjects: Adult; Adults; Alleles; Biopsy; Blood cells; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Clinical Study; Deoxyribonucleic acid; DNA; DNA methyltransferase; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Glioma; Glioma - drug therapy; Glioma - genetics; Humans; Medicine; Medicine & Public Health; Methylguanine; Myeloid Cells - drug effects; Myeloid Cells - pathology; Myelosuppression; Neurology; Neutropenia; O6-methylguanine-DNA methyltransferase; Oncology; Patients; Peripheral blood; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Single-nucleotide polymorphism; Statistical analysis; Temozolomide; Temozolomide - adverse effects; Thrombocytopenia; Toxicity; Tumor Suppressor Proteins - genetics; Myelotoxicity; Pharmacogenetic; Temozolomide; Glioma; MGMT; Polymorphism
• DOI: 10.1007/s11060-022-03944-6
• ISSN: 0167-594X; 1573-7373

Purpose Nearly 10% of patients with adult diffuse glioma develop clinically significant myelotoxicity while on temozolomide (TMZ) leading to treatment interruptions. This study aimed to assess single nucleotide polymorphisms (SNPs) in the O 6 -methylguanine-DNA methyltransferase ( MGMT ) gene in adults with biopsy-proven diffuse glioma who develop TMZ-induced myelotoxicity and correlate their presence with severity and duration of such toxicity. Methods This study assessed 33 adults treated with TMZ for diffuse glioma who developed ≥ grade 2 thrombocytopenia and/or ≥ grade 3 neutropenia. Genomic DNA was extracted from peripheral blood cells for MGMT SNP analysis after written informed consent. TMZ-induced severe myelotoxicity (≥ grade 3) was correlated with three specified SNPs commonly seen in the MGMT gene (L84F, I143V/K178R) using chi-square test or Fischer’s exact test as appropriate. Results Of the 33 adults, 24 (72.7%) experienced ≥ grade 3 thrombocytopenia and/or neutropenia, while 9 (27.3%) developed grade 2 thrombocytopenia only. The variant T allele of L84F was expressed in 28.7% (19/66) of analyzed alleles, which was substantially higher than previously reported for South Asian ancestry. The variant G allele of I143V/K178R was expressed in 9.3% (6/64) of analyzed alleles. Of which 3 patients showed statistically significant association with prolonged myelosuppression for > 2 months (p = 0.03). No significant correlation was established between the mentioned SNPs and severe myelotoxicity. Conclusions There is substantially higher frequency of variant T allele (L84F) in Indian patients than previously reported for South Asians. The presence of specific SNPs in the MGMT gene correlates with prolonged duration but not severity of TMZ-induced myelotoxicity.