Prithwijit Moitra1, Abhishek Chatterjee1, Priti Khatri Kota2, Sridhar Epari3, Vijay Patil4, Archya Dasgupta1, Pradnya Kowtal2, Rajiv Sarin1,2, Tejpal Gupta5. 1. Departments of Radiation Oncology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, 410210, India. 2. Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India. 3. Department of Pathology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India. 4. Department of Medical Oncology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India. 5. Departments of Radiation Oncology, Tata Memorial Hospital (TMH)/Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, 410210, India. tejpalgupta@rediffmail.com.
Abstract
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 O6-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.
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 O6-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.
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