Genetic polymorphisms in candidate genes are not associated with increased vincristine-related peripheral neuropathy in Arab children treated for acute childhood leukemia

Abstract

This study presents the first pharmacogenetic analysis of vincristine-related peripheral neuropathy in children with ALL in an Arab country. We have shown that genetic polymorphisms in candidate genes are not associated with peripheral neuropathy secondary to chronic therapy with high-dose vincristine (2 mg/m) during the continuation phase. Concerning CEP72, our results are in line with the findings from the St Jude cohort of children treated for ALL with higher vincristine doses during chronic treatment. Larger high-throughput genetic analyses may be warranted to evaluate variants in other candidate genes such as CYP3A5 and reveal new nonpreviously reported alleles that may be peculiar to this region of the world.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview

“…Mutations in CEP72 and CYP3A5 have been most extensively studied as factors possibly influencing the development of vincristine-induced neuropathy. Studies have demonstrated that SNPs that reduce CEP72 expression may lead to the development of neuropathy in patients on vincristine [29,30], although subsequent studies were unable to consistently reproduce this finding [31,32]. Vincristine is primarily metabolized by CYP3A4 and 3A5.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…McClain et al (2016) also found no significance with polymorphisms in the CEP72 gene, while Wright et al (2019) showed that CEP72 (rs924607), SLC547 (rs1013940) (choline transporter), and Alpha Tocopherol Transfer Protein (TTPA, binding to vitamin E) (rs1050436) were significant associated with a higher risk of developing neuropathy. No association was found by Zgheib et al (2018) between VIPN and CEP72 (rs924607), Ewing's tumor-associated antigen 1 (ETAA1) (rs17032980) and Melatonin Receptor 1B (MTNR1B) (rs12786200). Li et al (2019) investigated two independent cohorts and used a meta-analysis to assess the association between multiple SNPs and VIPN.…”

“…A significant higher risk of developing neurotoxicity grades 1 to 4 during vincristine treatment was found for rs3740066 and rs12826 in the ABCC2 gene. Zgheib et al. (2018) assessed the association between grade II or higher VIPN and ABCB1 (rs1045642), ABCB1 (rs1128503) and ABCC2 (rs717620).…”

“…(2019) showed that CEP72 (rs924607), SLC547 (rs1013940) (choline transporter), and Alpha Tocopherol Transfer Protein ( TTPA , binding to vitamin E) (rs1050436) were significant associated with a higher risk of developing neuropathy. No association was found by Zgheib et al. (2018) between VIPN and CEP72 (rs924607), Ewing’s tumor-associated antigen 1 (ETAA1 ) (rs17032980) and Melatonin Receptor 1B (MTNR1B) (rs12786200).…”

<p>Implementation of Pharmacogenetics to Individualize Treatment Regimens for Children with Acute Lymphoblastic Leukemia</p>

“… 74 , 161 Results were however not replicated in two other studies. 162 , 163 More recently whole-exome sequencing of DNA from 240 European children with ALL revealed an association between four variants in four genes ( BAHD1 rs3803357, MRPL47 rs10513762, SYNE2 rs2781377 , and CDH2 rs1944294 ) with VINC-related neuropathy, 66 however these results were not yet validated in other populations.…”