Polymorphisms of T- cell leukemia 1A gene loci are not related to the development of adjuvant letrozole-induced adverse events in breast cancer

Abstract

Letrozole, an aromatase inhibitor (AI), is the first-line adjuvant drug for treating hormone receptor-positive (HR+) breast cancer in postmenopausal women. However, harmful adverse events (AEs) and significant differences in drug response among individuals remain a significant problem in clinical application. Current evidence suggests that the observed individual variation in the treatment outcomes of AI is conferred by genetic variants. Hence, in this study, we examined the association of TCL1A gene polymorphisms with letrozole-induced AEs. The study subjects were postmenopausal HR+ breast cancer patients who were receiving adjuvant letrozole. Genomic DNA was isolated by a routine standard phenol-chloroform method. In total, 198 South Indian patients were genotyped for four single nucleotide polymorphisms (SNPs) in the TCL1A gene loci by the TaqMan allelic discrimination assay using the RT-PCR system. We used the odds ratio and 95% confidence interval to assess the genetic association. Musculoskeletal (MS) AEs and vasomotor symptoms (VMSs) are the most common side effects observed in the study cohort. Among 198 patients, 81 experienced musculoskeletal toxicity, reporting MS-AEs, 57 had VMSs, and 33 of them had both. The most frequently identified polymorphic variants in the patient series were rs11849538 (G), with an allele frequency of about 27.3%, followed by rs7158782-G (27.3%), rs7159713-G (25.8%), and rs2369049-G (22.5%). The genetic association analysis indicated no significant difference in the proportion of TCL1A gene variants between patients with and without AEs on either MS-AEs or VMSs. Though we observed high LD in all patient groups, the inferred haplotypes displayed a non-significant association with letrozole-induced specific AEs. However, the SNP functionality analysis by RegulomeDB provided a 2b rank score for rs7158782, suggesting a potential biological function. Our findings suggest that TCL1A gene polymorphisms may not play any role in the prediction of letrozole-induced AEs in South Indian HR+ breast cancer patients.

Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms

“…Additionally, a genome-wide association study (GWAS) identi ed variants in TCL1A that may predict AIMSS 20 , however, this has not been successfully validated in other cohorts. 20,21 . Our primary GWAS identi ed two new variants (rs79048288 and rs912571) that were associated with AIMSS risk in the ELPh cohort.…”

“…This variant was not included in the E1Z11 analysis and was not successfully replicated in our recent analysis of an independent cohort of 143 AI-treated women 49 . Taken together, there is weak evidence that any of these candidate variants in CYP17A1 14 , CYP19A1 [14][15][16] , ESR1 17,18 , or TCL1A 20,21 are associated with AIMSS risk.…”

“…P-values less than 5x10 −8 were considered genome-wide signi cant. For the twenty-ve variants in 11 genes that were previously reported to be associated with AIMSS risk 16,[18][19][20][21][30][31][32][33] , p-values less than 0.05 were considered statistically signi cantly. Where noted below, associations for a subset of these variants were previously reported in the ELPh cohort 22,23 .…”

“…Additionally, a genome-wide association study (GWAS) identi ed variants in TCL1A that may predict AIMSS; however, this has not been successfully validated in other cohorts. 20,21 Further pharmacogenetic discovery and replication are necessary to identify variants that may predict which patients are at increased risk of AIMSS and AI-treatment discontinuation.…”

Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management

“…Therefore the E2-dependent regulation of cytokine and cytokine receptor expression mediated by TCL1A might help explain the association of TCL1A and AIMSS. However, a small clinical study of 198 postmenopausal HR+ breast cancer patients was not able to find an association between patients with AIMSS and TCL1A polymorphisms ( 105 ).…”