Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity

Umamaheswaran, Gurusamy; Dharanipragada, Kadambari; Muthuvel, Suresh Kumar; Kalaivani, S.; Devi, J Sakthi Usha; Damodaran, Solai Elango; Pradhan, S.C.; Dubashi, Biswajit; Dkhar, Steven Aibor; Chandrasekaran, Adithan

doi:10.1007/s10549-020-05656-9

Cited by 8 publications

(7 citation statements)

References 33 publications

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“…In addition, CYP19A1 has been demonstrated to play an important role in the occurrence of breast cancer and even affect patients' survival [31]. Various drugs can inhibit the function of CYP19A1, such as Letrozole, have been used in clinical settings to treat breast cancer [32]. PCa and breast cancer share many similarities; for example, they are both hormone-dependent neoplasms.…”

Section: Discussionmentioning

confidence: 99%

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

Chen

Wang

et al. 2022

Preprint

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BackgroundCastration-resistant prostate cancer (CRPC) is the final stage of prostate cancer (PCa). Thus far, there is no effective method for CRPC treatment. Androgen and androgen receptor (AR) play a vital role in CRPC occurrence and drug tolerance. Testosterone is the main androgen in males. CYP19A1 can encode aromatase, a key enzyme that can catalyze the conversion of testosterone to estrogen, and may affect both androgen and AR. CYP19A1 may play a role in the occurrence of CRPC; however, the function of CYP19A1 in CRPC remain unclear.MethodsUsing data from public databases and clinical samples, we analyzed the expression of CYP19A1 in PCa and CRPC specimens. In addition, the influence of CYP19A1 on cell invasion and proliferation was detected in vivo and vitro. The affect of BRD4 on CYP19A1 and AR was detected by qRT-PCR and western blot experiments.ResultsWe found that CYP19A1 was downregulated in CRPC samples and cells. CYP19A1 overexpression decreased CRPC cell invasion and proliferation. In addition, CYP19A1 expression was negatively correlated with AR expression. CYP19A1 affected CRPC cell invasion and proliferation ability by suppressing the expression of AR, and this may be attributed to the metabolism of testosterone by CYP19A1. Moreover, the BRD4 inhibitor-JQ1 induced the expression of CYP19A1 and suppressed the expression of AR. Following BRD4 knockdown, CYP19A1 showed a higher expression level, and, AR expression was decreased. ConclusionsIn conclusion, our findings demonstrated that CYP19A1 could reduce CRPC cell invasion and proliferation by targeting AR, and this process could be regulated by BRD4. The BRD4-CYP19A1-AR pathway may be a potential cause of CRPC occurrence. Therefore, CYP19A1 may be a potential therapeutic target for treating CRPC.

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Section: Discussionmentioning

confidence: 99%

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

Chen

Wang

et al. 2022

Preprint

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“…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 .…”

Section: Methodsmentioning

confidence: 99%

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

Hertz

Douglas

Miller

et al. 2022

Support Care Cancer

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Aromatase inhibitors (AI) are commonly used to treat hormone receptor positive (HR+) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. MethodsIn the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR+ non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. ResultsFour hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide signi cance level in the primary analysis (p-value<5x10 −8 ), an intronic variant (rs79048288) within CCDC148 (HR=4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR=0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was signi cantly associated with discontinuation of letrozole therapy due to AIMSS (HR=5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. ConclusionsOur GWAS ndings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole speci cally. Validation of these associations in independent cohorts is needed before translating these ndings into clinical practice to improve treatment outcomes in patients with HR+ breast cancer.

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“…The diagnosis of breast cancer was confirmed by histopathological examination. Details of this study design, selection criteria, toxicity assessment, questionnaire, and treatment have been described previously [14].…”

Section: Patient Populationmentioning

confidence: 99%

“…Regarding menopause, 141 patients attained it naturally, and the rest 57 cases were induced either by surgery or chemotherapy. We previously reported the clinical and pathological characteristics of patients stratified by 'specific' adverse events for this patient cohort [14]. Table 2 describes the genotype and allele frequency distributions of TCL1A genetic variants in the study population.…”

Section: Baseline Characteristic Features Of the Study Cohortmentioning

confidence: 99%

“…These genetic variations, in particular, variants in the CYP19A1 gene, have evolved as essential contributors to predict the inter-patient differences in drug effectiveness and toxicity after the administration of AIs; particularly, the non-steroidal agent letrozole. Accordingly, we have identified a significant association between CYP19A1 variants and letrozole-induced AEs [14]. With different polymorphisms, treatment settings, endpoints, study design, and ethnic groups, these studies have yielded conflicting results.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity

Cited by 8 publications

References 33 publications

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

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

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

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