Allelic variants in xenobiotic metabolism genes predict susceptibility and worse prognosis of urothelial bladder cancer

IF 2.9 4区 医学 Q2 PATHOLOGY
Isabely Mayara da Silva , Flora Troina Maraslis , Julia Ayumi Ikeda Kawasaki , Natieli Kazue Aida , Gustavo Rafael Mazzaron Barcelos , Alexsandro Koike , Paulo Emílio Fuganti , Ilce Mara de Syllos Cólus , Roberta Losi Guembarovski , Juliana Mara Serpeloni
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引用次数: 0

Abstract

Biomarkers that identify tumors with better/worse prognosis can help reduce treatment costs and contribute to patient survival. In urothelial bladder cancer (UBC), accurate prediction of recurrence and progression is essential to inform therapeutic management. Herein, we explore the role of genetic variants of xenobiotic metabolic pathways in UBC susceptibility and prognosis. In total, 295 participants with UBC and 295 controls were genotyped using TaqMan® probes. CYP1A1 (rs1048943), CYP3A4 (rs4646437), CYP3A5 (rs4646450), UGT2B7 (rs7438135), and UGT2B15 (rs3100) allele frequencies were compared between UBC patients and controls and were analyzed concerning tumor grade, invasion, and recurrence. CYP3A4 (AA) increased susceptibility to UBC 3-fold when interacting with CYP3A5 (AA+AA). The susceptibility was higher in CYP3A4 (AA) males (OR=3.189) and individuals exposed to pesticides (OR=5.492). When interacting with hypertension, the allele C of CYP1A1 also increased UBC susceptibility by 2-fold. The UGT2B15 mutant allele was associated with high-grade tumors (OR=2.196) and recurrences (OR=2.561), as well as tumor grade when associated with mutated alleles of CYP3A4 (OR=6.171) and CYP3A5 (OR=3.492). Genes-encoding proteins were further analyzed using the STRING program, demonstrating that the proteins had known interactions in databases and were co-expressed. This study is a pioneer in evaluating these variants in a Latin American population from Brazil and confirms occupational pesticide exposure as a risk factor for UBC, mainly in genetically susceptible individuals. Furthermore, these variants may have additional clinical value for predicting susceptibility and prognostic stratification in patients with exposure-related cancers such as UBC.
异种代谢基因的等位变异预测尿路上皮性膀胱癌的易感性和不良预后。
识别预后较好/较差肿瘤的生物标志物有助于降低治疗成本并有助于患者生存。在尿路上皮性膀胱癌(UBC)中,准确预测复发和进展对于告知治疗管理至关重要。在此,我们探讨了外源代谢途径的遗传变异在UBC易感性和预后中的作用。共有295名UBC患者和295名对照组使用TaqMan®探针进行基因分型。比较UBC患者和对照组之间CYP1A1 (rs1048943)、CYP3A4 (rs4646437)、CYP3A5 (rs4646450)、UGT2B7 (rs7438135)和UGT2B15 (rs3100)等位基因频率,并分析肿瘤分级、侵袭和复发情况。CYP3A4 (AA)与CYP3A5 (AA+AA)相互作用时,UBC易感性增加3倍。CYP3A4 (AA)雄性个体(OR=3.189)和农药暴露个体(OR=5.492)的易感性较高。当与高血压相互作用时,CYP1A1等位基因C也使UBC易感性增加了2倍。UGT2B15突变等位基因与恶性肿瘤(OR=2.196)和复发(OR=2.561)相关,与CYP3A4 (OR=6.171)和CYP3A5 (OR=3.492)突变等位基因相关时,与肿瘤分级相关。使用STRING程序进一步分析基因编码蛋白,证明这些蛋白在数据库中已知相互作用并且共表达。这项研究是在巴西拉丁美洲人群中评估这些变异的先驱,并证实职业性农药暴露是UBC的一个风险因素,主要是在遗传易感个体中。此外,这些变异对于预测暴露相关癌症(如UBC)患者的易感性和预后分层可能具有额外的临床价值。
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来源期刊
CiteScore
5.00
自引率
3.60%
发文量
405
审稿时长
24 days
期刊介绍: Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.
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