Laboratory of Proteins Engineering and Bioactive Molecules (LIP-MB), INSAT, National Institute of Applied Sciences and Technology of Tunis, University of Carthage, Tunis, Tunisia.
Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, Tunis, Tunisia.
Mol Biol Rep. 2022 Feb;49(2):1233-1258. doi: 10.1007/s11033-021-06951-4. Epub 2021 Dec 1.
Bladder cancer (BCa) is a heterogeneous disease caused by the interaction between environmental and genetic risk factors. The goal of this case-control study was to evaluate the implication of a selected SNP panel in the risk of BCa development in a Tunisian cohort. We were also interested in studying the interaction between this predictive panel and environmental risk factors.
The case/control cohort was composed with 249 BCa cases and 255 controls. The designed Bladder cancer hereditary panel (BCHP) was composed of 139 selected variants. These variants were genotyped by an amplification-based targeted Next-Generation Sequencing (NGS) on the Ion Torrent Proton sequencer (Life Technologies, Ion Torrent technology).
We have found that rs162555, rs2228000, rs10936599, rs710521, rs3752645, rs804276, rs4639, rs4881400 and rs288980 were significantly associated with decreased risk of bladder cancer. However the homozygous genotypes for VPS37C (rs7104333, A/A), MPG (rs1013358, C/C) genes or the heterozygous genotype for ARNT gene (rs1889740, rs2228099, rs2256355, rs2864873), GSTA4 (rs17614751) and APOBR/IL27 (rs17855750) were significantly associated with increased risk of bladder cancer development compared to reference group (OR 2.53, 2.34, 1.99, 2.00, 2.00, 1.47, 1.96 and 2.27 respectively). We have also found that non-smokers patients harboring heterozygous genotypes for ARNT/rs2864873 (A > G), ARNT/ rs1889740 (C > T) or GSTA4/rs17614751 (G-A) were respectively at 2.775, 3.069 and 6.608-fold increased risk of Bca development compared to non-smokers controls with wild genotypes. Moreover the ARNT CT (rs1889740), ARNT CG (rs2228099), ARNT TC (rs2864873) and GSS GA genotypes were associated with an increased risk of BCa even in absence of professional risk factors. Finally the decision-tree analysis produced a three major BCa classes. These three classes were essentially characterized by an intensity of tobacco use more than 20 pack years (PY) and the CYP1A2 (rs762551) genotype.
The determined association between environmental factors, genetic variations and the risk of Bca development may provide additional information to urologists that may help them for clinical assessment and treatment decisions. Nevertheless, the underlying mechanisms through which these genes or SNPs affect the clinical behavior of BCas require further studies.
膀胱癌（BCa）是一种由环境和遗传风险因素相互作用引起的异质性疾病。本病例对照研究的目的是评估选定的 SNP 面板在突尼斯队列中对 BCa 发展风险的影响。我们还对研究该预测面板与环境风险因素之间的相互作用感兴趣。
病例/对照队列由 249 例 BCa 病例和 255 例对照组成。设计的膀胱癌遗传面板（BCHP）由 139 个选定的变体组成。这些变体通过基于扩增的靶向下一代测序（NGS）在 Ion Torrent Proton 测序仪（Life Technologies，Ion Torrent 技术）上进行基因分型。
我们发现 rs162555、rs2228000、rs10936599、rs710521、rs3752645、rs804276、rs4639、rs4881400 和 rs288980 与膀胱癌风险降低显著相关。然而，VPS37C（rs7104333，A/A）、MPG（rs1013358，C/C）基因的纯合基因型或 ARNT 基因（rs1889740、rs2228099、rs2256355、rs2864873）、GSTA4（rs17614751）和 APOBR/IL27（rs17855750）的杂合基因型与膀胱癌发展风险增加显著相关，与参考组相比（OR 2.53、2.34、1.99、2.00、2.00、1.47、1.96 和 2.27）。我们还发现，与携带野生基因型的非吸烟者对照相比，携带 ARNT/rs2864873（A>G）、ARNT/rs1889740（C>T）或 GSTA4/rs17614751（G-A）杂合基因型的非吸烟者患者患 Bca 的风险分别增加了 2.775、3.069 和 6.608 倍。此外，ARNT CT（rs1889740）、ARNT CG（rs2228099）、ARNT TC（rs2864873）和 GSS GA 基因型即使在没有专业风险因素的情况下也与 BCa 风险增加相关。最后，决策树分析产生了三个主要的 BCa 类别。这三个类别主要由超过 20 包年（PY）的烟草使用强度和 CYP1A2（rs762551）基因型来表征。
环境因素、遗传变异与 BCa 发展风险之间的确定关联，可能为泌尿科医生提供额外信息，有助于他们进行临床评估和治疗决策。然而，这些基因或 SNP 通过何种机制影响 BCas 的临床行为，需要进一步研究。
