Morganti Maria, Ciantelli Monica, Giglioni Beatrice, Putignano Anna L, Nobili Stefania, Papi Laura, Landini Ida, Napoli Cristina, Valanzano Rosa, Cianchi Fabio, Boddi Vieri, Tonelli Francesco, Cortesini Camillo, Mazzei Teresita, Genuardi Maurizio, Mini Enrico
Dipartimento di Farmacologia, Unità di Chemioterapia, Università degli Studi di Firenze, viale Pieraccini, 6, 50139, Firenze, Italy.
Eur J Cancer. 2005 Sep;41(14):2176-83. doi: 10.1016/j.ejca.2005.06.016.
Thymidylate synthase (TS) intratumoural expression may be a prognostic marker and predict outcome of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer patients. The TS gene promoter enhancer region contains two different polymorphisms which can influence TS mRNA transcriptional and translational efficiency: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism (SNP), G > C, within the second repeat of the 3R alleles. We studied the relationship between tumoural TS mRNA expression levels and TS gene polymorphisms in the colonic mucosa of 48 colorectal cancer patients. The 3R/3R genotype was characterised by higher TS mRNA levels in the tumour than the 2R/2R-2R/3R genotypes (P = 0.071). Regarding the relationship with the SNP polymorphism, a statistically significant difference in TS gene expression between the 3RG/3RG genotype and 2R/2R-2R/3RC-2R/3RG genotype subset was observed (P = 0.017). No statistically significant correlation was observed between experimental data and baseline clinical-pathological characteristics as well as clinical outcome in the relatively small patient series investigated. This is the first study reporting an association between the TS intra-repeat SNP and gene expression levels in colorectal cancer patients. These results suggest that in 3R/3R patients, the G > C polymorphism may be an important factor in determining TS mRNA expression levels, and warrant further investigation of the role of TS promoter polymorphisms as predictors of sensitivity to 5-FU-based chemotherapy in larger case series.
胸苷酸合成酶（TS）的肿瘤内表达可能是一种预后标志物，并可预测结直肠癌患者基于5-氟尿嘧啶（5-FU）化疗的疗效。TS基因启动子增强子区域包含两种不同的多态性，它们可影响TS mRNA的转录和翻译效率：一种多态性串联重复序列（2或3个重复；2R和3R）以及3R等位基因第二个重复序列内的单核苷酸多态性（SNP），G>C。我们研究了48例结直肠癌患者结肠黏膜中肿瘤TS mRNA表达水平与TS基因多态性之间的关系。与2R/2R-2R/3R基因型相比，3R/3R基因型的肿瘤TS mRNA水平更高（P = 0.071）。关于与SNP多态性的关系，观察到3RG/3RG基因型与2R/2R-2R/3RC-2R/3RG基因型亚组之间TS基因表达存在统计学显著差异（P = 0.017）。在所研究的相对较小的患者系列中，实验数据与基线临床病理特征以及临床结局之间未观察到统计学显著相关性。这是第一项报道结直肠癌患者TS重复序列内SNP与基因表达水平之间存在关联的研究。这些结果表明，在3R/3R患者中，G>C多态性可能是决定TS mRNA表达水平的重要因素，并且有必要在更大的病例系列中进一步研究TS启动子多态性作为基于5-FU化疗敏感性预测指标的作用。
