Abderrahmane Rym, Louhibi Lotfi, Moghtit Fatima Zohra, Boubekeur Amina, Benseddik Khedidja, Boudjema Abdellah, Benrrahal Fouzia, Aberkane Meriem, Fodil Mostefa, Saidi-Mehtar Nadhira
Laboratoire de Génétique Moléculaire et Cellulaire, Département de Génétique Moléculaire Appliquée, Faculté des sciences de la nature et de la vie, Université des Sciences et de la Technologie d'Oran- Mohamed BOUDIAF-USTOMB, BP 1505 El M'naouer, 31000, Oran, Algeria,
Pathol Oncol Res. 2015 Jul;21(3):629-35. doi: 10.1007/s12253-014-9867-6. Epub 2014 Dec 24.
The tumor suppressor gene TP53 and its regulator MDM2 are both key players involved in multiple pathways including apoptosis, cellular transcriptional control and cell cycle regulation. Common germline polymorphisms in these genes may affect colorectal cancer (CRC) susceptibility. An arginine-to-proline substitution at codon 72 in the TP53 gene is reported to decrease apoptotic potential, while a thymine-to-guanine polymorphism at nucleotide 309 (named SNP309) of murine double minute 2 MDM2 gene increases its transcription. These two polymorphisms therefore may be of importance in colorectal carcinogenesis. The relation of these polymorphisms to colorectal cancer in the Algerian population was addressed in this study. DNA samples from 121 controls and 116 cases were genotyped for these two polymorphisms by PCR/RFLP then confirmed by sequencing. Unexpectedly no significant association was found between this potential marker TP53 Arg72Pro and CRC (p > 0.05). However, our findings reveal that individuals with the MDM2 SNP309 GG genotype have a low risk of CRC as compared to the TT genotype (OR = 0.49; 95 % CI: 0.24-0.98, p = 0.04), with more significance for females (OR = 0.16; 95 % CI: 0.06-0.41, p < 0.05). Moreover, no significant association was observed between the combined TP53 and MDM2 genotypes and CRC. Contrary to initial expectations that the GG genotype with high MDM2 levels would increase cancer risk, our results demonstrate that the MDM2 SNP309 GG genotype is associated with decreased risk of colorectal cancer. This is suggesting that other mechanisms independent of increased MDM2 levels can influence cancer susceptibility.
肿瘤抑制基因TP53及其调节因子MDM2都是参与多种途径的关键因子，这些途径包括细胞凋亡、细胞转录控制和细胞周期调控。这些基因中常见的种系多态性可能会影响结直肠癌（CRC）的易感性。据报道，TP53基因第72位密码子的精氨酸到脯氨酸的替换会降低细胞凋亡潜能，而鼠双微体2 MDM2基因第309位核苷酸（命名为SNP309）的胸腺嘧啶到鸟嘌呤的多态性会增加其转录。因此，这两种多态性可能在结直肠癌的发生过程中具有重要意义。本研究探讨了这些多态性与阿尔及利亚人群结直肠癌的关系。通过PCR/RFLP对121例对照和116例病例的DNA样本进行这两种多态性的基因分型，然后通过测序进行确认。出乎意料的是，在这个潜在标志物TP53 Arg72Pro与结直肠癌之间未发现显著关联（p > 0.05）。然而，我们的研究结果显示，与TT基因型相比，具有MDM2 SNP309 GG基因型的个体患结直肠癌的风险较低（OR = 0.49；95%CI：0.24 - 0.98，p = 0.04），对女性而言更具显著性（OR = 0.16；95%CI：0.06 - 0.41，p < 待办事项1: 完成翻译，此处p < 0.05）。此外，在TP53和MDM2联合基因型与结直肠癌之间未观察到显著关联。与最初认为具有高MDM2水平的GG基因型会增加癌症风险的预期相反，我们的结果表明MDM2 SNP309 GG基因型与结直肠癌风险降低相关。这表明独立于MDM2水平升高的其他机制可以影响癌症易感性。
