Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Int J Colorectal Dis. 2010 Feb;25(2):141-51. doi: 10.1007/s00384-009-0779-y. Epub 2009 Aug 11.
The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient outcome after treatment with 5-FU-based chemotherapy to determine the contribution of MTHFR genotypes in the risk of colorectal cancer (CRC) and in the response to therapy.
Genomic DNA of 143 Spanish sporadic CRC and 103 controls was analyzed by polymerase chain reaction/restriction fragment length polymorphism and sequencing.
The C677T polymorphism has protective effect on CRC showing TT genotype an odds ratios of 0.06 (95% confidence interval (CI): 0.10-0.32) and the CT of 0.51 (95% CI: 0.3-0.87). MTHFR A1298C polymorphism is not associated with CRC risk. Patients with 1298CC and AC genotypes exhibit worse survival than those with the wild genotype (log rank, p = 0.001), whereas C677T genotypes do not affect patient survival (log rank, p = 0.92). MTHFR 677T allele carriers responded better to 5-FU-based chemotherapy than patients with the wild CC genotype (log rank, p = 0.05). The variant C allele of A1298C affects negatively the response to 5-FU-based chemotherapy (log rank, p = 0.009).
The variant allele of the C677T has a protective effect on CRC development, whereas the variant allele of the A1298C does not produce any effect on disease risk. Both MTHFR polymorphisms are relevant and independent factors of patient outcome after 5FU-based treatment of CRC, and MTHFR genotyping may be of predictive benefit in selecting treatment regimens.
MTHFR 酶在叶酸代谢中起着重要作用，而叶酸在 DNA 甲基化、修复和合成中起着作用，因此与致癌作用有关。我们分析了 MTHFR C677T 和 A1298C 多态性与肿瘤的生物学、临床病理、遗传和表观遗传特征以及患者接受 5-FU 为基础的化疗后的结果之间的关系，以确定 MTHFR 基因型在结直肠癌（CRC）风险和对治疗的反应中的作用。
通过聚合酶链反应/限制性片段长度多态性和测序分析了 143 例西班牙散发性 CRC 和 103 例对照的基因组 DNA。
C677T 多态性对 CRC 具有保护作用，TT 基因型的比值比为 0.06（95%置信区间（CI）：0.10-0.32），CT 为 0.51（95%CI：0.3-0.87）。MTHFR A1298C 多态性与 CRC 风险无关。携带 1298CC 和 AC 基因型的患者的生存状况比野生型基因型差（对数秩检验，p = 0.001），而 C677T 基因型不影响患者的生存（对数秩检验，p = 0.92）。MTHFR 677T 等位基因携带者对 5-FU 为基础的化疗反应优于野生 CC 基因型的患者（对数秩检验，p = 0.05）。A1298C 的变体 C 等位基因对 5-FU 为基础的化疗反应产生负面影响（对数秩检验，p = 0.009）。
C677T 的变体等位基因对 CRC 的发生具有保护作用，而 A1298C 的变体等位基因对疾病风险没有影响。MTHFR 两个多态性都是 CRC 患者接受 5FU 为基础的治疗后的相关且独立的预后因素，MTHFR 基因分型可能有助于预测治疗方案的选择。
