Infection and Cancer Group, School of Medicine, Universidad de Antioquia, Carrera 51D No 62-29, 050010, Medellín, Colombia.
Centre for Cancer Prevention, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
Eur J Nutr. 2024 Mar;63(2):563-572. doi: 10.1007/s00394-023-03289-4. Epub 2023 Dec 21.
To our knowledge, there are very few studies evaluating if the levels of folate modify the risk of cervical intraepithelial neoplasia grade 2 and higher (CIN2+ and CIN3+) associated with the levels of HPV genome methylation, two cofactors related to single carbon metabolism and independently associated with cervical cancer in previous studies. We conducted a case-control study nested in a three-arm randomized clinical pragmatic trial (ASCUS-COL trial) to evaluate the risk of CIN3+ associated with methylation levels according to serum folate concentrations.
Cases (n = 155) were women with histologically confirmed CIN2+ (113 CIN2, 38 CIN3, and 4 SCC) and controls were age and follow-up time at diagnosis-matched women with histologically confirmed ≤ CIN1 (n = 155), selected from the 1122 hrHPV + women of this trial. The concentrations of serum folate were determined by the radioimmunoassay SimulTRAC-SNB-VitaminB12/Folate-RIAKit and the methylation levels by the S5 classifier. Stepwise logistic regression models were used to estimate the association between folate or methylation levels and CIN2+ or CIN3+. The joint effect of folate levels and methylation on the risk of CIN3+ was estimated using combinations of categorical stratifications.
Folate levels were significantly lower in women with CIN3+ than in other diagnostic groups (p = 0.019). The risk of CIN3+ was eight times higher (OR 8.9, 95% CI 3.4-24.9) in women with folate deficiency and high methylation levels than in women with normal folate and high methylation levels (OR 1.4, 95% CI 0.4-4.6).
High methylation and deficient folate independently increased the risk of CIN3+ while deficient folate combined with high methylation was associated with a substantially elevated risk of CIN3+.
据我们所知，评估叶酸水平是否会改变与 HPV 基因组甲基化水平相关的宫颈上皮内瘤变 2 级及以上（CIN2+和 CIN3+）风险的研究非常少，这两个因素都与单碳代谢有关，并且在之前的研究中与宫颈癌独立相关。我们进行了一项病例对照研究，该研究嵌套在一项三臂随机临床实用试验（ASCUS-COL 试验）中，以评估根据血清叶酸浓度与 HPV 基因组甲基化水平相关的 CIN3+的风险。
病例组（n=155）为组织学确诊为 CIN2+的女性（113 例 CIN2、38 例 CIN3 和 4 例 SCC），对照组为组织学确诊为≤CIN1 的年龄和随访时间匹配的女性（n=155），均来自该试验的 1122 例 hrHPV+女性。血清叶酸浓度采用放射免疫分析法 SimulTRAC-SNB-VitaminB12/Folate-RIAKit 测定，甲基化水平采用 S5 分类器测定。采用逐步逻辑回归模型估计叶酸或甲基化水平与 CIN2+或 CIN3+之间的关联。采用分类分层组合的方法估计叶酸水平和甲基化水平对 CIN3+风险的联合作用。
CIN3+女性的叶酸水平明显低于其他诊断组（p=0.019）。叶酸缺乏和高甲基化水平的女性 CIN3+的风险是叶酸正常和高甲基化水平女性的 8 倍（OR 8.9，95%CI 3.4-24.9）（OR 1.4，95%CI 0.4-4.6）。
高甲基化和叶酸缺乏独立增加了 CIN3+的风险，而叶酸缺乏与高甲基化相结合与 CIN3+的风险显著升高有关。
