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Folate deficiency modifies the risk of CIN3+ associated with DNA methylation levels: a nested case–control study from the ASCUS-COL trial

2023; Springer Science+Business Media; Volume: 63; Issue: 2 Linguagem: Inglês

10.1007/s00394-023-03289-4

1436-6215

María Cecilia Agudelo, Samuel Agudelo, Attila T. Lörincz, Arianis Tatiana Ramírez, Kelly Melisa Castañeda, Isabel Palacio, Arnold H. Zea, Chandrika J. Piyathilake, Gloria Inés Sánchez,

Urinary and Genital Oncology Studies

Abstract Purpose 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. Methods 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. Results 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). Conclusion 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+.