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Randomized Controlled Trial
. 2024 Mar;63(2):563-572.
doi: 10.1007/s00394-023-03289-4. Epub 2023 Dec 21.

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

María C Agudelo  1 , Samuel Agudelo  1 , Attila Lorincz  2 , Arianis Tatiana Ramírez  1   3 , Kelly Melisa Castañeda  1 , Isabel Garcés-Palacio  4 , Arnold H Zea  5 , Chandrika Piyathilake  6 , Gloria Ines Sanchez  7
Affiliations
Randomized Controlled Trial

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

María C Agudelo et al. Eur J Nutr. 2024 Mar.

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+.

Keywords: Cervical cancer; DNA methylation; Folate; HPV.

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Conflict of interest statement

Not conflict of interest by any of the authors is declared. The HC2-hrHPV DNA test was donated by QIAGEN©. The funders had no role in the data collection, analysis, or interpretation of the results.

Figures

Fig. 1
Fig. 1
Flowchart. This diagram indicates the number of women with ASC-US cytology included in the ASCUS-COL trial. We selected all CIN2+ cases diagnosed at any time during the clinical trial. Controls were selected among women of the trial that remained free of disease (negative and/or CIN1verified by colposcopy AND biopsy) during the study and 1:1 paired to cases by age and time to colposcopy/biopsy. Women were HPV tested at recruitment in the HPV arm only and samples collected from women of the other 2 arms were all blindly tested after close-out study visit. All cases and controls were selected among HPV positive women. All cases and controls have similar chance for follow-up and received diagnosis and treatment if required
Fig. 2
Fig. 2
Comparison of folate distribution. A Comparison among women ≤CIN2 and CIN3. B Comparison among women ≤ CIN1 and CIN3+
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