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Telomerase activation through hypomethylation of the <jats:italic>TERT<\/jats:italic> promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be fully defined. A recent genome\u2010wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to <jats:italic>TERT\u2010CLPTM1L<\/jats:italic>) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the <jats:italic>TERT<\/jats:italic> promoter region and 3 CpG islands nearby, and 21 CpG sites within <jats:italic>CLPTM1L<\/jats:italic> in 190 bisulfite\u2010converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within <jats:italic>TERT<\/jats:italic> intron 2 where methylation was significantly associated with the genotypes of cervical cancer risk variants rs27070 and rs459961 in cervical tumors after multiple testing correction (<jats:italic>p<\/jats:italic>\u2009&lt;\u20099.4\u2009\u00d7\u200910E\u22125). Hypermethylation at chr5:1289663 correlated with decreased <jats:italic>TERT<\/jats:italic> mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal <jats:italic>CLPTM1L<\/jats:italic> levels and with the absence of <jats:italic>TERT<\/jats:italic> mRNA in HPV\u2010negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased <jats:italic>CLPTM1L<\/jats:italic> and <jats:italic>TERT<\/jats:italic> levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both <jats:italic>TERT<\/jats:italic> and <jats:italic>CLPTM1L<\/jats:italic> as genes modulated by genomic background and HPV infection during cervical cancer development.<\/jats:p>","DOI":"10.1002\/mc.23822","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T14:09:15Z","timestamp":1727791755000},"page":"14-24","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Methylation, Gene Expression, and Risk Genotypes at the <i>TERT<\/i>\u2010<i>CLPTM1L<\/i> Locus in Cervical Cancer"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8139-7799","authenticated-orcid":false,"given":"Dhanya","family":"Ramachandran","sequence":"first","affiliation":[{"name":"Gynaecology Research Unit Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Mao","sequence":"additional","affiliation":[{"name":"Gynaecology Research Unit Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Liao","sequence":"additional","affiliation":[{"name":"Gynaecology Research Unit Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maud","family":"Kamal","sequence":"additional","affiliation":[{"name":"Department of Drug Development and Innovation (D3i) Institut Curie, Paris and Saint\u2010Cloud  France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Sch\u00fcrmann","sequence":"additional","affiliation":[{"name":"Gynaecology Research Unit Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rieke","family":"Eisenbl\u00e4tter","sequence":"additional","affiliation":[{"name":"Gynaecology Research Unit Hannover Medical School Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[{"name":"Genome Analytics, Helmholtz Center for Infection Research Braunschweig Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balazs","family":"Balint","sequence":"additional","affiliation":[{"name":"SeqOmics Biotechnology Ltd. 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