Ramachandran Dhanya, Mao Qianqian, Liao Dandan, Kamal Maud, Schürmann Peter, Eisenblätter Rieke, Geffers Robert, Balint Balazs, Lecompte Lolita, Servant Nicolas, Chérif Linda Larbi, Lamy Constance, Baulande Sylvain, Legoix Patricia, Le Tourneau Christophe, Latouche Aurélien, Hillemanns Peter, Scholl Suzy, Dörk Thilo
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Department of Drug Development and Innovation (D3i), Institut Curie, Paris and Saint-Cloud, France.
Mol Carcinog. 2025 Jan;64(1):14-24. doi: 10.1002/mc.23822. Epub 2024 Oct 1.
The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high-grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT 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-wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to TERT-CLPTM1L) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the TERT promoter region and 3 CpG islands nearby, and 21 CpG sites within CLPTM1L in 190 bisulfite-converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within TERT 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 (p < 9.4 × 10E-5). Hypermethylation at chr5:1289663 correlated with decreased TERT mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal CLPTM1L levels and with the absence of TERT mRNA in HPV-negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased CLPTM1L and TERT levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both TERT and CLPTM1L as genes modulated by genomic background and HPV infection during cervical cancer development.
端粒酶的逆转录酶亚基TERT在子宫颈高级别发育异常和浸润性癌中经常被激活。通过TERT启动子低甲基化激活端粒酶有望成为宫颈癌进展的生物标志物，然而，与宫颈癌风险相关的特定CpG位点仍有待完全明确。最近一项关于宫颈癌的全基因组关联研究确定了5p13.33（靠近TERT-CLPTM1L）的基因多态性，但其潜在机制尚未确定。我们对来自BioRAIDs（NCT02428842）的190个经亚硫酸氢盐转化的宫颈肿瘤DNA样本中的TERT启动子区域内的529个CpG位点和附近的3个CpG岛，以及CLPTM1L内的21个CpG位点进行了研究。我们在TERT内含子2中确定了8个CpG位点，在多次检验校正后，这些位点的甲基化与宫颈肿瘤中宫颈癌风险变异rs27070和rs459961的基因型显著相关（p < 9.4 × 10E-5）。chr5:1289663处的高甲基化与TERT mRNA水平降低相关。在一个由188个正常或发育异常宫颈组织组成的独立系列中，rs27070和rs459961的罕见等位基因与低基础CLPTM1L水平以及HPV阴性样本中TERT mRNA的缺失相关，这与其作为宫颈癌保护变异的作用一致。HPV感染与CLPTM1L和TERT水平升高相关。总体而言，我们的结果提供了宫颈癌风险变异、甲基化和基因表达之间的联系，并表明TERT和CLPTM1L都是在宫颈癌发展过程中受基因组背景和HPV感染调节的基因。
