Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray
{"title":"EPB41L3、HTERT和FAM19A4的单个CpG位点的DNA甲基化有助于检测宫颈高级别鳞状上皮内病变（HSIL）或更严重的病变：对单个 CpG 位点的分析优于平均分析。","authors":"Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray","doi":"10.1016/j.tvr.2024.200288","DOIUrl":null,"url":null,"abstract":"<div><p>Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.</p><p>Methylation of <em>EPB41L3</em> (1–6 CpG-sites), <em>hTERT</em> (1–10 CpG-sites) and <em>FAM19A4</em> (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for <em>FAM19A4</em> directed to the first exon region not explored previously.</p><p>In clinician-collected samples, methylation at CpG-sites 4 and 5 of <em>EPB41L3</em> were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of <em>EPB41L3</em> sites 2/4 plus <em>FAM19A4</em> site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].</p><p>Methylation at CpG-site 5 of <em>FAM19A4</em> was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of <em>FAM19A4</em> for cancer (0.77). Combined, <em>FAM19A4</em> site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.</p><p>In conclusion, methylation at individual CpG-sites of <em>EPB41L3</em> and <em>FAM19A4</em> outperformed global analysis and improved HSIL+ detection, warranting further investigation.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200288"},"PeriodicalIF":4.7000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000120/pdfft?md5=211b8be54b2e08277c81b68123f37b1d&pid=1-s2.0-S2666679024000120-main.pdf","citationCount":"0","resultStr":"{\"title\":\"DNA methylation at individual CpG-sites of EPB41L3, HTERT and FAM19A4 are useful for detection of cervical high-grade squamous intraepithelial lesions (HSIL) or worse: Analysis of individual CpG-sites outperforms averaging\",\"authors\":\"Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray\",\"doi\":\"10.1016/j.tvr.2024.200288\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.</p><p>Methylation of <em>EPB41L3</em> (1–6 CpG-sites), <em>hTERT</em> (1–10 CpG-sites) and <em>FAM19A4</em> (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for <em>FAM19A4</em> directed to the first exon region not explored previously.</p><p>In clinician-collected samples, methylation at CpG-sites 4 and 5 of <em>EPB41L3</em> were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of <em>EPB41L3</em> sites 2/4 plus <em>FAM19A4</em> site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].</p><p>Methylation at CpG-site 5 of <em>FAM19A4</em> was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of <em>FAM19A4</em> for cancer (0.77). Combined, <em>FAM19A4</em> site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.</p><p>In conclusion, methylation at individual CpG-sites of <em>EPB41L3</em> and <em>FAM19A4</em> outperformed global analysis and improved HSIL+ detection, warranting further investigation.</p></div>\",\"PeriodicalId\":52381,\"journal\":{\"name\":\"Tumour Virus Research\",\"volume\":\"18 \",\"pages\":\"Article 200288\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2666679024000120/pdfft?md5=211b8be54b2e08277c81b68123f37b1d&pid=1-s2.0-S2666679024000120-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Tumour Virus Research\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2666679024000120\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"VIROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tumour Virus Research","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666679024000120","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"VIROLOGY","Score":null,"Total":0}
DNA methylation at individual CpG-sites of EPB41L3, HTERT and FAM19A4 are useful for detection of cervical high-grade squamous intraepithelial lesions (HSIL) or worse: Analysis of individual CpG-sites outperforms averaging
Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.
Methylation of EPB41L3 (1–6 CpG-sites), hTERT (1–10 CpG-sites) and FAM19A4 (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for FAM19A4 directed to the first exon region not explored previously.
In clinician-collected samples, methylation at CpG-sites 4 and 5 of EPB41L3 were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].
Methylation at CpG-site 5 of FAM19A4 was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of FAM19A4 for cancer (0.77). Combined, FAM19A4 site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.
In conclusion, methylation at individual CpG-sites of EPB41L3 and FAM19A4 outperformed global analysis and improved HSIL+ detection, warranting further investigation.
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