Cargando…

CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions

Background: Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Mos...

Descripción completa

Detalles Bibliográficos
Autores principales: del Pino, Marta, Sierra, Adriana, Marimon, Lorena, Martí Delgado, Cristina, Rodriguez-Trujillo, Adriano, Barnadas, Esther, Saco, Adela, Torné, Aureli, Ordi, Jaume
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539131/
https://www.ncbi.nlm.nih.gov/pubmed/31067838
http://dx.doi.org/10.3390/ijms20092262
_version_ 1783422313358688256
author del Pino, Marta
Sierra, Adriana
Marimon, Lorena
Martí Delgado, Cristina
Rodriguez-Trujillo, Adriano
Barnadas, Esther
Saco, Adela
Torné, Aureli
Ordi, Jaume
author_facet del Pino, Marta
Sierra, Adriana
Marimon, Lorena
Martí Delgado, Cristina
Rodriguez-Trujillo, Adriano
Barnadas, Esther
Saco, Adela
Torné, Aureli
Ordi, Jaume
author_sort del Pino, Marta
collection PubMed
description Background: Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Most HSIL/CIN2-3 are considered as transforming hrHPV infections, so truly CC precursors, although some clear spontaneously. hrHPV testing has a high sensitivity for the detection of HSIL/CIN2-3 but a relatively low specificity for identifying transforming lesions. We aimed to determine whether the combination of CADM1, MAL and miR124 promoter methylation status assessed in histological samples can be used as a biomarker in the identification of transforming HSIL/CIN lesions. Design: 131 cervical biopsies, including 8 cases with no lesion and a negative hrHPV test result (control group), 19 low-grade (L)SIL/CIN1, 30 HSIL/CIN2, 60 HSIL/CIN3, and 14 CC were prospectively collected. hrHPV was detected and genotyped using the polymerase chain reaction (PCR)-based technique SPF10 HPV LIPA. A multiplex quantitative methylation-specific PCR (qMSP) was used to identify the methylation status of the CADM1, MAL, and miR124 promoter genes. Results: Significantly higher methylation levels of CADM1, MAL and miR-124 were found in HSIL/CIN2-3 and CC compared with normal and LSIL lesions. DNA methylation of at least one gene was detected in 12.5% (1/8) of normal samples, 31.5% (6/19) of LSIL/CIN1, 83.3% (25/30) of HSIL/CIN2, 81.6% (49/60) of HSIL/CIN3 and 100% (14/14) of CC (p < 0.001). The sensitivity and specificity for HSIL/CIN2-3 and CC of having at least one methylated gene were 84.6% and 74.0%, respectively. The sensitivity and specificity of the combination of at least one methylated gene and a positive hrHPV test were 80.7% and 85.1% for HSIL/CIN2-3 and CC, respectively. Conclusions: The methylation rate of CADM1, MAL and miR124 increases with the severity of the lesion. Further research is warranted to evaluate the usefulness of these biomarkers for the identification of transforming HSIL/CIN.
format Online
Article
Text
id pubmed-6539131
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-65391312019-06-04 CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions del Pino, Marta Sierra, Adriana Marimon, Lorena Martí Delgado, Cristina Rodriguez-Trujillo, Adriano Barnadas, Esther Saco, Adela Torné, Aureli Ordi, Jaume Int J Mol Sci Article Background: Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Most HSIL/CIN2-3 are considered as transforming hrHPV infections, so truly CC precursors, although some clear spontaneously. hrHPV testing has a high sensitivity for the detection of HSIL/CIN2-3 but a relatively low specificity for identifying transforming lesions. We aimed to determine whether the combination of CADM1, MAL and miR124 promoter methylation status assessed in histological samples can be used as a biomarker in the identification of transforming HSIL/CIN lesions. Design: 131 cervical biopsies, including 8 cases with no lesion and a negative hrHPV test result (control group), 19 low-grade (L)SIL/CIN1, 30 HSIL/CIN2, 60 HSIL/CIN3, and 14 CC were prospectively collected. hrHPV was detected and genotyped using the polymerase chain reaction (PCR)-based technique SPF10 HPV LIPA. A multiplex quantitative methylation-specific PCR (qMSP) was used to identify the methylation status of the CADM1, MAL, and miR124 promoter genes. Results: Significantly higher methylation levels of CADM1, MAL and miR-124 were found in HSIL/CIN2-3 and CC compared with normal and LSIL lesions. DNA methylation of at least one gene was detected in 12.5% (1/8) of normal samples, 31.5% (6/19) of LSIL/CIN1, 83.3% (25/30) of HSIL/CIN2, 81.6% (49/60) of HSIL/CIN3 and 100% (14/14) of CC (p < 0.001). The sensitivity and specificity for HSIL/CIN2-3 and CC of having at least one methylated gene were 84.6% and 74.0%, respectively. The sensitivity and specificity of the combination of at least one methylated gene and a positive hrHPV test were 80.7% and 85.1% for HSIL/CIN2-3 and CC, respectively. Conclusions: The methylation rate of CADM1, MAL and miR124 increases with the severity of the lesion. Further research is warranted to evaluate the usefulness of these biomarkers for the identification of transforming HSIL/CIN. MDPI 2019-05-07 /pmc/articles/PMC6539131/ /pubmed/31067838 http://dx.doi.org/10.3390/ijms20092262 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
del Pino, Marta
Sierra, Adriana
Marimon, Lorena
Martí Delgado, Cristina
Rodriguez-Trujillo, Adriano
Barnadas, Esther
Saco, Adela
Torné, Aureli
Ordi, Jaume
CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions
title CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions
title_full CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions
title_fullStr CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions
title_full_unstemmed CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions
title_short CADM1, MAL, and miR124 Promoter Methylation as Biomarkers of Transforming Cervical Intrapithelial Lesions
title_sort cadm1, mal, and mir124 promoter methylation as biomarkers of transforming cervical intrapithelial lesions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539131/
https://www.ncbi.nlm.nih.gov/pubmed/31067838
http://dx.doi.org/10.3390/ijms20092262
work_keys_str_mv AT delpinomarta cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT sierraadriana cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT marimonlorena cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT martidelgadocristina cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT rodrigueztrujilloadriano cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT barnadasesther cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT sacoadela cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT torneaureli cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions
AT ordijaume cadm1malandmir124promotermethylationasbiomarkersoftransformingcervicalintrapitheliallesions