Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas

Wilting, Saskia M.; Steenbergen, Renske D.M.; Tijssen, Marianne; Wieringen, Wessel N. van; Helmerhorst, Theo J.M.; Kemenade, Folkert J. van; Bleeker, Maaike; Wiel, Mark A. van de; Carvalho, Beatriz; Meijer, Gerrit A.; Ylstra, Bauke; Meijer, Chris J.L.M.; Snijders, Peter J.F.

doi:10.1158/0008-5472.can-08-2478

Cited by 50 publications

(53 citation statements)

References 55 publications

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“…For end-point measure CIN2 þ cytology and the combination of cytology and HPV 16/18 genotyping performed slightly better than the methylation panel. Possible reasons for low methylation levels in these cases could be sampling error, the presence of early onset CIN3 lesions with few chromosomal abnormalities (38), or CIN2 lesions representing productive hrHPV infections with a low risk to progress to invasive cancer till the next screening round after 5 years.…”

Section: Discussionmentioning

confidence: 99%

Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women

Hesselink

Heideman

Steenbergen

et al. 2011

Clinical Cancer Research

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128

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Purpose: Screening women for high-grade cervical intraepithelial neoplasia or cervical cancer (CIN3 þ ) by high-risk human papillomavirus (hrHPV) testing has as side-effect the detection of hrHPV-positive women without clinically relevant lesions. Here, we developed an objective assay assessing the methylation status of the promoter regions of CADM1 and MAL to triage hrHPV-positive women for CIN3 þ .Experimental Design: In a training set (51 women with CIN3 þ and 224 without CIN2 þ ), panels consisting of one to four quantitative methylation-specific PCR (qMSP) assays (CADM1-m12,CADM1-m18,MAL-m1,MAL-m2) were analyzed. Cross-validated receiver-operating characteristics (ROC) curves were constructed and the panel with highest partial cross-validated area under the curve (AUC) was used for validation in an independent set of 236 consecutive hrHPV-positive women from a screening cohort. In the validation set, the ROC curve of the panel was compared with CIN3 þ sensitivity and specificity of cytology and of cytology combined with HPV16/18 genotyping. Results: In the training set, CADM1-m18 combined with MAL-m1 was the best panel (cross-validated partial AUC ¼ 0.719). In the validation set, this panel revealed CIN3 þ sensitivities ranging from 100%

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Section: Discussionmentioning

confidence: 99%

Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women

Hesselink

Heideman

Steenbergen

et al. 2011

Clinical Cancer Research

Self Cite

128

183

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“…25 --28 In cervical cancer we previously showed that particularly gains on chromosomes 1, 3q and 20q may be involved in malignant progression. 29 Integration of chromosomal alterations with miRNA expression may further clarify the functional role of frequent chromosomal alterations and aid in the identification of novel potential tumour suppressors and oncogenes in cervical carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Genome-wide miRNA expression profiles of micro-dissected specimens of normal squamous epithelium, CIN2 --3, SCCs and AdCAs were obtained and directly integrated with previously generated chromosomal profiles of the same samples. 29,30 Functional effects of altered expression of hsa-miR-9, which was associated with a frequent chromosomal gain, were further investigated in vitro.…”

Section: Introductionmentioning

confidence: 99%

Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis

et al. 2012

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Little is known about the alterations in microRNA (miRNA) expression patterns during the consecutive stages of cervical cancer development and their association with chromosomal instability. In this study, miRNA expression in normal cervical squamous epithelium, high-grade precancerous lesions (cervical intraepithelial neoplasia (CIN2-3)), squamous cell carcinomas (SCCs) and adenocarcinomas (AdCAs) was integrated with previously generated chromosomal profiles of the same samples. Significantly differential expression during the consecutive stages of cervical SCC development was observed for 106 miRNAs. Of these differentially expressed miRNAs, 27 showed early transiently altered expression in CIN2-3 lesions only, 46 miRNAs showed late altered expression in SCCs only and 33 showed continuously altered expression in both CIN2-3 and SCCs. Altered expression of five significantly differentially expressed miRNAs, hsa-miR-9 (1q23.2), hsa-miR-15b (3q25.32), hsa-miR-28-5p (3q27.3), hsa-miR-100 and hsa-miR-125b (both 11q24.1), was directly linked to frequent chromosomal alterations. Functional analyses were performed for hsa-miR-9, representing a potential oncogene with increased expression linked to a chromosomal gain of 1q. Hsa-miR-9 overexpression was found to increase cell viability, anchorage-independent growth and migration in vitro. Upon organic raft culturing, hsa-miR-9 hampered differentiation and induced proliferation in all strata of the epithelial layer. These findings support a potential oncogenic function of hsa-miR-9 in cervical cancer. In summary, differential expression of 106 miRNAs, partly associated with chromosomal alterations, was observed during cervical SCC development. Altered expression of hsa-miR-9 associated with a chromosomal gain of chromosome 1q was shown to be functionally relevant, underlining the importance of deregulated miRNA expression in cervical carcinogenesis.

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“…The possibility that the genotypes detected could be influenced by allelic somatic losses in the dysplastic cervical epithelium seems rather unlikely. First, cytologic specimens used in this study comprised cells from the whole uterine cervix, including both dysplastic and normal cells, and second, comparative genomic hybridization experiments have demonstrated that the entire or fragments of chromosome 1, where the FcGR3A locus is present, have not been found to be affected by loses in SIL or CC [30]. FcGR3A gene is not subjected to genetic rearrangements as those happening in IgH and TCR genes during B-and T-cell lymphocyte maturation, respectively.…”

Section: Discussionmentioning

confidence: 99%

Association of polymorphism in FcGR3A gene and progression of low-grade precursor lesions of cervical carcinoma

et al. 2010

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Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas

Cited by 50 publications

References 55 publications

Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women

Combined Promoter Methylation Analysis of CADM1 and MAL: An Objective Triage Tool for High-Risk Human Papillomavirus DNA–Positive Women

Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis

Association of polymorphism in FcGR3A gene and progression of low-grade precursor lesions of cervical carcinoma

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