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Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions

Key Points

  • Cervical intraepithelial neoplasia (CIN) lesions can be divided into productive (CIN1 and CIN2) and transforming (CIN2 and CIN3) lesions. Morphologically, productive CIN2 cannot be distinguished from transforming CIN2.

  • Transforming CIN reflects a heterogeneous disease. Early and advanced transforming CIN lesions, displaying a low and high short-term progression risk for cancer, respectively, can be distinguished on the basis of molecular host cell alterations.

  • When applied to cervical scrapings, specific methylation markers, such as cell adhesion molecule 1 (CADM1), myelin and lymphocyte (MAL) and mir-124-2, detect advanced transforming CIN and cancer with a high sensitivity.

  • CIN2/CIN3 lesions detected by specific methylation markers are in need of immediate treatment, given their high short-term progression risk for cancer.

  • Cytology detects morphological cellular abnormalities associated with CIN2, CIN3 and cancer with a moderate sensitivity, but may miss cancer and advanced transforming CIN with a high short-term progression risk for cancer.

  • Human papilloma virus (HPV) testing will replace cytology as the primary screening tool for cervical cancer.

  • Clinically validated panels of methylation markers, such as CADM1, MAL and mir-124-2, can be used as triage markers for HPV-positive women. Methylation marker panels with a high sensitivity for cancer have the potential to function as a primary screening tool.

  • DNA methylation marker panels may also be used for the management of women with CIN lesions to prevent overtreatment of CIN2/CIN3 lesions.

  • The compatibility of methylation markers with HPV testing and self-sampling has the potential for full molecular cervical screening in the near future.

Abstract

Infection of cervical epithelium with high-risk human papilloma virus (hrHPV) might result in productive or transforming cervical intraepithelial neoplasia (CIN) lesions, the morphology of which can overlap. In transforming CIN lesions, aberrations in host cell genes accumulate over time, which is necessary for the ultimate progression to cancer. On the basis of (epi)genetic changes, early and advanced transforming CIN lesions can be distinguished. This paves the way for new molecular tools for cervical screening, diagnosis and management of cervical cancer precursor lesions.

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Figure 1: HPV-mediated cervical carcinogenesis.
Figure 2: Cellular changes required for the progression of transforming cervical intraepithelial neoplasia (tCIN) to cancer.
Figure 3: Triage tools in cervical scrapings of human papilloma virus (HPV)-positive women.

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Acknowledgements

The research in the laboratory of R.D.M.S., P.J.F.S., D.A.M.H. and C.J.L.M.M. is supported by grants from the Dutch Cancer Society (KWF2007-3771, KWF2009-4413, KWF2009-4522 and KWF2010-4668), Zorgonderzoek Nederland-Medische Wetenschappen (ZON-MW), the European community Program Health-FP7 Program (PreHdIct FP7-Health 2009-24206- and CoheaHr-Health-F3-2013-603019) and the European Research Council (ERC advanced 2012-AdG, proposal 322986 Mass-care).

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Correspondence to Renske D. M. Steenbergen.

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Competing interests

C.J.L.M.M. has been a member of the scientific advisory board of Qiagen, has received speaker's fees from GlaxoSmithKline, Merck, and Roche and his institution has received board membership and consultancy fees from Qiagen. P.J.F.S. has received speaker's fees from Roche, Abbott, Qiagen, and Gen-Probe. P.J.F.S. and C.J.L.M.M. hold a patent for HPV detection by GP5+/6+ PCR through Qiagen, for which their institution has received honoraria. C.J.L.M.M., R.D.M.S., and P.J.F.S. hold a patent for promoter methylation of CADM1 as a specific marker for CIN grade 2 or 3 or cervical cancer through MdxHealth, for which their institution received honoraria. C.J.L.M.M., P.J.F.S., R.D.M.S., and D.A.M.H. are shareholders of Self-screen.

Supplementary information

41568_2014_BFnrc3728_MOESM177_ESM.pdf

Supplementary information S1 (table) | Summary of differentially expressed miRNAs in transforming cervical intraepithelial neoplasia (tCIN) compared to normal cervical biopsies (column 1) of which altered expression persists or increases in cervical squamous cell carcinomas (SCC). (PDF 253 kb)

41568_2014_BFnrc3728_MOESM178_ESM.pdf

Supplementary information S2 (table) | Summary of methylated gene promoters detected in abnormal cytological specimens with and/or without confirmed underlying CIN2+ lesion. (PDF 214 kb)

PowerPoint slides

Glossary

Epigenetic alterations

Changes in DNA methylation and chromatin that do not involve a change in the DNA sequence.

Cervical intraepithelial neoplasia

(CIN; also known as cervical dysplasia). A premalignant condition of the uterine cervix, which can be histologically subdivided into CIN1, CIN2 and CIN3.

Episomes

Extrachromosomal DNA elements that can replicate independently from host chromosomal DNA.

DNA methylation

The addition of a methyl group at a cytosine in a CpG dinucleotide pair. DNA methylation of CpG-rich areas in gene promoters can result in gene silencing.

(Micro)array comparative genomic hybridization

((Micro)arrayCGH). A platform on which DNA copy-number aberrations can be assessed at a genome-wide level in a single experiment.

Self-samples

Self (at home)-collected cervicovaginal specimens, collected using a lavage or brush-based sampler. The self-collected cells can be used for cervical cancer screening by human papilloma virus (HPV) detection and triage by methylation marker analysis.

Methylation marker panel

A panel of genes, most often involving gene promoter sequences, in which methylation of CpG sites represents a biomarker for a specific condition, such as a cancerous or precancerous lesion of the cervix.

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Steenbergen, R., Snijders, P., Heideman, D. et al. Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions. Nat Rev Cancer 14, 395–405 (2014). https://doi.org/10.1038/nrc3728

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