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Open Access Highly Accessed Research article

HPV type-related chromosomal profiles in high-grade cervical intraepithelial neoplasia

Mariska Bierkens1, Saskia M Wilting1, Wessel N van Wieringen23, Mark A van de Wiel2, Bauke Ylstra1, Chris JLM Meijer1, Peter JF Snijders1 and Renske DM Steenbergen1*

Author Affiliations

1 Department of Pathology, Unit of Molecular Pathology, VU University Medical Center, PO box 7057, 1007 MB Amsterdam, The Netherlands

2 Epidemiology & Biostatistics, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands

3 Department of Mathematics, VU University, de Boelelaan 1081A, 1081 HV Amsterdam, The Netherlands

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BMC Cancer 2012, 12:36  doi:10.1186/1471-2407-12-36

Published: 24 January 2012

Abstract

Background

The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected.

Methods

Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (≥ 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58.

Results

Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2).

Conclusions

Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.

Keywords:
Array CGH; Cervical cancer; Chromosomal aberrations; High-grade cervical intraepithelial neoplasia; HPV