Department of Pathology, Unit of Molecular Pathology, VU University Medical Center, PO box 7057, 1007 MB Amsterdam, The Netherlands.
BMC Cancer. 2012 Jan 24;12:36. doi: 10.1186/1471-2407-12-36.
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.
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.
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).
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.
宫颈癌及其高级别前体病变（宫颈上皮内瘤变 2/3 级 [CIN2/3]）的发展是由高危型人乳头瘤病毒（hrHPV）持续感染和（表观）遗传宿主细胞异常积累引起的。流行病学研究表明，不同 hrHPV 类型的 CIN2/3 和癌症风险存在差异。最近的基因组分析研究显示，在形态上无法区分的 CIN2/3 中，染色体异常存在显著的异质性，提示癌症风险存在差异。本研究旨在探讨不同 hrHPV 类型的 CIN2/3 是否在染色体谱方面存在差异，包括异常数量和受影响的染色体部位。
对长期（≥ 5 年）感染 hrHPV 的女性的 43 例 p16INK4a 免疫阳性 CIN2/3 进行了染色体谱分析。其中 16 例病变携带 HPV16，3 例携带 HPV18，14 例携带 HPV31，1 例携带 HPV33，4 例携带 HPV45，1 例携带 HPV51，2 例携带 HPV52，2 例携带 HPV58。
染色体谱的无监督层次聚类分析显示，存在两个主要聚类，分别以染色体异常数量少或多为特征。大多数 87.5%的 HPV16 病变位于染色体异常数量相对较少的聚类中，而其他 hrHPV 类型的病变则没有这种不平衡分布。对该数据集的两种最常见类型（HPV16 和 HPV31）进行分析，结果显示 HPV31 阳性病变的缺失数量是 HPV16 阳性病变的三倍。特别是，HPV31 阳性病变中染色体 2q、4p、4q、6p、6q、8q 和 17p 的缺失以及 1p 和 1q 的增益明显更为频繁（FDR < 0.2）。
CIN2/3 的染色体异常至少部分与存在的 hrHPV 类型有关。HPV16 阳性 CIN2/3 中观察到的染色体异常数量较少，表明这些病变的发展较少依赖于遗传损伤，而不是由 HPV31 等其他类型引起的。
