Halec Gordana, Alemany Laia, Lloveras Belen, Schmitt Markus, Alejo Maria, Bosch Franz X, Tous Sara, Klaustermeier Jo Ellen, Guimerà Nuria, Grabe Niels, Lahrmann Bernd, Gissmann Lutz, Quint Wim, Bosch Francesc X, de Sanjose Silvia, Pawlita Michael
Division of Genome Modifications and Carcinogenesis, Infections and Cancer Program, German Cancer Research Center, Heidelberg, Germany.
J Pathol. 2014 Dec;234(4):441-51. doi: 10.1002/path.4405. Epub 2014 Sep 12.
Eight HPV types (HPV26, 53, 66, 67, 68, 70, 73 and 82) that are phylogenetically closely related to 12 WHO-defined high-risk (HR) HPV have been rarely but consistently identified as single HPV infections in about 3% of cervical cancer (CxCa) tissues. Due to lack of biological data, these types are referred to as probable/possible (p) HR-HPV. To analyse their biological activity in direct comparison to HR-HPV types, we selected 55 formalin-fixed, paraffin-embedded (FFPE) CxCa tissues harbouring single pHR-HPV infections (2-13 cases per type) and 266 tissues harbouring single HR-HPV (7-40 cases per type) from a worldwide, retrospective, cross-sectional study. Single HPV infection was verified by two genotyping methods. Presence of type-specific spliced E6I mRNA transcripts and expression of cellular proteins indicative of HPV transformation were assessed in all cases. In 55 CxCa tissues with pHR-HPV, E6I mRNA expression was 100%; high p16(INK4a) , 98%; low pRb, 96%; low CyD1, 93%; and low p53, 84%. Compared to HPV16 tissues as a reference, individual frequencies of these five markers did not differ significantly, either for any of the eight pHR-HPV and the 11 other HR types individually or for the groups of pHR and HR types without HPV16. We conclude that the eight pHR-HPV types, when present as a single infection in CxCa, are biologically active and affect the same cellular pathways as any of the fully recognized carcinogenic HR-HPV types. Therefore we have provided molecular evidence of carcinogenicity for types currently classified as probably/possibly carcinogenic. Although this evidence is crucial for HPV-type carcinogenicity classification, per se it is not sufficient for inclusion of these HPV types into population-wide primary and secondary prevention programmes. Such decisions have to include careful estimation of effectiveness and cost-benefit analyses.
8种与世界卫生组织定义的12种高危（HR）人乳头瘤病毒（HPV）在系统发育上密切相关的HPV类型（HPV26、53、66、67、68、70、73和82），在约3%的宫颈癌（CxCa）组织中很少但一直被鉴定为单一HPV感染。由于缺乏生物学数据，这些类型被称为可能/潜在（p）HR-HPV。为了直接与HR-HPV类型比较分析它们的生物学活性，我们从一项全球范围的回顾性横断面研究中选取了55例福尔马林固定、石蜡包埋（FFPE）的CxCa组织，这些组织中存在单一pHR-HPV感染（每种类型2 - 13例）以及266例存在单一HR-HPV感染的组织（每种类型7 - 40例）。通过两种基因分型方法验证单一HPV感染。在所有病例中评估了特定类型的剪接E6I mRNA转录本的存在情况以及指示HPV转化的细胞蛋白的表达。在55例存在pHR-HPV的CxCa组织中，E6I mRNA表达为100%；高p16(INK4a)为98%；低pRb为96%；低CyD1为93%；低p53为84%。以HPV16组织作为参照，这五个标志物的个体频率，无论是对于8种pHR-HPV中的任何一种以及11种其他HR类型单独而言，还是对于不含HPV16的pHR和HR类型组而言，均无显著差异。我们得出结论，这8种pHR-HPV类型在CxCa中作为单一感染存在时具有生物学活性，并且与任何一种完全公认的致癌性HR-HPV类型一样影响相同的细胞途径。因此，我们为目前分类为可能/潜在致癌的类型提供了致癌性的分子证据。尽管这一证据对于HPV类型致癌性分类至关重要，但就其本身而言，并不足以将这些HPV类型纳入全人群一级和二级预防计划。此类决策必须包括对有效性的仔细评估和成本效益分析。
