Mucosal alpha-papillomaviruses are not associated with esophageal squamous cell carcinomas: Lack of mechanistic evidence from South Africa, China and Iran and from a world-wide meta-analysis

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• 作者：Gordana Halec ; Markus Schmitt ; Sam Egger ; Christian C. Abnet ; Chantal Babb ; Sanford M. Dawsey ; Christa Flechtenmacher ; Tarik Gheit ; Martin Hale ; Dana Holzinger ; Reza Malekzadeh ; Philip R. Taylor ; Massimo Tommasino ; Margaret I. Urban ; Tim Waterboer ; Michael Pawlita ; Freddy Sitas and on behalf of the InterSCOPE Collaboration
• 关键词：esophageal cancer ; human papillomavirus ; HPV RNA ; serology ; HPV-transformed phenotype ; p16INK4 ; meta-analysis
• 刊名：International Journal of Cancer
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：139
• 期：1
• 页码：85-98
• 全文大小：318K
• ISSN：1097-0215

文摘

Epidemiological and mechanistic evidence on the causative role of human papillomaviruses (HPV) in esophageal squamous cell carcinoma (ESCC) is unclear. We retrieved alcohol- and formalin-fixed paraffin-embedded ESCC tissues from 133 patients seropositive for antibodies against HPV early proteins, from high-incidence ESCC regions: South Africa, China and Iran. With rigorous care to prevent nucleic acid contamination, we analyzed these tissues for the presence of 51 mucosotropic human alpha-papillomaviruses by two sensitive, broad-spectrum genotyping methods, and for the markers of HPV-transformed phenotype: (i) HPV16/18 viral loads by quantitative real-time PCR, (ii) type-specific viral mRNA by E6*I/E6 full-length RT-PCR assays and (iii) expression of cellular protein p16<sup>INK4asup>. Of 118 analyzable ESCC tissues, 10 (8%) were positive for DNA of HPV types: 16 (4 tumors); 33, 35, 45 (1 tumor each); 11 (2 tumors) and 16, 70 double infection (1 tumor). Inconsistent HPV DNA+ findings by two genotyping methods and negativity in qPCR indicated very low viral loads. A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16<sup>INK4asup> negative (HPV16 E1 seropositive patient). Another HPV16 DNA+ tumor from an HPV16 E6 seropositive patient showed p16<sup>INK4asup> upregulation but no HPV16 mRNA. In the tumor tissues of these serologically preselected ESCC patients, we did not find consistent presence of HPV DNA, HPV mRNA or p16<sup>INK4asup> upregulation. These results were supported by a meta-analysis of 14 other similar studies regarding HPV-transformation of ESCC. Our study does not support the etiological role of the 51 analyzed mucosotropic HPV types in the ESCC carcinogenesis.