Abstract
Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer.
Highlights
Lung cancer accounts for over a million deaths worldwide each year [1]
The retrospective Central Europe study contributed the largest number of participants (n 1⁄4 3,321), followed by the European Prospective Investigation into Cancer and Nutrition (EPIC) nested case–control study (n 1⁄4 3,048)
In determining the causal association between human papillomavirus (HPV) infection and lung cancer, we considered the expression of HPV E6 mRNA as the gold standard
Summary
Lung cancer accounts for over a million deaths worldwide each year [1]. smoking is the most important risk factor, lung cancer occurs in never smokers with high rates reported among women in south Asia [2, 3]. The few studies on the expression of HPV oncogenes in lung tumors have been inconclusive [14,15,16] These limitations led the International Agency for Research on Cancer (IARC; Lyon, France) Monograph expert group to conclude that there was limited evidence for the carcinogenicity of HPV to the lung. To conclusively evaluate the causal role of HPV infection in lung cancer, we have (i) examined the association between type-specific HPV antibodies and lung cancer risk in multiple series of lung cancer cases and controls; (ii) tested lung tumors for the presence of HPV genomes of all high-risk types and two low-risk types using rigorous precautions against potential contamination; (iii) assessed the expression of p16 protein; and (iv) examined the transcriptional state of the HPV oncogene E6
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