EGFR mutations and human papillomavirus in lung cancer
Introduction
Human papillomavirus (HPV) is a well-established risk factor of cervical cancer [1]. HPV types 16 and 18 are classified as carcinogenic to humans (Group 1) by International Agency for Research on Cancer [2], and these HPV types were also detected in a part of lung cancer [3]. In spite of many studies reporting the HPV presence, its role in lung carcinogenesis is still unclear. Although HPV-16 integration in host genome has been reported in the most of HPV-16-positive lung squamous cell carcinomas (SQCs) [4], its low viral load makes it difficult to determine the etiological significance.
A Taiwanese study reported a significant association between HPV-16/18 and lung adenocarcinomas (ACs) among nonsmoking female patients [5]. We also reported a higher prevalence of high-risk HPV in ACs (30%, 9/30) than that of SQCs (7%, 2/27) [6]. Furthermore, high-risk HPV genome was more frequently observed in lung ACs with response to gefitinib (75%, 6/8) than that of those without response to the treatment (0%, 0/12) [6].
Clinical responsiveness to gefitinib is associated with somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene [7], [8], which are most frequently observed in lung ACs of non-smoking women in far-East Asian countries [9]. It is worth noting that these clinicopathological features, non-smoking female lung ACs, are similar to that observed in the Taiwanese study [5].
In the present study, we investigated the association between EGFR mutations and the presence of HPV DNA in Japanese lung cancer. Furthermore, viral load and physical status of high-risk HPV-16 were examined.
Section snippets
Clinical specimens
The present study examined a total of 42 paraffin-embedded tissue samples of lung cancer cases, including 26 ACs, 12 SQCs and 4 other histological types, diagnosed at Kagoshima University Hospital during the period from December 2007 to December 2008. Institutional Review Boards of Kagoshima University Hospital, Japan, approved the present study.
HPV detection, typing and physical status
The HPV genome was detected by PCR with broad-spectrum SPF10-biotinylated primers [10]. HPV typing was performed using the INNO-LiPA HPV Genotyping CE
Results
Among 42 lung tumors, 13 cases (31%) had mutations in either exon 19 or 21 of the EGFR gene (Table 1). Exon 19 deletion and exon 21 L858R were detected in 7 (54%) and 6 (46%) out of 13 mutations, respectively. These mutations were mutually exclusive. The frequency of the mutations was significantly higher in smaller tumors (Table 1, P = 0.043).
HPV DNA was detected in 7/42 (17%) lung tumors (Table 1). HPV-16 was the most frequently detected type (n = 5). High-risk HPV-58 was detected in the
Discussion
The present study showed a significant association between high-risk HPV detection and EGFR mutations in Japanese lung cancer cases (P = 0.021). Similar results were described in a Taiwanese study [14]. On the other hand, EGFR mutations were quite rare in cervical cancer [15], and the EGFR mutations were not related to HPV presence in SQCs of the tongue and tonsil [16]. These findings suggest that the association between EGFR mutations and HPV presence is restricted to lung cancer.
HPV-16
Conflict of interest
None declared.
Acknowledgements
This study was supported by Grants-in-Aid for Scientific Research on Priority Areas (17015037) of the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Ms. Yoshie Minakami for excellent technical work and Joint Research Laboratory, Kagoshima University Graduate School of Medical and Dental Sciences, for the use of their facilities.
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