HPV and lung cancer risk: A meta-analysis

doi:10.1016/j.jcv.2014.09.014

Journal of Clinical Virology

Volume 63, February 2015, Pages 84-90

https://doi.org/10.1016/j.jcv.2014.09.014 Get rights and content

Highlights

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Whether HPV associated with lung cancer is quantified using a meta-analysis.
•
HPV increases risk of lung cancer, especially lung squamous cell carcinoma.
•
HPV might play a potential role in lung cancer progression.

Abstract

The potential causal association between human papillomavirus (HPV) and lung cancer (LC) remains controversial. We performed this meta-analysis to evaluate whether HPV infection in lung tissue is associated with LC compared with non-cancer controls. We also quantified this association in different LC subtypes. MEDLINE, EMBASE and Web of Science were searched through March 2014, using the search terms “lung cancer”, “human papillomavirus”, “HPV” and their combinations. Association was tested using odds ratio (OR) with 95% confidence intervals (95% CI). Heterogeneity was assessed using Q and I² statistic. Finally, nine studies, for a total of 1094 LCs and 484 non-cancer controls, were identified as eligible publications. The pooled results showed that HPV infection was associated with LC (OR = 5.67, 95% CI: 3.09–10.40, P < 0.001). Similar results were also observed in HPV16 and/or HPV18 (HPV16/18) infection analyses (OR = 6.02, 95% CI: 3.22–11.28, P < 0.001). HPV16/18 was significantly associated with lung squamous cell carcinoma (SCC) (OR = 9.78, 95% CI: 6.28–15.22, P < 0.001), while the pooled OR was 3.69 in lung adenocarcinoma (95% CI: 0.99–13.71, P = 0.052). Our results suggest that lung tissue with HPV infection has a strong association with LC, and especially, HPV16/18 infection significantly increases SCC risk, which indicates a potential pathogenesis link between HPV and LC.

Section snippets

Background

Lung cancer (LC) is the most common cause of cancer morbidity and mortality worldwide and in China. The pathogenesis of LC is believed to result from the interaction between environmental and genetic factors. Although smoking is the major etiologic factor, not all smokers develop LC, and approximately 25% of those with LC are never smokers [1]. Other etiologic factors, including passive smoking, occupational exposure to asbestos and certain metals, and air population have been implicated as

Objectives

The aim of this meta-analysis is to quantify the association between HPV infection in lung tissue and LC.

Search strategy

MEDLINE (PubMed), EMBASE (OVID) and Web of Science were searched to find relevant publications up to March 2014, using the search terms “lung cancer”, “human papillomavirus”, “HPV” and combinations thereof. The search was limited to studies that had been conducted on human subjects and written in English. Meeting abstracts were excluded because of limited data they offered. Reference lists of the retrieved articles, reviews and editorials were also screened to find all additional eligible

Eligible studies

Systematic searching was performed to identify all relevant and eligible studies (Supplementary Fig. 1). Using the search terms, 287 potential studies were identified from three databases, and 195 studies were required for further assessment. After reviewing the full text of the studies, 184 were excluded because of inappropriate study design or control samples. When two studies were published by the same authors with the same patients [22], [23], we selected the more recent and highest quality

Discussion

Since Syrjänen first suggestion in 1979 that HPV may be associated with LC, several studies have explored this relationship. However, the results of these studies have often been controversial. HPV DNA has been identified in the serum, plasma and peripheral blood mononuclear cells of cervical cancers, head and neck cancers, LCs and healthy subjects [33], [34], [35], [36]. These data indicate that blood circulation plays a vital role in HPV transmission. Based on many etiological studies, it is

Authors’ contribution

Conceived and designed the experiments: K. Zhai and H.Z. Shi. Performed the experiments: K. Zhai and J. Ding. Analyzed the data: K. Zhai, J. Ding and H.Z. Shi. Wrote the paper: K. Zhai, J. Ding and H.Z. Shi.

Funding

This work was supported by National Natural Science Foundation of China (No. 81302052) and Natural Science Foundation of Beijing (No. 7142061).

Competing interests

None.

Ethical approval

Not required.

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Cited by (46)

Microbes in lung cancer initiation, treatment, and outcome: Boon or bane?
2022, Seminars in Cancer Biology
Citation Excerpt :
In addition to the infections confined in one organ, several systemic infectious diseases also contribute to lung cancer. Surprisingly, despite that HPV has been considered a major reason for cervical cancer, the correlation of HPV infection with a higher risk of lung cancer also existed (OR:5.67; 95 % CI: 3.09–10.40) [50]. Moreover, HPV 16/18 infection was more correlated with LUSC (OR: 9.78; 95 % CI: 6.28–15.22) than adenocarcinoma (OR: 3.69; 95 % CI: 0.99–13.71) [50].
Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.
Human papillomavirus infection and lung adenocarcinoma: special benefit is observed in patients treated with immune checkpoint inhibitors
2022, ESMO Open
Human papilloma virus (HPV) has been associated with the development and modulation of response in a series of neoplasms. In the case of lung adenocarcinoma, its role in etiology and pathogenesis is still controversial. Considering that this infection brings foreign epitopes, it could be of prognostic significance in patients with lung adenocarcinoma treated with immunotherapy.
In a retrospective cohort study we evaluated the presence of HPV genomic material in lung adenocarcinoma primary lesions with the INNO-LiPA platform. Viral replication was also evaluated by detecting the presence of oncoprotein E6/E7 messenger RNA (mRNA) by quantitative RT-PCR. To confirm possible hypotheses regarding viral oncogenesis, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF1) were evaluated with stromal fibrosis and immunoscore.
A total of 133 patients were included in the analysis, of whom 34 tested positive for HPV, reaching an estimated prevalence of 25.6% [95% confidence interval (CI) 18.2% to 32.9%]. E6/7 mRNA was identified in 28 out of the 34 previously positive cases (82.3%). In immune checkpoint inhibitor (ICI)-treated patients, the median overall survival reached 22.3 months [95% CI 19.4 months- not reached (NR)] for HPV-negative and was not reached in HPV-positive (HPV+) ones (95% CI 27.7-NR; P = 0.008). With regard to progression-free survival, HPV− patients reached a median of 9.2 months (95% CI 7.9-11.2 months) compared to 14.3 months (95% CI 13.8-16.4 months) when HPV was positive (P = 0.001). The overall response rate for HPV+ patients yielded 82.4% compared to 47.1% in negative ones. No differences regarding programmed death-ligand 1, VEGF, HIF1, stromal fibrosis, or immunoscore were identified.
In patients with HPV+ lung adenocarcinoma, a significant benefit in overall response and survival outcomes is observed.
Metachronous second primary neoplasia in oropharyngeal cancer patients: Impact of tumor HPV status. A GETTEC multicentric study
2021, Oral Oncology
Citation Excerpt :
In 1979, Syrjanen et al.[32] were the first authors to mention a possible involvement of HPV in lung cancer carcinogenesis. In 2015, Zhai et al.[33] carried out a meta-analysis on the link between HPV and lung cancer. They showed that presence of HPV (mainly HPV-16 and −18) in lung tissue was associated with an increased risk of lung cancer, and principally of squamous cell carcinomas (OR = 9.78; 95% CI: 6.28–15.22; p < 0.001).
Patients with oropharyngeal squamous cell carcinoma (OPSCC) display a significant risk to develop a metachronous second primary neoplasia (MSPN). HPV and non-HPV-related OPSCC are 2 distinct entities with biological, clinical and prognostic differences. The aims of our study were to analyze the impact of tumor HPV status and other relevant clinical factors, such as tobacco and/or alcohol (T/A) consumption, on the risk and distribution of MSPN in OPSCC patients and to assess the impact of MSPN on patient survival.
All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. P16 immunohistochemical expression was used as a surrogate maker of tumor HPV status. The impact of tumor p16 status on the risk of MSPN was assessed in uni- and multivariate analyses. Overall survival (OS) was determined by Kaplan–Meier analysis.
Among the 1291 patients included in this study, 138 (10.7%) displayed a MSPN which was preferentially located in the head and neck area (H&N), lung and esophagus. Multivariate analyses showed that p16- tumor status (p = 0.003), T/A consumption (p = 0.005) and soft palate tumor site (p = 0.009) were significantly associated with a higher risk of MSPN. We found no impact of p16 tumor status on the median time between index OPSCC diagnosis and MSPN development, but a higher proportion of MSPN arising outside the H&N, lung and esophagus was found in p16 + than in p16- patients. MSPN development had an unfavorable impact (p = 0.04) on OS only in the p16 + patient group.
P16 tumor status and T/A consumption were the main predictive factors of MSPN in OPSCC patients. This study provides crucial results with a view to tailoring global management and follow-up of OPSCC patients.
Long non-coding RNAs regulate the hallmarks of cancer in HPV-induced malignancies
2021, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Regarding other cancers potentially related to high-risk HPV, oesophageal cancer, particularly oesophageal squamous cell carcinoma, has been proposed to be correlated with HPV infection (Santos et al., 2018; Guo et al., 2016; Liyanage et al., 2013). The role of HPV in lung cancer remains a matter of debate, but HPV16 oncoproteins seem to have an important role in non-small cell lung cancer progression (Santos et al., 2018; de Freitas et al., 2016; Zhai et al., 2015). HPVs, like other viruses, are able to intensely alter the expression profile of host cellular lncRNAs (Sharma and Munger, 2020a; Carnero et al., 2016; Imam et al., 2015).
High-risk human papillomavirus (HPV) is the most frequent sexually transmitted agent worldwide and is responsible for approximately 5% of human cancers. Identifying novel biomarkers and therapeutic targets for these malignancies requires a deeper understanding of the mechanisms involved in the progression of HPV-induced cancers. Long non-coding RNAs (lncRNAs) are crucial in the regulation of biological processes. Importantly, these molecules are key players in the progression of multiple malignancies and are able to regulate the development of the different hallmarks of cancer. This review highlights the action of lncRNAs in the regulation of cellular processes leading to the typical hallmarks of cancer. The regulation of lncRNAs by HPV oncogenes, their targets and also their mechanisms of action are also discussed, in the context of HPV-induced malignancies. Overall, accumulating data indicates that lncRNAs may have a significant potential to become useful tools for clinical practice as disease biomarkers or therapy targets.
Risk factors of Lung Cancer in nonsmoker
2017, Current Problems in Cancer
Citation Excerpt :
Some studies have also detected the presence of HPV E6-E7 mRNA in lung cancer cells.62,63 The association between lung cancer and human papillomavirus infection remains controversial but in a meta-analysis by Zhai et al,64 it was suggested that there is a strong association between HPV 16/18 genotypes and lung cancer leading to an increased risk of lung squamous cell carcinoma. HPV 16/18, as well as E6 and E7, up-regulates the expression of interleukin-6 and antiapoptotic Mcl-1, which plays an important role in the development of lung cancer through autocrine or paracrine mechanism.65
Generally, the cause of lung cancer is attributed to tobacco smoking. But many of the new lung cancer cases have been reported in nonsmokers. Apart from smoking; air pollution, environmental exposure, mutations, and single-nucleotide polymorphisms are known to be associated with lung cancer. Improper diet, alcohol consumption, marijuana smoking, estrogen, infections with human papillomavirus (HPV), HIV, and Epstein-Barr virus are suggested to be linked with lung cancer but clear evidences to ascertain their relation is not available. This article provides a comprehensive review of various risk factors and the underlying molecular mechanisms responsible for increasing the incidence of lung cancer. The pathologic, histologic, and genetic differences exist with lung cancer among smokers and nonsmokers. A better understanding of the risk factors, differences in pathology and molecular features of lung cancer in smokers and nonsmokers and the mode of action of various carcinogens will facilitate the prevention and management of lung cancer.
Microbiota dysbiosis in select human cancers: Evidence of association and causality
2017, Seminars in Immunology
Citation Excerpt :
There is interest in exploring if various factors beyond smoking may be associated with or, in fact, contribute to lung carcinogenesis. Various studies suggest lung cancer development is fostered, in part, by certain specific microorganisms including Chlamydia pneumoniae [91,92], human immunodeficiency virus [100–103], HPV [68,104,105], Pneumoccocus [94], and mycobacteria. However, this is an area of active debate given that current studies are limited by small sample size, observational study designs and inconsistent results [90,105,106].
The human microbiota is a complex ecosystem of diverse microorganisms consisting of bacteria, viruses, and fungi residing predominantly in epidermal and mucosal habitats across the body, such as skin, oral cavity, lung, intestine and vagina. These symbiotic communities in health, or dysbiotic communities in disease, display tremendous interaction with the local environment and systemic responses, playing a critical role in the host’s nutrition, immunity, metabolism and diseases including cancers. While the profiling of normal microbiota in healthy populations is useful and necessary, more recent studies have focused on the microbiota associated with disease, particularly cancers. In this paper, we review current evidence on the role of the human microbiota in four cancer types (colorectal cancer, head and neck cancer, pancreatic cancer, and lung cancer) proposed as affected by both the oral and gut microbiota, and provide a perspective on current gaps in the knowledge of the microbiota and cancer.

View all citing articles on Scopus

¹: These authors contributed equally to this work.

View full text

ReviewHPV and lung cancer risk: A meta-analysis

Highlights

Abstract

Section snippets

Background

Objectives

Search strategy

Eligible studies

Discussion

Authors’ contribution

Funding

Competing interests

Ethical approval

Lancet Oncol

Lung Cancer

Cancer Lett

Gynecol Oncol

Chest

J Clin Virol

Int J Cancer

J Clin Virol

Lung cancer in never smokers – a different disease

Nat Rev Cancer

Occupational exposure and lung cancer

J Thorac Dis

Detection of human papillomavirus in lung cancer: systematic review and meta-analysis

Anticancer Res

Papillomavirus life cycle organization and biomarker selection

Dis Markers

Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product

EMBO J

Association of human papillomavirus types 16 and 18 E6 proteins with p53

Science

HPV: from infection to cancer

Biochem Soc Trans

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

J Pathol

HPV-mediated transformation of the anogenital tract

J Clin Virol

Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma

J Clin Oncol

Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review

Cancer Epidemiol Biomarkers Prev

Human papillomavirus and head and neck cancer: a systematic review and meta-analysis

Clin Otolaryngol

Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review

Oral Dis

Condylomatous changes in neoplastic bronchial epithelium. Report of a case

Respiration

HPV infections and lung cancer

J Clin Pathol

Human papillomavirus type 16 and 18 in primary lung cancers – a meta-analysis

Carcinogenesis

Review
HPV and lung cancer risk: A meta-analysis