Human papillomavirus-16 is integrated in lung carcinomas: a study in Chile

Aguayo, Francisco; Castillo, Andrés; Koriyama, Chihaya; Higashi, Michiyo; Itoh, Tetsuhiko; Capetillo, M; Shuyama, K; Corvalán, Alejandro; Eizuru, Yoshito; Akiba, Suminori

doi:10.1038/sj.bjc.6603848

Cited by 55 publications

(62 citation statements)

References 40 publications

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“…The present study also showed that HPV-16 detected in lung carcinomas are frequently integrated, confirming the finding of our previous report examining lung carcinomas in Chile (12). However, the following three points should be taken into account: i) disrupted viral copies may be flanked by intact viral copies (40), ii) HPV integration does not always cause E2 disruption (41,42); and iii) more than a 10-fold excess of episomal form to integrated form of the virus interferes with E2 amplification, regardless the amount of viral DNA, resulting in lower E2/E6 ratios (43).…”

Section: ------------------------------------------------------------supporting

confidence: 93%

“…On the other hand, the etiological significance of HPV in lung carcinogenesis is yet unclear. Interestingly, however, HPV integration in the host genome has been reported in lung carcinomas (12). The expressions of HPV E6 and E7 genes, important HPV oncogenes, are regulated by HPV E2 gene, whose disruption is caused by HPV genome integration into the host genome.…”

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus is frequently detected in gefitinib-responsive lung adenocarcinomas

Baba

Castillo²,

Koriyama³

et al. 2010

Oncol Rep

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Abstract.A number of studies have reported the presence of human papillomavirus (HPV) in lung carcinoma. Interestingly, its detection rate appears to differ histologically and geographically. The present study examined 30 adenocarcinomas and 27 squamous cell carcinomas of the lung in a southern area of Japan, and detected high-risk HPV genome in 9 (30%) adenocarcinomas and 2 (7%) squamous cell carcinomas, using PCR with SPF10 primers and INNO-LiPA HPV genotyping assay. The difference of HPV detection rates in adenocarcinomas and squamous cell carcinomas was statistically significant (P=0.044, Fisher's exact test). HPV-16 was the most prevalent HPV genotype, and was detected in 27% (8/30) of adenocarcinomas and in 7% (2/27) of squamous cell carcinomas. High-risk-HPV positive carcinomas had decreased proportions of pRb (P=0.107) and significantly increased proportions of p16INK4a expressing cells (P=0.031) when compared to HPV-negative lung carcinomas. All HPV-16-positive cases were considered to have an integrated form of HPV-16 but its viral load was low (geometric mean = 0.02 copy per cell). In 20 additional adenocarcinomas treated with gefitinib, a tyrosine kinase inhibitor specific for epidermal growth factor receptor, the presence of HPV was examined. Note that East Asian ethnicity is a predictive factor of gefitinib response. High-risk HPV genome was found in 75% (6/8) of adenocarcinomas with complete or partial response to gefitinib but was not found in the remaining 12, which did not respond to gefitinib. In conclusion, the present study suggests that high-risk HPV may be more strongly related to adenocarcinomas, particularly gefitinib-responsive adenocarcinomas, when compared to squamous cell carcinomas. However, its low viral load makes it difficult to determine the etiological significance of these findings.

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Section: ------------------------------------------------------------supporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Human papillomavirus is frequently detected in gefitinib-responsive lung adenocarcinomas

Baba

Castillo²,

Koriyama³

et al. 2010

Oncol Rep

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“…In our study, real-time PCR was used in 27 samples to confirm the presence of HPV-16. E 2 was not found in 59.3% (16/27) of the samples, suggesting that at least a partial HPV-16 genome was integrated into the host genome, which is similar to the 66.7% reported in Chile (31) .…”

Section: Discussionsupporting

confidence: 79%

Correlation of HPV-16/18 infection of human papillomavirus with lung squamous cell carcinomas in Western China

Yan

2009

Oncol Rep

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Abstract. Prevalent inconsistency of human papillomavirus (HPV) infection in lung cancer was found among recent studies from different countries with racial and geographic variations. Even in Chinese populations, the prevalent discrepancy of HPV infection in lung cancer patients was also found with the geographic variations and tumor types. To study the difference of HPV-16/18 infection in lung squamous cell carcinomas and non-cancer controls, we conducted this study to verify whether there was a similar HPV infection prevalence pattern in lung squamous cell carcinoma patients from the Western part of China. Paraffinembedded samples (180), of 72 lung squamous cell carcinomas, 37 lung adenocarcinomas and 71 non-cancer controls, were analyzed by INNO-LIPA Genotype polymerase chain reaction (PCR) and real-time PCR analysis. The data showed that 51.4% (37/72) of lung squamous cell carcinoma samples, 16.2% (6/37) of adenocarcinoma, and 22.5% (16/71) of non-cancer controls were HPV DNA positive. The risk of lung squamous cell carcinomas was 3.5 times higher among people HPV-positive (odds ratio 3.5, 95% CI 1.6-7.3, p<0.001) compared with the HPV-negative population. Adjusted by smoking status, the risk of lung squamous cell carcinomas was 3.5 times higher among people HPVpositive (odds ratio 3.5, 95% CI 1.7-7.5, p=0.001) compared with the HPV-negative population. The risk of lung squamous cell carcinomas was 16.9 times higher for patients with positive HPV-16 (odds ratio 16.9, 95% CI 3.8-75.3, p<0.0001) than negative HPV-16. Adjusted by smoking status, the risk of lung squamous cell carcinomas was 17.4 times higher among people HPV-16 positive (odds ratio 17.4, 95% CI 3.9-77.5, p<0.0001) compared with HPV-16 negative people. INNO-LIPA Genotype analysis revealed that the frequency of high risk HPV-16 and 18 genotype in lung squamous cell carcinoma cases appeared to be significant higher than that in the non-cancer controls (P<0.001), and the most frequent genotype was HPV-16 (21 cases), followed by HPV-18 (6 cases), HPV-16/18 (4 cases) in lung squamous cell carcinomas, respectively, and the majority genotype was HPV-6 (9 cases) in controls. The HPV-16 E 2 /E 6 ratio was significantly lower than the unity, suggested that the main presence of integrated form of HPV-16 genome (16/27) may contribute more to lung squamous cell carcinomas, despite its viral load estimated to be only <1 to 2 copies per cell.

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“…It would have been interesting, for instance, to assess whether the transcriptionally inactive integrant with a VL of 10 2 identified in a clinical samples [57] was silent because of epigenetic suppression or for other reasons such as loss of the viral promoter. Remarkably, transgenic mice showed the lowest proportion of actively transcribing proviruses, clearly indicating that despite bearing at least one copy of integrated virus in each cell, the viral genetic expression was modulated by the cellular environment; epigenetic mechanisms were evoked to explain the transcriptional silencing [53,54].…”

Section: 2217/fvl-2017-0063mentioning

confidence: 99%

“…The reactivation of the virus was postulated to be dependent on protein kinase C (PKC): TPA is a direct stimulator of PKC and PKC is also activated by increased intracellular calcium levels. No infectious HHV-6 particles were produced after reactivation.Overall the viral load (VL) of the samples gathered in the present study ranged between 10 −7 and 10 3 copies per cell [35,57] 1982 1984 1985 1986 1987 1988 1989 1992 1994 1995 1997 1998 1999 2000 2002 2003 2004 2006 2007 2008 2009 2011 2013 2014 2015 2016 Remarkably, an HPV integrant with 217 copies was reported being transcriptionally silent; it was not indicated whether the HPV sequences were dispersed in more than one integration site [57]. The data regarding the integration sites were limited and did not provide information regarding a possible association between the targeted locus and transcriptional status of the provirus; neither was present a description of the chromatin context of the targeted loci.…”

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confidence: 99%

Proportion of Transcriptionally Active Dna Virus Integrants: A Meta-Analysis

Marongiu

2017

Future Virol.

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Oncoviruses are collectively responsible for over 1,000,000 new cases of cancer per year; some can integrate into the host's chromosomes. The present work was aimed at assessing the proportion of transcriptionally active viral integrants through a systematic review of the scientific publications present on the MedLine database. From the articles screened, 628 viral integrants overall were retrieved, of which 530.84 were transcriptionally active (84.53%); among the clinical samples, 264 of 323 integrants were active (81.73%). The causes for the silencing were not addressed in the articles analyzed. These findings might highlight a possible risk factor for the insurgence of cancer since some oncovirus integrants could be reactivated by stimuli of disparate nature. Further studies should address such possibility. About 16% of all cancer cases have been identified having an infectious aetiology [1]. Hepatitis B virus (HBV), human papilloma virus (HPV), human herpes 4 virus (HHV-4, historically known as Epstein-Barr virus [EBV]) and human herpes 8 virus (HHV-8, previously Kaposi sarcoma herpes virus) are collectively responsible for 56.2% of the incident microbial-related cancer cases, corresponding to over 1,200,000 new cases per year [2].HBV, HPV and HHV-4 share the capability of integrating into the host's chromosomes whereas HHV-8 integrants have not been observed [3]. In addition, other DNA viruses with transformation potential can integrate: Merkel cell polyomavirus (MCPV), human herpes 6 virus (HHV-6) and, in a lesser extent, adenovirus (AdV) [4][5][6]. The infection with these viruses is associated with a wide range of cancer types: HBV with hepatocarcinoma; HPV with virtually all cases of cervical cancer and in a significant proportion of other tumors, for instance in the head and neck; HHV-4 with a number of malignancies, in particular Burkitt and Hodgkin lymphomas, in both immunologically deficient and competent patients; HHV-8 DNA has been retrieved in all Kaposi sarcoma lesions even in immunocompetent hosts; MCPV is recognized as the causative agent of the Merkel cell carcinoma; HHV-6 has been involved in lymphoproliferative diseases; and AdV has been shown to transform rodent cells [1,[7][8][9].All these viruses encode for proteins that disrupt the cell cycle and DNA damage repair response to sustain the viral replication. For example, HBV X, HPV E6/E7, HHV-8 LANA and MCPV large T proteins, all hinder the function of p53, a pivotal factor of the DNA damage response, and pRb, an oncosuppressor that prevents over-replication of the cellular DNA [10][11][12][13][14]. HHV-4 encodes for a plethora of early proteins with oncogenic potential; for instance, BARF1 and BCRF1 have antiapoptotic function and the viral DNAse enzyme can cause genomic instability, therefore induction of the lytic cycle can contribute to the development of malignant phenotypes [15]. Even during the lysogenic cycle, HHV-4 encodes for proteins and interfering RNAs that have oncogenic potential [16].Integration can disrupt the transcripti...

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Human papillomavirus-16 is integrated in lung carcinomas: a study in Chile

Cited by 55 publications

References 40 publications

Human papillomavirus is frequently detected in gefitinib-responsive lung adenocarcinomas

Human papillomavirus is frequently detected in gefitinib-responsive lung adenocarcinomas

Correlation of HPV-16/18 infection of human papillomavirus with lung squamous cell carcinomas in Western China

Proportion of Transcriptionally Active Dna Virus Integrants: A Meta-Analysis

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