HPVs Cause Skin Cancer

Human papilloma virus in melanoma biopsy specimens and its relation to melanoma progression. D Dreau, C Culbertson, S Wyatt, WD Holder Jr. Ann Surg 2000 May;231(5):664-671. "The presence of HPV was found in 58% of the biopsy specimens... and correlated with rapid melanoma progression. HPV may serve as a cofactor in the development of melanoma and may modulate a more aggressive phenotype in HPV-containing melanoma cells."

Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. CA Harwood, T Surentheran, JM McGregor, PJ Spink, IM Leigh, J Breuer, CM Proby. J Med Virol 2000 Jul;61(3):289-297.

Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. MC Feltkamp, R Broer, FM di Summa, L Struijk, E van der Meijden, BP Verlaan, RG Westendorp, J ter Schegget, WJ Spaan, JN Bouwes Bavinck. Cancer Res 2003 May 15;63(10):2695-2700. Seroreactivity to L1 virus-like particles of EV-HPV types 5, 8, 15, 20, 24, and 38 and the genital type HPV16 in 540 cases with a history of skin cancer. "After adjusting for age and sex, the estimated squamous cell carcinoma relative risk was significantly increased in HPV8 and HPV38 seropositives [odds ratio (OR) = 14.7 (95% confidence interval (CI), 1.6-135) and OR = 3.0 (95% CI, 1.1-8.4), respectively]. The estimated relative risk for nodular and superficial multifocal basal cell carcinoma was also significantly increased in the HPV8 seropositives [OR = 9.2 (95% CI, 1.1-78.2) and OR = 17.3 (95% CI, 2.1-143), respectively] and in the HPV20 seropositives [OR = 3.2 (95% CI 1.3-7.9) and OR = 3.4 (95% CI 1.2-9.5), respectively]. The relative risk of developing malignant melanoma was not increased among HPV seropositives, and no associations were found for HPV16."

Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals. C Masini, PG Fuchs, F Gabrielli, S Stark, F Sera, M Ploner, CF Melchi, G Primavera, G Pirchio, O Picconi, P Petasecca, MS Cattaruzza, HJ Pfister, D Abeni. Arch Dermatol 2003 Jul;139(7):890-894. In 46 cutaneous SCC cases versus 84 controls, "Positive serologic findings for HPV type 8 were associated with SCC (odds ratio, 3.2; 95% confidence interval, 1.3-7.9) independently of other risk factors, whereas positive serologic findings for HPV type 15 were negatively associated with SCC (odds ratio, 0.4; 95% confidence interval, 0.2-0.9)."

Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. SJ Weissenborn, I Nindl, K Purdie, C Harwood, C Proby, J Breuer, S Majewski, H Pfister, U Wieland. J Invest Dermatol 2005 Jul;125(1):93-97. In 26 actinic keratoses, 31 non-melanoma skin cancers, 22 perilesional tissue samples, and 8 metastases of squamous cell carcinomas which were previously shown to be positive for HPV5, 8, 15, 20, 24, or 36: "Viral loads in SCC, basal cell carcinomas, and perilesional tissue were similar. But, viral loads found in AK were significantly higher than in SCC (p=0.035). Our data suggest that persistence of HPV is not necessary for the maintenance of the malignant phenotype of individual NMSC cells. Although a passenger state cannot be excluded, the data are compatible with a carcinogenic role of HPV in early steps of tumor development."

The expression of P53 protein and infection of human papilloma virus in conjunctival and eyelid neoplasms. J Reszec, S Sulkowski. Int J Mol Med 2005 Oct;16(4):559-564. "Malignant type HPV 16 and 18 were detected in three squamous cell papillomas, two BCCs and one SCC," out of 45 benign papillomas, 27 basal cell carcinomas and 11 squamous cell carcinomas.

Markers of cutaneous human papillomavirus infection in individuals with tumor-free skin, actinic keratoses, and squamous cell carcinoma. L Struijk, L Hall, E van der Meijden, P Wanningen, JN Bavinck, R Neale, AC Green, J Ter Schegget, MC Feltkamp. Cancer Epidemiol Biomarkers Prev 2006 Mar;15(3):529-535. 57 tumor-free controls, 126 AK, and 64 SCC cases. "Presence of HPV L1 and E6 seroreactivity and viral DNA were determined for HPV types 5, 8, 15, 16, 20, 24, and 38. Significant positive associations with increasing severity of the lesions (controls, AK, and SCC, respectively) were observed for overall HPV L1 seropositivity (13%, 26%, and 37%) and for HPV8 (4%, 17%, and 30%). In parallel, the proportion of L1 seropositive individuals against multiple HPV types increased from 14% to 39% and 45%. The overall E6 seroreactivity, however, tended to decline with AK and SCC, especially for HPV8 (21%, 11%, and 2%). HPV DNA positivity was most prevalent in the AK cases (54%) compared with the SCC cases (44%) and the tumor-free controls (40%)... Smoking was not associated with AK or SCC."

Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. MR Karagas, HH Nelson, P Sehr, T Waterboer, TA Stukel, A Andrew, AC Green, JN Bavinck, A Perry, S Spencer, JR Rees, LA Mott, M Pawlita. J Natl Cancer Inst 2006 Mar 15;98(6):389-395. Antibodies to 16 types of HPV in squamous cell carcinoma patients versus controls, OR = 1.6, 95% CI = 1.2 to 2.3. "Among HPV types, seropositivity to HPV types in genus beta (OR = 1.5, 95% CI = 1.0 to 2.1), particularly HPV 5 (OR = 1.8, 95% CI = 1.0 to 3.1), was associated with SCC risk."

Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the skin. N Hama, T Ohtsuka, S Yamazaki. J Dermatol 2006 May;33(5):331-337. "[W]e detected HPV DNA in none of the 17 normal controls, two of the three BP (66.7%), one of the 21 BD (4.8%), and six of the 26 SCC of the skin samples (23.0%). The occurrence rates of HPV in BP and SCC were significantly elevated compared to that of normal controls (P < 0.01 and P < 0.01, respectively). In addition, the occurrence rate of HPV in BP was significantly elevated compared to that of BD (P < 0.05). The reproducibility was confirmed with a polymerase chain reaction (PCR) with another primer pair. Of the two cases of BP with positive HPV DNA, one case showed HPV 31 and the other case HPV 16. The case of BD with positive HPV DNA showed HPV 31. Of the six cases of SCC with positive HPV DNA, one case showed HPV 16, another case HPV 34, and the other four cases HPV 31. These results showed that mucosal HPV, including HPV 31 and 16, could be detected in SSC of the skin. Mucosal HPV, not only the epidermodysplasia verruciformis type, appear to induce malignant skin tumors."

Prevalence of mucosal types of human papillomavirus in skin lesions in north part of Iran. S Shahmahmoudi, M Mahmoodi, TM Azad, KS Rad, H Tabatabaie, M Sarijlou, YY Pour, M Yousefi, M Ghasemi, KJ Far, R Nategh. Cancer Lett 2007 Mar 8;247(1):72-76. 288 paraffin embedded biopsies from benign and malignant skin lesions. "[M]ucosal HPVs were detected in 25.7% of malignant specimens, but just in 0.7% of benign lesions. Direct sequencing revealed HPV18 as the most frequent type, which was found in 75% of HPV-positive specimens. HPV16 and HPV56 were also detected, 22.3 and 2.7%, respectively."

Cutaneous human papillomaviruses found in sun-exposed skin: Beta-papillomavirus species 2 predominates in squamous cell carcinoma. O Forslund, T Iftner, K Andersson, B Lindelof, E Hradil, P Nordin, B Stenquist, R Kirnbauer, J Dillner, EM de Villiers; Viraskin Study Group. J Infect Dis 2007 Sep 15;196(6):876-883. 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). "RESULTS: Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44-8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79-7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92-10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72-6.99])."

Early studies date from 1934

"Although it was suggested long ago that certain epithelial cancers preceded by papillomas might be caused by viruses, the first proof that papillomaviruses were associated with cancer dates from the work on rabbits in 1934 by Shope and Rose. In the 1970s, the introduction of the blot hybridization technique enabled Orth and his co-workers at the Institut Pasteur, Paris, to demonstrate the presence in man of the DNA of human papillomavirus type 5 (HPV-5) in cancers following Lutz-Lewandovsky epidermodysplasia verruciformis. Some years later, it was possible to demonstrate the presence of the same HPV-5 DNA in the skin cancer of an immunosuppressed recipient of a renal transplant...." (Papillomaviruses and skin cancer in Africa. MA Lutzner. IARC Sci Publ 1984;(63):607-623.

Mechanisms

Human fibroblasts expressing the human papilloma virus E6 gene are deficient in global genomic nucleotide excision repair and sensitive to ultraviolet irradiation. JM Ford, EL Baron, PC Hanawalt. Cancer Res 1998 Feb 15;58(4):599-603. "We investigated the role of wild-type p53 activity in modulating nucleotide excision repair after UV irradiation in normal and p53-deficient primary human fibroblasts created by expression of the human papillomavirus 16 E6 gene. Compared with parental cells, the E6-expressing fibroblasts were deficient in global genomic repair of both UV-induced cyclobutane pyrimidine dimers and 6-4 photoproducts but exhibited normal transcription-coupled repair. The E6-expressing cells were also more sensitive than their parental counterparts to UV irradiation and displayed similar levels of UV-induced apoptosis. These results suggest that disruption of wild-type p53 function by E6 expression results in selective loss of p53-dependent global genomic nucleotide excision repair, but not UV-induced apoptosis, leading to enhanced UV sensitivity."

Human papillomavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways. S Song, GA Gulliver, PF Lambert. Proc Natl Acad Sci 1998 Mar;95(5):2290-2295.

Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk types. M Thomas, L Banks. J Gen Virol 1999 Jun;80(Pt 6):1513-1517. The carcinogenicity of "high risk" versus "low risk" HPVs is only a difference of degree.

The promoter of a novel human papillomavirus (HPV77) associated with skin cancer displays UV responsiveness, which is mediated through a consensus p53 binding sequence. KJ Purdie, J Pennington, CM Proby, S Khalaf, EM de Villiers, IM Leigh, A Storcy. EMBO J 1999 Oct 1;18(19):5359-5369.

Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. S Jackson, C Harwood, M Thomas, L Banks, A Storey. Genes Dev 2000 Dec 1;14(23):3065-3073. "We have found that a protein produced by HPV causes the destruction of Bak protein in skin cells, rendering them unable to die in order to protect themselves from turning into a cancer. This mechanism also explains how HPV promotes its own survival in infected cells." And: "HPV positive skin cancers had undetectable levels of Bak in contrast to HPV negative cancers, which expressed Bak."

The E6 and E7 proteins of the cutaneous human papillomavirus type 38 display transforming properties. S Caldeira, I Zehbe, R Accardi, H Malanchi, W Dong, M Giarre, E-M de Villiers, R Filotico, P Boukamp, M Tommasino. J Virol 2003 Feb;77(3):2195-2206. "Our study shows that E6 and E7 of this cutaneous HPV type have transforming activity in primary human cells, suggesting a role for HPV38 infection in skin carinogenesis. In further support of such a role, we detected HPV38 DNA in approximately 50% of nonmelanoma skin cancers, but only in 10% of healthy skin specimens."

Assessment of the presence of mucosal human papillomaviruses in malignant melanomas using combined fluorescent in situ hybridization and chemiluminescent immunohistochemistry. S Ambretti, S Venturoli, M Mirasoli, M La Placa, F Bonvicini, M Cricca, M Zerbini, A Roda, M Musiani. Br J Dermatol 2007 Jan;156(1):38-44. "The combined fluorescent ISH and chemiluminescent IHC demonstrated a sharp colocalization (in the range 60-80%) of HPV nucleic acids and melanoma marker inside the same sections of melanoma biopsies, with a strong specificity and sensitivity. CONCLUSIONS: The strong colocalization of mucosal HR-HPV nucleic acids and HMB-45 melanocytic marker emphasized that viral nucleic acids were specifically present in melanoma cells and supported a possible active role of HPV in malignant melanoma."

Comparative transforming potential of different human papillomaviruses associated with non-melanoma skin cancer. P Massimi, M Thomas, V Bouvard, I Ruberto, MS Campo, M Tommasino, L Banks. Virology 2008 Feb 20;371(2):374-379. "Using oncogene cooperation assays with activated ras, we have shown that diverse cutaneous types, including 12, 14, 15, 24, 36 and 49, have significant transforming potential. Interestingly, most of this activity appears to be encoded by the E6 gene product. In contrast, the common HPV-10 exhibits no significant transforming potential in these assays. This difference may be a reflection of different patterns of cellular localization, with transforming E6s being nuclear and non-transforming being cytoplasmic."

The E6 oncoproteins from beta-HPVs differentially activate telomerase through an E6AP dependent mechanism and prolong the lifespan of primary keratinocytes. KM Bedard, MP Underbrink, HL Howie, DA Galloway. J Virol 2008 Apr;82(8):3894-3902. "HFKs expressing 38E6 exhibit significant telomerase activity but to a lesser degree than that observed with 16E6; however, other beta-E6 proteins including 5E6, 8E6, 20E6 and 22E6 exhibit low or background levels of telomerase activity. Utilizing GST pull-down and coimmunoprecipitation experiments, the beta-E6 proteins were shown to interact with the cellular proteins E6AP and NFX1-91, two proteins known to be important for telomerase activation by 16E6. Interestingly, the relative strength of the interaction between the E6 and E6AP or NFX1-91 was proportionate to the activation of telomerase by each beta-E6 protein. To address the requirement for E6AP in telomerase activation by beta-E6 proteins, we utilized a shRNA to knockdown endogenous levels of E6AP. Lysates with decreased levels of E6AP showed a reduced ability to activate telomerase, suggesting that E6AP is a necessary component. This data suggests that complex formation between E6, E6AP, and NFX1-91 is a critical step in mediating telomerase activation, which may be one contributing factor to cellular lifespan extension during beta-HPV infection."

Detection methodology is still developing

Frequency and spectrum of HPV types detected in cutaneous squamous cell carcinoma depend on the HPV detection system: A comparison of four PCR assays. T Meyer, R Arndt, E Christophers, E Stockfleth. Dermatology 2000;201(3):204-211.

The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses. A Antonsson, O Forslund, H Ekberg, G Sterner, BG Hansson. J Virol 2000 Dec;74(24):11636-11641. "20 previously described and 30 putatively new types were identified by cloning and sequencing of 33 samples from 13 individuals. These results demonstrate that normal human skin harbors an array of papillomaviruses, most of them previously unknown."

Development of a general-primer-PCR-reverse-line-blotting system for detection of beta and gamma cutaneous human papillomaviruses. AATP Brink, B Lloveras, I Nindl, DAM Heideman, D Kramer, R Pol, MJ Fuente, CJLM Meijer, and PJF Snijders. J Clin Microbiol 2005 Nov;43(11):5581-5587. HPV5 and HPV8 were the predominant types detected nonmelanoma skin tumors (21/25 from transplant patients and 6/15 from immunocompetent individuals).

The anti-smokers' deliberate fraud

Human papillomaviruses have been implicated in skin cancer for a number of years (Papillomavirus infections - a major cause of human cancers. H zur Hausen. Biochim Biophys Acta 1996 Oct 9;1288(2):F55-F78). The anti-smokers' claims that smoking causes cervical cancer have turned out to be entirely the product of confounding by HPV infection. Despite this, the anti-smoking conspirators as usual ignore the confounding role of HPV infection in skin cancer, and purposely use defective studies to deceive the public that smoking causes skin cancer (Smoking 'triples skin cancer risk.' BBC News 2000 Dec 29).

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cast 03-26-08