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])."

Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: a case-control study. AS Patel, MR Karagas, M Pawlita, T Waterboer, HH Nelson. Int J Cancer 2008 May 15;122(10):2377-2379. 239 SCC cases and 432 controls. "Among controls, variant genotype was associated with beta-HPV seropositvity (OR = 2.3, 95%CI = 1.2-4.3), specifically HPV5 or 8 seropositivity (OR = 2.4, 95%CI = 1.1-5.1) and seropositivity for multiple beta-HPV types (OR = 2.7, 95%CI = 1.1-6.6). Furthermore, variant genotype was also related to SCC risk [adjusted OR for homozygous variant versus homozygous wild type for the EVER2 polymorphism 1.7, 95% CI 1.1-2.7]."

Detection of human papillomavirus DNA in cutaneous squamous cell carcinoma among immunocompetent individuals. MM Asgari, NB Kiviat, CW Critchlow, JE Stern, ZB Argenyi, GJ Raugi, D Berg, PB Odland, SE Hawes, EM de Villiers. J Invest Dermatol 2008 Jun;128(6):1409-1417. 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. "The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from beta-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio=4.0, confidence interval=1.3-12.0)."

Serological association of beta and gamma human papillomaviruses with squamous cell carcinoma of the skin. T Waterboer, D Abeni, F Sampogna, A Rother, C Masini, P Sehr, KM Michael, M Pawlita. Br J Dermatol 2008 Aug;159(2):457-459. "Significantly increased SCC risks were observed for the beta HPV types 15, 17 and 38, as well as for the gamma HPV type 50, with type-specific odds ratios (ORs) ranging from 2.6 to 3.4. Significant associations were also found in cases of seropositivity for any type of the beta 2 species (OR 3.3, 95% confidence interval [CI] 1.2-8.7) and for any type of the gamma genus (OR 3.1, 95% CI 1.1-8.6). With regression models that included all HPV types and forward stepwise selection, two gamma HPV types (HPV 95, OR 25, 95% CI 1.2-509; HPV 50, OR 3.6, 95% CI 1.4-9.4) were each significantly associated with skin SCC."

HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). N Termine, V Panzarella, S Falaschini, A Russo, D Matranga, L Lo Muzio, G Campisi. Ann Oncol 2008 Oct;19(10):1681-1690. "The pooled prevalence of HPV DNA in the overall samples (Sigma: 4852) was 34.5%, in OSCC it was 38.1% and in the not site-specific HNSCC was 24.1%. With regard to the detection method, PCR-based studies reported a higher prevalence rate than ISH-based rates (34.8, versus 32.9%) especially in the OSCC subgroup (OSCC PCR based: 39.9%)."

Use of in situ hybridization to detect human papillomavirus in head and neck squamous cell carcinoma patients without a history of alcohol or tobacco use. WT Lee, RR Tubbs, AM Teker, J Scharpf, M Strome, B Wood, RR Lorenz, J Hunt. Arch Pathol Lab Med 2008 Oct;132(10):1653-1656. 14 male and 8 female non-alcohol / tobacco users; tongue (n = 8), tonsil (n = 7), and larynx (n = 7). "Only 2 cases were positive for high-risk HPV, and both demonstrated an integrated pattern. Both cases were tumors of the tonsil. No cases were positive for low-risk HPV."

Measures of cutaneous human papillomavirus infection in normal tissues as biomarkers of HPV in corresponding nonmelanoma skin cancers. DE Rollison, M Pawlita, AR Giuliano, MR Iannacone, VK Sondak, JL Messina, CW Cruse, NA Fenske, LF Glass, M Kienstra, KM Michael, T Waterboer, T Gheit, M Tommasino. Int J Cancer 2008 Nov 15;123(10):2337-2342. 60% of 20 basal or squamous cell carcinomas of the skin were positive for beta-Papillomavirus DNA.

Exposure profiles and human papillomavirus infection in skin cancer: an analysis of 25 genus beta-types in a population-based study. AS Patel, MR Karagas, AE Perry, HH Nelson. J Invest Dermatol 2008 Dec;128(12):2888-2893. 101 squamous cell carcinomas and 101 basal cell carcinomas. "When testing for all known beta-HPV types, we found no significant difference in HPV prevalence between the two histologies. However, SCC lesions were significantly more likely to be infected with HPV genus beta-species 1 (includes types 5 and 8), than BCC samples (P=0.01); this difference was not observed for any other species. A histologic difference was also observed for those HPV types previously reported to be important in skin cancer (P=0.003). SCC samples showed a higher rate of infectivity (that is, were positive for multiple types) than BCC tumors (P=0.02)."

Presence of beta human papillomaviruses in nonmelanoma skin cancer from organ transplant recipients and immunocompetent patients in the West of Scotland. LJ Mackintosh, MN de Koning, WG Quint, J Ter Schegget, IM Morgan, RM Herd, MS Campo. Br J Dermatol 2009 Mar 28. [Epub ahead of print]. 27 actinic keratosis, 41 intraepidermal carcinoma, 53 squamous cell carcinoma, and 11 normal skin samples. In immunocompetent patients, "betaPV was detected in 30 of 59 (51%) tumours and two of 11 (18%) normal skin samples (P = 0.046). In IS patients, betaPV was found in 27 of 62 (44%) tumours; no normal skin samples were available for comparison. The most frequently found genotypes were HPV-24, HPV-15 and HPV-38. Of those tumours infected with betaPV, 28 of 57 (49%) were infected with more than one genotype (range 2-8)."

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."

The E6E7 oncoproteins of cutaneous human papillomavirus type 38 interfere with the interferon pathway. P Cordano, V Gillan, S Bratlie, V Bouvard, L Banks, M Tommasino, MS Campo. Virology 2008 Aug 1;377(2):408-418. "Here we show that HPV-38 E6 and E7 affect the IFN-induced up-regulation of MHC class I. Expression of the two viral proteins in HaCaT keratinocytes led to a decrease of MHC I levels. This down-regulation is associated with a reduction of expression of MHC I heavy chain, of the peptide chaperone TAP and of the STAT-1 downstream effector IRF-1. The down-regulation of these proteins is ultimately due to the inhibition of STAT-1 expression. Analysis of cells expressing either HPV-38 E6 or E7 suggests that these effects are primarily the result of E6 expression, although a contribution by E7 cannot be excluded. We conclude that HPV-38 encodes oncoproteins that potentially contribute to the evasion of host immune surveillance."

Differences in transcriptional activity of cutaneous human papillomaviruses. N Vasiljević, L Nielsen, G Doherty, J Dillner, O Forslund, B Norrild. Virus Res 2008 Nov;137(2):213-219. "Transcription from HPV-8, 93 and 96 URR was up-regulated by cellular differentiation, linking the activity of these HPVs to the cellular state. UV-B irradiation activated HPV-8 but inhibited HPV-38 and HPV-93 whereas HPV-92 and 96 were not affected."

Carriage and Transmission

Human papillomavirus type spectrum in normal skin of individuals with or without a history of frequent sun exposure. AC Chen, NA McMillan, A Antonsson. J Gen Virol 2008 Nov;89(Pt 11):2891-2897. Forehead skin swab samples from 50 healthy males frequently exposed to the sun and 50 healthy males who were not frequently exposed to the sun. "HPV prevalence was higher in individuals who spent more time outdoors and in individuals with a history of skin cancers (P=0.044 and P=0.04, respectively). Furthermore, individuals wearing sunglasses as a means of sun protection had a lower prevalence of HPV (P=0.018). Interestingly, HPV-76 was only detected in the group without frequent sun-exposure (P=0.001)."

Intrafamilial Transmission and Family-Specific Spectra of Cutaneous Beta-Papillomaviruses. SJ Weissenborn, MN De Koning, U Wieland, WG Quint, HJ Pfister. J Virol 2009 Jan;83(2):811-816. In parents and children from 10 families, "All participants were found to be beta-HPV DNA positive, with 1 to 13 types at study entry (median, 4.0 types). Initial and cumulative (2 to 16 types) HPV type multiplicities varied widely between different families but only a little between family members. The high intrafamilial correlation of HPV multiplicity is already obvious for babies aged 10 days to 10 months. Family members typically displayed similar spectra of HPV types. More than 75% of the HPV types in babies were also detected in their parents. This indicates that HPV transmission mainly results from close contact between family members. Type-specific persistence for at least 9 months was more prevalent in parents (92%) than in children (66%). Of the types detected throughout the study, 24% turned out to persist in the parents and only 11% in the children. Interestingly, about one-half of the HPV types found to persist in one of the parents occurred less frequently or even only sporadically in the spouse. Similarly, only one-third of the persisting parental types also persisted in their children. This indicates that even regular exposure to cutaneous HPV does not necessarily lead to the establishment of a persistent infection, which may point to type-specific susceptibilities of different individuals."

Detection methodologies are 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).

Extension of the typing in a general-primer-PCR reverse-line-blotting system to detect all 25 cutaneous beta human papillomaviruses. I Nindl, A Köhler, M Gottschling, T Forschner, M Lehmann, CJ Meijer, PJ Snijders, E Stockfleth. J Virol Methods 2007 Dec;146(1-2):1-4. "The analytical sensitivity was between 10 copies (HPV 75, 80, 92, 93, and 96) and 100 copies (HPV 76). Except for that of HPV 76, none of the added probes showed any cross-hybridization with other beta-HPV."

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).

Merkel Cell Polyomavirus Causes Skin Cancer

Clonal integration of a polyomavirus in human Merkel cell carcinoma. H Feng, M Shuda, Y Chang, PS Moore. Science 2008 Feb 22;319(5866):1096-1100. "MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells."

Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. A Kassem, A Schöpflin, C Diaz, W Weyers, E Stickeler, M Werner, A Zur Hausen. Cancer Res 2008 Jul 1;68(13):5009-5013. Merkel cell polyomavirus was found in 30 of 39 (77%) Merkel cell carcinomas.

Merkel cell polyomavirus and Merkel cell carcinoma, France. V Foulongne, N Kluger, O Dereure, N Brieu, B Guillot, M Segondy. Emerg Infect Dis 2008 Sep;14(9):1491-1493. MCPyV was found in 8 of 9 patients with MCC, of whom 2 were immunocompromised.; versus 0 of 15 patients with diverse proliferative or inflammatory skin or mucosa lesions as controls.

Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. KM Garneski, AH Warcola, Q Feng, NB Kiviat, JH Leonard, P Nghiem. J Invest Dermatol 2009 Jan;129(1):246-248. "16 of 37 Merkel cell carcinoma tumor tissues were positive for Merkel cell polyomavirus DNA (43%)," 11/16 (69%) from North America, versus 5/21 (24%) from Australia. "We observed MCPyV in 5 of 8 primary tumors, 3 of 13 recurrences, 7 of 15 nodal metastases, and in the single studied distant metastasis... The majority of Australian samples were nodal metastases, whereas most North American samples were primaries." Also, "most of the Australian tumor specimens were collected in the 1990’s and most North American specimens were collected after the year 2000." "MCPyV was not detected in any of the normal skin DNA, but was present in 2 of 15 SCC tumors (13%)."

Ultrastructural proof of polyomavirus in Merkel cell carcinoma tumour cells and its absence in small cell carcinoma of the lung. CT Wetzels, JG Hoefnagel, JM Bakkers, HB Dijkman, WA Blokx, WJ Melchers. PLoS ONE 2009;4(3):e4958. MCPyV was found in 2/5 Merkel cell carcinomas and 0/10 small cell lung carcinomas.

Frequent occurrence of RASSF1A promoter hypermethylation and merkel cell polyomavirus in merkel cell carcinoma. P Helmbold, C Lahtz, A Enk, P Herrmann-Trost, WC Marsch, H Kutzner, RH Dammann. Mol Carcinog 2009 Mar 26. [Epub ahead of print]. "MCPyV was found in 90 of 98 (92%) MCC, however, no SV40 signal was detected. No correlation between TSG hypermethylation and viral infection was found."

Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma. EJ Duncavage, BA Zehnbauer, JD Pfeifer. Mod Pathol 2009 Apr;22(4):516-521. 41 cases of Merkel cell carcinoma (from 29 different patients). Of these, 20 cases were primary cutaneous tumors, 4 were local recurrences, and 17 were metastases. 22/29 (76%) were positive for MCVPS1 (109 bp amplicon).

Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. YL Tolstov, DV Pastrana, H Feng, JC Becker, FJ Jenkins, S Moschos, Y Chang, CB Buck, PS Moore. Int J Cancer 2009 Apr 14. [Epub ahead of print]. "Among MCC patients, all 21 (100%) patients tested with MCV-positive tumors had high serum MCV IgG but not high MCV IgM levels. Only 3 of 6 (50%) MCC patients with MCV-negative tumors were positive for MCV antibodies. Sera from most adults, including 107 of 166 (64%) blood donors, 63 of 100 (63%) commercial donors and 37 of 50 (74%) systemic lupus erythematosus patients, show evidence for prior MCV exposure. Age-specific MCV prevalence was determined by examining a cross-sectional distribution of 150 Langerhans cell histiocytosis (an unrelated neoplasm) patient sera. MCV prevalence increases from 50% among children age 15 years or younger to 80% among persons older than 50 years. We did not find evidence for vertical transmission among infants."

Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. X Sastre-Garau, M Peter, MF Avril, H Laude, J Couturier, F Rozenberg, A Almeida, F Boitier, A Carlotti, B Couturaud, N Dupin. J Pathol 2009 May;218(1):48-56. "MCV DNA sequences were found in all ten cases of MCC and in none of the 1241 specimens of other tumour types. Clonal integration of MCV into the host genome was seen in all MCC cases and was checked by FISH in one case. A recurrent pattern of conserved viral sequences which encompassed the replication origin, the small tumour (ST), and the 5' part of the large tumour (LT) antigen DNA sequences was observed. Both ST and LT viral sequences were found to be significantly expressed in all MCCs. Neither recurrent site of integration nor alteration of cellular genes located near the viral sequences was observed. The tight association of MCV with MCC, the clonal pattern of MCV integration, and the expression of the viral oncoproteins strongly support a causative role for MCV in the tumour process."

Detection of Merkel cell polyomavirus DNA in Merkel cell carcinomas. E Varga, M Kiss, K Szabó, L Kemény. Br J Dermatol 2009 May 12. [Epub ahead of print]. "Nine primary or recurrent MCCs from seven patients were examined; 29 other tumours (squamous cell, basal cell and basosquamous carcinomas and malignant melanomas) were examined for comparative purposes.... The presence of viral T antigen and/or viral capsid DNA sequences was demonstrated in seven of the eight MCC lesions. None of the comparative samples contained MCV DNA."

Merkel cell polyomavirus strains in patients with merkel cell carcinoma. A Touzé, J Gaitan, A Maruani, E Le Bidre, A Doussinaud, C Clavel, A Durlach, F Aubin, S Guyétant, G Lorette, P Coursaget. Emerg Infect Dis 2009 Jun;15(6):960-962. 21 of 32 (66%) samples of Merkel cell carcinoma with suitable quality DNA were positive for Merkel cell polyomavirus DNA. All 12 frozen samples were positive versus only 9/20 (45%) of formalin-fixed and paraffin-embedded samples. "MCPyV DNA was not detected for any of the 9 patients with non-MCC neuroendocrine carcinomas," which were 5 small-cell lung carcinomas, 3 well-differentiated intestinal carcinomas, and 1 high-grade neuroendocrine carcinoma of the cervix.

Array-CGH reveals recurrent genomic changes in Merkel cell carcinoma including amplification of L-Myc. KG Paulson, BD Lemos, B Feng, N Jaimes, PF Peñas, X Bi, E Maher, L Cohen, JH Leonard, SR Granter, L Chin, P Nghiem. J Invest Dermatol 2009 Jun;129(6):1547-1555. "Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions."

Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. A Kassem, K Technau, AK Kurz, D Pantulu, M Löning, G Kayser, E Stickeler, W Weyers, C Diaz, M Werner, D Nashan, A Zur Hausen. Int J Cancer 2009 Jul 15;125(2):356-361. 56 nonmelanoma skin cancers (squamous cell carcinoma, basal cell carcinoma, and Bowen's disease) from 11 immunosuppressed patients and 147 NMSCs of 125 immunocompetent patients; normal skin and 89 colorectal cancers as comparison. "MCPyV specific sequences were significantly more frequently found in NMSC of immunosuppressed patients compared to immunocompetent patients (p < 0.001). In particular BD and BCC revealed a significant increased association of MCPyV of immunosuppressed patients (p = 0.002 and p = 0.006). Forty-seven of 147 (32%) sporadic NMSC were MCPyV positive. Interestingly, 37.5% (36/96) of sporadic BCC of immunocompetent patients were MCPyV positive. No MCPyV was detected within normal skin and only 3 out of 89 of additionally tested colorectal cancers were MCPyV positive."

Clinical Factors Associated With Merkel Cell Polyomavirus Infection in Merkel Cell Carcinoma. H Sihto, H Kukko, V Koljonen, R Sankila, T Böhling, H Joensuu. J Natl Cancer Inst 2009 Jun 17. [Epub ahead of print]. 79.8 % of 114 patients with Merkel cell carcinoma in Finland were positive for Merkel cell polyomavirus DNA."Compared with MCPyV DNA-negative cancers, MCPyV DNA-positive cancers were more often located in a limb (40.7% vs 8.7%, P = .015) and less frequent in patients who had regional nodal metastases at diagnosis (6.6% vs 21.7%, P = .043). Patients with MCPyV DNA-positive tumors had better overall survival than those with MCPyV DNA-negative tumors (5-year survival: 45.0% vs 13.0%, respectively; P < .001, two-sided log-rank test)."

Mechanisms

A specific signature of Merkel cell polyomavirus persistence in human cancer cells. H zur Hausen. Proc Natl Acad Sci USA. 2008 Oct 21;105(42):16063-16064. Mutations in the helicase part of the large T antigen of MCpyV result in replication incompetence. These types of mutation in other polyomaviruses have been shown to increase their transformation potential.

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. M Shuda, H Feng, HJ Kwun, ST Rosen, O Gjoerup, PS Moore, Y Chang. Proc Natl Acad Sci USA 2008 Oct 21;105(42):16272-16277. "Nine MCC tumor-derived LT genomic sequences have been examined, and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation." The mutations "do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity." "Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-positive MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a "passenger virus" that secondarily infects MCC tumors."

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cast 06-19-09