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."

Dreau - Ann Surg 2000 abstract / PubMed

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.

Harwood - J Med Virol 2000 abstract / PubMed

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."

Feltkamp / Cancer Res 2003 full article

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)."

Masini - Arch Dermatol 2003 abstract / PubMed

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."

Weissenborn - J Invest Dermatol 2005 abstract / PubMed

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.

Reszec - Int J Mol Med 2005 abstract / PubMed

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."

Struijk / Cancer Epidemiol Biomarkers Prev 2006 full article

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."

Karagas / J Natl Cancer Inst 2006 full article

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."

Hama - J Dermatol 2006 abstract / PubMed

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."

Shahmahmoudi - Cancer Lett 2007 abstract / PubMed

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])."

Forslund - J Infect Dis 2007 abstract / PubMed

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]."

Patel - Int J Cancer 2008 abstract / PubMed

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)."

Asgari - J Invest Dermatol 2008 abstract / PubMed

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."

Waterboer - Br J Dermatol 2008 abstract / PubMed

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%)."

Termine - Ann Oncol 2008 abstract / PubMed

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."

Lee - Arch Pathol Lab Med 2008 abstract / PubMed

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.

Rollison - Int J Cancer 2008 abstract / PubMed

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)."

Patel - J Invest Dermatol 2008 abstract / PubMed

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 Jul;161(1):56-62. 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)."

Mackintosh - Br J Dermatol 2009 abstract / PubMed

Diversity of human papillomavirus types in periungual squamous cell carcinoma. A Kreuter, T Gambichler, H Pfister, U Wieland. Br J Dermatol 2009 Dec;161(6):1262-1269. HPV typing for 36 high-risk and low-risk alpha-HPV types and 25 beta-HPV types. All six periungual lesions, one of eight lesions from the proximal or lateral part of the finger, and none of 11 lesions from the dorsal part of the hand were positive for HPV (HPV26, HPV33, HPV51, HPV56 and HPV73); beta-HPV types were found in only two biopsies.

Kreuter - Br J Dermatol 2009 abstract / PubMed

High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients. M Reuschenbach, T Tran, F Faulstich, W Hartschuh, S Vinokurova, M Kloor, E Krautkrämer, M Zeier, M von Knebel Doeberitz, C Sommerer. Br J Cancer 2011 Apr 12;104(8):1334-1341. 140 non-melanoma skin lesions from 54 immunocompetent patients and 33 immunosuppressed renal allograft recipients. "The highest prevalence of HR-HPV was found in squamous cell cancer (SCC) (46.2% (6 out of 13) in immunosuppressed and 23.5% (4 out of 17) in immunocompetent patients). High-risk human papillomavirus positivity was accompanied by diffuse p16(INK4a) expression in most SCC (P<0.001) and basal cell cancers (P=0.02), while almost all SCC in situ were p16(INK4a) positive irrespective of HR-HPV presence (P=0.66). Diffuse p16(INK4a) expression was associated with lack of pRB expression (P=0.001). p53 was strongly expressed in 40.0% (56 out of 140) of the lesions irrespective of HR-HPV presence."

Reuschenbach - Br J Cancer 2011 abstract / PubMed

Unbiased approach for virus detection in skin lesions. D Bzhalava, H Johansson, J Ekström, H Faust, B Möller, C Eklund, P Nordin, B Stenquist, J Paoli, B Persson, O Forslund, J Dillner. PLoS One 2013 Jun 28;8(6):e65953. 82 swab samples, 28 paraffin-embedded biopsies, 85 fresh-frozen biopsies of squamous cell carcinomas of the skin plus other lesions. They found 15 known (HPV8, HPV12, HPV20, HPV36, HPV38, HPV45, HPV57, HPV59, HPV104, HPV105, HPV107, HPV109, HPV124, HPV138, HPV147), four previously described putative (HPV 915 F 06 007 FD1, FA73, FA101, SE42) and two putatively new HPV types (SE46, SE47).

Bzhalava - PLoS One 2013 full article / PubMed Central
Bzhalava / PLoS One 2013 full article

Apoptosis and In Situ and Invasive Squamous Cell Carcinoma in Sun-Exposed Sites. PP Aung, M Batrani, S Yang, M Mahalingam. Am J Dermatopathol 2013 Dec;35(8):797-803. "Of the selected cases studied with reverse hybridization assay, 7 of 10 (70%) of SCCIS and 3 of 10 (30%) of SCC had β-HPV with HPV-5 being the most common subtype detected... Expression of Bak in 100% of HPV-containing lesions from sun-exposed sites suggests that the virus does not abrogate UV-induced apoptosis."

Aung - Am J Dermatopathol 2013 abstract / PubMed

Human beta papillomavirus DNA study in primary cutaneous squamous cell carcinomas and their corresponding metastases. A Toll, B Lloveras, E Masferrer, C Ferrándiz-Pulido, V García-Patos, T Gheit, RM Pujol, M Tommasino. Arch Dermatol Res 2014 Jan;306(1):93-95. "35 primary cSCCs from 35 patients and their corresponding lymph node metastases. DNA from beta HPV types was detected in 9 % of primary cSCCs and in 13 % of metastases. No primary cutaneous SCC or lymphatic metastases were found to share the same HPV DNA. These data suggest that beta HPV types do not play an etiopathogenic role in advanced stages of squamous cell carcinogenesis."

Toll - Arch Dermatol Res 2014 abstract / PubMed

Association Between β-Genus Human Papillomavirus and Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals-A Meta-analysis. J Chahoud, A Semaan, Y Chen, M Cao, AG Rieber, P Rady, SK Tyring. JAMA Dermatol 2015 Dec 30 [Epub ahead of print]. 14 studies with 3112 adult immunocompetent study participants and 6020 controls. "For all detection methods, the overall association between β-HPV and cSCC was significant with an adjusted pooled OR (95% CI) of 1.42 (1.18-1.72). As for the type-specific analysis, types 5, 8, 15, 17, 20, 24, 36, and 38 showed a significant association with adjusted pooled ORs (95% CIs) of 1.4 (1.18-1.66), 1.39 (1.16-1.66), 1.25 (1.04-1.50), 1.34 (1.19-1.52), 1.38(1.21-1.59), 1.26 (1.09-1.44), 1.23 (1.01-1.50) and 1.37 (1.13-1.67) respectively."

Chahoud - JAMA Dermatol 2015 abstract / PubMed

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.

Lutzner - IARC Sci Publ 1984 abstract / PubMed

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."

Ford - Cancer Res 1998 abstract / PubMed

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.

Song - PNAS 1998 full article / PubMed Central
Song / PNAS 1998 full article

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.

Thomas - J Gen Virol 1999 abstract / PubMed
Thomas / J Gen Virol 1999 full article (pdf)

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.

Purdie - EMBO J 1999 abstract / PubMed
Purdie / EMBO J 1999 full article

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."

Jackson - Genes Dev 2000 abstract / PubMed
Jackson - Genes Dev 2000 Full Article
BAK1 (BCL2 Antagonist Killer 1) / OMIM

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."

Caldeira / J Virol 2003 Full Article

Skin human papillomavirus type 38 alters p53 functions by accumulation of deltaNp73. R Accardi, W Dong, A Smet, R Cui, A Hautefeuille, AS Gabet, BS Sylla, L Gissmann, P Hainaut, M Tommasino. EMBO Rep 2006 Mar;7(3):334-340. "Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of deltaNp73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. DeltaNp73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis."

Accardi - EMBO Rep 2006 full article / PubMed Central
Accardi / EMBO Rep 2006 full article

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."

Ambretti - Br J Dermatol 2007 abstract / PubMed

HPV8 early genes modulate differentiation and cell cycle of primary human adult keratinocytes. B Akgül, L Ghali, D Davies, H Pfister, IM Leigh, A Storey. Exp Dermatol 2007 Jul;16(7):590-599. "The expression of HPV8 early genes either individually or simultaneously caused distinct changes in the keratinocyte morphology and induced an abnormal keratin expression pattern, that included simple epithelial (K8, K18, K19), hyperproliferation-specific (K6, K16), basal-specific (K14, K15) and differentiation-specific (K1, K10) keratins. Our results indicate that expression of HPV8 early genes disrupts the normal keratin expression pattern in vitro. Expression of HPV8-E7 alone caused polyploidy that was associated with decreased expression of p21 and pRb."

Akgül - Exp Dermatol 2007 abstract / PubMed

Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38. AS Gabet, R Accardi, A Bellopede, S Popp, P Boukamp, BS Sylla, JA Londoño-Vallejo, M Tommasino. FASEB J 2008 Feb;22(2):622-632. "Despite elevated levels of hTERT mRNA, the telomerase activity detected in HPV38 E6/E7 keratinocytes was lower than that observed in HPV16 E6/E7 keratinocytes. The low telomerase activation in highly proliferative HPV38 E6/E7 keratinocytes resulted in the presence of extremely short and unstable telomeres. In addition, we observed anaphase bridges, mitotic multipolarity, and dramatic genomic aberrations."

Gabet - FASEB J 2008 abstract / PubMed

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."

Massimi - Virology 2008 abstract / PubMed

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."

Bedard / J Virol 2008 full article

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."

Cordano - Virology 2008 abstract / PubMed

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."

Vasiljević - Virus Res 2008 abstract / PubMed

Cutaneous papillomavirus E6 proteins must interact with p300 and block p53-mediated apoptosis for cellular immortalization and tumorigenesis. P Muench, S Probst, J Schuetz, N Leiprecht, M Busch, S Wesselborg, F Stubenrauch, T Iftner. Cancer Res 2010 Sep 1;70(17):6913-6924. "[T]he cottontail rabbit papillomavirus (CRPV) rapidly induces skin cancer without additional cofactors, and CRPVE6 and E7 immortalize rabbit keratinocytes in vitro. However, CRPVE6 neither interacts with E6AP and p53 nor does it induce p53 degradation... In this study, we show that the interaction of CRPVE6, or HPV38E6, with the histone acetyltransferase p300 is crucial to inhibit the ability of p53 to induce apoptosis."

Muench - Cancer Res 2010 abstract / PubMed

Transcriptome Sequencing Demonstrates that Human Papillomavirus Is Not Active in Cutaneous Squamous Cell Carcinoma. ST Arron, JG Ruby, E Dybbro, D Ganem, JL Derisi. J Invest Dermatol 2011 Aug;131(8):1745-1753. No transcripts of HPV16 or HPV18 were found in any of 20 cutaneous squamous cell carcinomas positive for β-HPV.

Arron - J Invest Dermatol 2011 abstract / PubMed

Dendritic cell subsets and immunological milieu in inflammatory human papilloma virus-related skin lesions. Y Nakayama, K Asagoe, A Yamauchi, T Yamamoto, Y Shirafuji, S Morizane, G Nakanishi, K Iwatsuki. J Dermatol Sci 2011 Sep;63(3):173-183. "The numbers of Langerhans cells (LCs) and the expression levels of MIP-3α and E-cadherin were decreased in non-inflammatory warts and HPV-Bowen, as compared with normal skin. Both epidermal LCs and MIP-3α expression reappeared in inflammatory warts, associated with dermal infiltrates composed of many cytotoxic T cells and various subsets of DCs, while cellular infiltrates in HPV-Bowen contained many B cells and plasma cells with sparse infiltration of DCs. The upregulation of MIP-3α gene expression was confirmed in the inflammatory warts and HPV-Bowen by ISH and RT-qPCR."

Nakayama - J Dermatol Sci 2011 abstract / PubMed

Comparative analysis of transforming properties of E6 and E7 from different beta HPV types. I Cornet, V Bouvard, MS Campo, M Thomas, L Banks, L Gissmann, J Lamartine, BS Sylla, R Accardi, M Tommasino. J Virol 2012 Feb;86(4):2366-2370. 6 uncharacterized beta HPVs (14, 22, 23, 24, 36, 49). "Only HPV49 E6 and E7 immortalize primary human keratinocytes and efficiently deregulate the p53 and pRb pathways. Furthermore, HPV49 E6, similarly to E6 from the oncogenic HPV16, promotes p53 degradation."

Cornet - J Virol 2012 abstract / PubMed

HPV 5 and 8 E6 Abrogate ATR Activity Resulting in Increased Persistence of UVB Induced DNA Damage. NA Wallace, K Robinson, HL Howie, DA Galloway. PLoS Pathogens 2012 Jul;8(7):e1002807. "Here, we show that the expression of HPV 5 and 8 E6 increases thymine dimer persistence as well as the likelihood of a UVB induced double strand break (DSB). Importantly, we provide a mechanism for the increased DNA damage by showing that both extended thymine dimer persistence as well as elevated DSB levels are dependent on the ability of HPV 8 E6 to promote p300 degradation. We further demonstrate that HPV 5 and 8 E6 expression reduces the mRNA and protein levels of ATR, a PI3 kinase family member that plays a key role in UV damage signaling, but that these levels remain unperturbed in cells expressing a mutated HPV 8 E6 incapable of promoting p300 degradation."

Wallace / PLoS Pathogens 2012 full article

The Human Papillomavirus Type 8 E6 Protein Interferes with NOTCH Activation during Keratinocyte Differentiation. JM Meyers, JM Spangle, K Munger. J Virol 2013 Apr;87(8):4762-4767. "Here we report that HPV type 8 (HPV8) E6 subverts NOTCH activation during keratinocyte differentiation by inhibiting RBPJ/MAML1 transcriptional activator complexes at NOTCH target DNA. NOTCH inhibition impairs epithelial differentiation and may thus contribute to β-HPV replication and viral oncogenesis."

Meyers - J Virol 2013 abstract / PubMed

β-HPV E6 expression inhibits p53 stabilization and increases the tolerance of genomic instability. NA Wallace, K Robinson, DA Galloway. J Virol 2014 Jun;88(11):6112-6127. "We show that β-HPV E6 proteins can prevent the stabilization of p53 in response to two types of genome destabilizing events, aberrant mitosis as well as disregulated centrosome duplication. The inability to stabilize p53 in response to these stimuli allows HPV 5, 8, and 38 E6 expressing cells to remain proliferatively active, leading to further genome deterioration in a proportion of the cells undergoing."

Wallace - J Virol 2014 abstract / PubMed

β-HPV 5 and 8 E6 Disrupt Homology Dependent Double Strand Break Repair by Attenuating BRCA1 and BRCA2 Expression and Foci Formation. NA Wallace, K Robinson, HL Howie, DA Galloway. PLoS Pathog 2015 Mar 24;11(3):e1004687. "Here we show that β-HPV 5 and 8 E6 further disrupt the repair of these DSBs and provide a mechanism for this attenuation. By binding and destabilizing a histone acetyltransferase, p300, β-HPV 5 and 8 E6 reduce the enrichment of the transcription factor at the promoter of two genes critical to the homology dependent repair of DSBs (BRCA1 and BRCA2). The resulting diminished BRCA1/2 transcription not only leads to lower protein levels but also curtails the ability of these proteins to form repair foci at DSBs."

Wallace / PLoS Pathog 2015 full article

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)."

Chen - J Gen Virol 2008 abstract / PubMed

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."

Weissenborn / J Virol 2009 abstract

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.

Meyer - Dermatology 2000 abstract / PubMed

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."

Antonsson - J Virol 2000 Full Article / PubMed Central
Antonsson - J Virol 2000 Full Article

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).

Brink / J Clin Microbiol 2005 abstract

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."

Nindl - J Virol Methods 2007 abstract / PubMed

Bead-based multiplex genotyping of 58 cutaneous human papillomavirus types. KM Michael, O Forslund, O Bacevskij, T Waterboer, IG Bravo, M Pawlita, M Schmitt. J Clin Microbiol 2011 Oct;49(10):3560-3567. Assay for 38 defined and 20 putative cutaneous HPVs of the beta, gamma, mu, and nu genera. "McPG is characterized by high reproducibility (κ= 0.84, 95% confidence interval = 0.79 to 0.88), good concordance with the original nested FAP PCR, followed by sequencing (70.2% complete or partial agreement) when 322 skin biopsy DNA samples were analyzed, and improved ability to detect multiple infections (on average 2.5 HPV types per HPV-positive sample compared to 1.7 HPV types with nested FAP-PCR)."

Michael - J Clin Microbiol 2011 abstract / PubMed

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).

zur Hausen - Biochim Biophys Acta 1996 abstract / PubMed
BBC News 2000

See Also:

Merkel Cell Polyomavirus Causes Skin Cancer
Confounding By Infection - why studies that don't include full detection of HPV (and other causal infections) are defective, and falsely blame smoking and other non-causal associations.
HPV Strains and Oncogenicity
HPV Causes Head and Neck Cancers
HPV Causes Oral Cancer
HPV is implicated in laryngeal cancer
HPV Causes Lung Cancer
HPV Infects Kids

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cast 01-10-16