Association Between β-Genus Human Papillomavirus and Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals—A Meta-analysis | Dermatology | JAMA Dermatology | JAMA Network
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Gloster  HM  Jr, Neal  K.  Skin cancer in skin of color.  J Am Acad Dermatol. 2006;55(5):741-760.PubMedGoogle ScholarCrossref
Alam  M, Ratner  D.  Cutaneous squamous-cell carcinoma.  N Engl J Med. 2001;344(13):975-983.PubMedGoogle ScholarCrossref
Deady  S, Sharp  L, Comber  H.  Increasing skin cancer incidence in young, affluent, urban populations: a challenge for prevention.  Br J Dermatol. 2014;171(2):324-331.PubMedGoogle ScholarCrossref
Hollestein  LM, de Vries  E, Aarts  MJ, Schroten  C, Nijsten  TEC.  Burden of disease caused by keratinocyte cancer has increased in The Netherlands since 1989.  J Am Acad Dermatol. 2014;71(5):896-903.PubMedGoogle ScholarCrossref
Euvrard  S, Kanitakis  J, Claudy  A.  Skin cancers after organ transplantation.  N Engl J Med. 2003;348(17):1681-1691.PubMedGoogle ScholarCrossref
Feltkamp  MC, de Koning  MN, Bavinck  JN, Ter Schegget  J.  Betapapillomaviruses: innocent bystanders or causes of skin cancer.  J Clin Virol. 2008;43(4):353-360.PubMedGoogle ScholarCrossref
Aldabagh  B, Angeles  JGC, Cardones  AR, Arron  ST.  Cutaneous squamous cell carcinoma and human papillomavirus: is there an association?  Dermatol Surg. 2013;39(1 Pt 1):1-23.PubMedGoogle ScholarCrossref
McLaughlin-Drubin  ME.  Human papillomaviruses and non-melanoma skin cancer.  Semin Oncol. 2015;42(2):284-290.PubMedGoogle ScholarCrossref
Bernard  HU, Burk  RD, Chen  Z, van Doorslaer  K, zur Hausen  H, de Villiers  EM.  Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments.  Virology. 2010;401(1):70-79.PubMedGoogle ScholarCrossref
Van Doorslaer  K, Tan  Q, Xirasagar  S,  et al.  The Papillomavirus Episteme: a central resource for papillomavirus sequence data and analysis.  Nucleic Acids Res. 2013;41(Database issue):D571-D578.PubMedGoogle ScholarCrossref
Feltkamp  MCW, Broer  R, di Summa  FM,  et al.  Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer.  Cancer Res. 2003;63(10):2695-2700.PubMedGoogle Scholar
Lewandowski  F, Lutz  W.  A case of a not previously described skin disease (Epidemodysplasia verruciformis) [in German].  Arch Derrm Syph. 1922;141:193-203.Google ScholarCrossref
Reuschenbach  M, Tran  T, Faulstich  F,  et al.  High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients.  Br J Cancer. 2011;104(8):1334-1341.PubMedGoogle ScholarCrossref
Ulrich  C, Kanitakis  J, Stockfleth  E, Euvrard  S.  Skin cancer in organ transplant recipients—where do we stand today?  Am J Transplant. 2008;8(11):2192-2198.PubMedGoogle ScholarCrossref
Howley  PM, Pfister  HJ.  Beta genus papillomaviruses and skin cancer.  Virology. 2015;479-480:290-296.PubMedGoogle ScholarCrossref
Leitz  J, Reuschenbach  M, Lohrey  C,  et al.  Oncogenic human papillomaviruses activate the tumor-associated lens epithelial-derived growth factor (LEDGF) gene.  PLoS Pathog. 2014;10(3):e1003957.PubMedGoogle ScholarCrossref
Viarisio  D, Decker  KM, Aengeneyndt  B, Flechtenmacher  C, Gissmann  L, Tommasino  M.  Human papillomavirus type 38 E6 and E7 act as tumour promoters during chemically induced skin carcinogenesis.  J Gen Virol. 2013;94(Pt 4):749-752.PubMedGoogle ScholarCrossref
Wallace  NA, Robinson  K, Howie  HL, Galloway  DA.  HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage.  PLoS Pathog. 2012;8(7):e1002807.PubMedGoogle ScholarCrossref
Buitrago-Pérez  Á, Hachimi  M, Dueñas  M,  et al.  A humanized mouse model of HPV-associated pathology driven by E7 expression.  PLoS One. 2012;7(7):e41743.PubMedGoogle ScholarCrossref
Masini  C, Fuchs  PG, Gabrielli  F,  et al.  Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals.  Arch Dermatol. 2003;139(7):890-894.PubMedGoogle ScholarCrossref
Karagas  MR, Nelson  HH, Sehr  P,  et al.  Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin.  J Natl Cancer Inst. 2006;98(6):389-395.PubMedGoogle ScholarCrossref
Casabonne  D, Michael  KM, Waterboer  T,  et al.  A prospective pilot study of antibodies against human papillomaviruses and cutaneous squamous cell carcinoma nested in the Oxford component of the European Prospective Investigation into Cancer and Nutrition.  Int J Cancer. 2007;121(8):1862-1868.PubMedGoogle ScholarCrossref
Waterboer  T, Abeni  D, Sampogna  F,  et al.  Serological association of beta and gamma human papillomaviruses with squamous cell carcinoma of the skin.  Br J Dermatol. 2008;159(2):457-459.PubMedGoogle ScholarCrossref
Bouwes Bavinck  JN, Neale  RE, Abeni  D,  et al; EPI-HPV-UV-CA group.  Multicenter study of the association between betapapillomavirus infection and cutaneous squamous cell carcinoma.  Cancer Res. 2010;70(23):9777-9786.PubMedGoogle ScholarCrossref
Karagas  MR, Waterboer  T, Li  Z,  et al; New Hampshire Skin Cancer Study Group.  Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study.  BMJ. 2010;341:c2986.PubMedGoogle ScholarCrossref
Plasmeijer  EI, Pandeya  N, O’Rourke  P,  et al.  The Association between cutaneous squamous cell carcinoma and betapapillomavirus seropositivity: a cohort study.  Cancer Epidemiol Biomarkers Prev. 2011;20(6):1171-1177.PubMedGoogle ScholarCrossref
Andersson  K, Michael  KM, Luostarinen  T,  et al.  Prospective study of human papillomavirus seropositivity and risk of nonmelanoma skin cancer.  Am J Epidemiol. 2012;175(7):685-695.PubMedGoogle ScholarCrossref
Struijk  L, Hall  L, van der Meijden  E,  et al.  Markers of cutaneous human papillomavirus infection in individuals with tumor-free skin, actinic keratoses, and squamous cell carcinoma.  Cancer Epidemiol Biomarkers Prev. 2006;15(3):529-535.PubMedGoogle ScholarCrossref
Iannacone  MR, Gheit  T, Waterboer  T,  et al.  Case-control study of cutaneous human papillomaviruses in squamous cell carcinoma of the skin.  Cancer Epidemiol Biomarkers Prev. 2012;21(8):1303-1313.PubMedGoogle ScholarCrossref
Struijk  L, Bouwes Bavinck  JN, Wanningen  P,  et al.  Presence of human papillomavirus DNA in plucked eyebrow hairs is associated with a history of cutaneous squamous cell carcinoma.  J Invest Dermatol. 2003;121(6):1531-1535.PubMedGoogle ScholarCrossref
Termorshuizen  F, Feltkamp  MC, Struijk  L, de Gruijl  FR, Bavinck  JN, van Loveren  H.  Sunlight exposure and (sero)prevalence of epidermodysplasia verruciformis-associated human papillomavirus.  J Invest Dermatol. 2004;122(6):1456-1462.PubMedGoogle ScholarCrossref
Iannacone  MR, Gheit  T, Pfister  H,  et al.  Case-control study of genus-beta human papillomaviruses in plucked eyebrow hairs and cutaneous squamous cell carcinoma.  Int J Cancer. 2014;134(9):2231-2244.PubMedGoogle ScholarCrossref
Struijk  L, van der Meijden  E, Kazem  S,  et al.  Specific betapapillomaviruses associated with squamous cell carcinoma of the skin inhibit UVB-induced apoptosis of primary human keratinocytes.  J Gen Virol. 2008;89(Pt 9):2303-2314.PubMedGoogle ScholarCrossref
Plasmeijer  EI, Neale  RE, Buettner  PG,  et al.  Betapapillomavirus infection profiles in tissue sets from cutaneous squamous cell-carcinoma patients.  Int J Cancer. 2010;126(11):2614-2621.PubMedGoogle Scholar
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634.PubMedGoogle ScholarCrossref
Begg  CB, Mazumdar  M.  Operating characteristics of a rank correlation test for publication bias.  Biometrics. 1994;50(4):1088-1101.PubMedGoogle ScholarCrossref
Duval  S, Tweedie  R.  Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.  Biometrics. 2000;56(2):455-463.PubMedGoogle ScholarCrossref
Quint  KD, Genders  RE, de Koning  MN,  et al.  Human Beta-papillomavirus infection and keratinocyte carcinomas.  J Pathol. 2015;235(2):342-354.PubMedGoogle ScholarCrossref
Mendoza  JA, Jacob  Y, Cassonnet  P, Favre  M.  Human papillomavirus type 5 E6 oncoprotein represses the transforming growth factor beta signaling pathway by binding to SMAD3.  J Virol. 2006;80(24):12420-12424.PubMedGoogle ScholarCrossref
Shterzer  N, Heyman  D, Shapiro  B,  et al.  Human papillomavirus types detected in skin warts and cancer differ in their transforming properties but commonly counteract UVB induced protective responses in human keratinocytes.  Virology. 2014;468-470:647-659.PubMedGoogle ScholarCrossref
White  EA, Sowa  ME, Tan  MJ,  et al.  Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses.  Proc Natl Acad Sci U S A. 2012;109(5):E260-E267.PubMedGoogle ScholarCrossref
Akgül  B, Cooke  JC, Storey  A.  HPV-associated skin disease.  J Pathol. 2006;208(2):165-175.PubMedGoogle ScholarCrossref
Fei  JW, de Villiers  EM.  Differential regulation of cutaneous oncoprotein HPVE6 by wtp53, mutant p53R248W and ΔNp63α is HPV type dependent.  PLoS One. 2012;7(4):e35540.PubMedGoogle ScholarCrossref
Cordano  P, Gillan  V, Bratlie  S,  et al.  The E6E7 oncoproteins of cutaneous human papillomavirus type 38 interfere with the interferon pathway.  Virology. 2008;377(2):408-418.PubMedGoogle ScholarCrossref
Gabet  AS, Accardi  R, Bellopede  A,  et al.  Impairment of the telomere/telomerase system and genomic instability are associated with keratinocyte immortalization induced by the skin human papillomavirus type 38.  FASEB J. 2008;22(2):622-632.PubMedGoogle ScholarCrossref
Cornet  I, Bouvard  V, Campo  MS,  et al.  Comparative analysis of transforming properties of E6 and E7 from different beta human papillomavirus types.  J Virol. 2012;86(4):2366-2370.PubMedGoogle ScholarCrossref
Cohen  DN, Lawson  SK, Shaver  AC,  et al.  Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy.  Clin Cancer Res. 2015;21(11):2624-2634.PubMedGoogle ScholarCrossref
Kalinska-Bienias  A, Kostrzewa  G, Malejczyk  M, Ploski  R, Majewski  S.  Possible association between actinic keratosis and the rs7208422 (c.917A→T, p.N306l) polymorphism of the EVER2 gene in patients without epidermodysplasia verruciformis.  Clin Exp Dermatol. 2015;40(3):318-323.PubMedGoogle ScholarCrossref
Vuillier  F, Gaud  G, Guillemot  D, Commere  P-H, Pons  C, Favre  M.  Loss of the HPV-infection resistance EVER2 protein impairs NF-κB signaling pathways in keratinocytes.  PLoS One. 2014;9(2):e89479.PubMedGoogle ScholarCrossref
Gibbs  NK, Norval  M.  Photoimmunosuppression: a brief overview.  Photodermatol Photoimmunol Photomed. 2013;29(2):57-64.PubMedGoogle ScholarCrossref
Original Investigation
December 2016

Association Between β-Genus Human Papillomavirus and Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals—A Meta-analysis

Author Affiliations
  • 1Department of Internal Medicine, The University of Texas Health Science Center, University of Texas Medical School at Houston, Houston
  • 2Department of Management Policy and Community Health, The University of Texas School of Public Health, Houston
  • 3Department of Biostatistics, The University of Texas School of Public Health, Houston
  • 4Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston
  • 5Department of Dermatology, The University of Texas Medical School at Houston, Houston
JAMA Dermatol. 2016;152(12):1354-1364. doi:10.1001/jamadermatol.2015.4530

Importance  Existing epidemiological evidence remains controversial regarding the association between β-genus human papillomavirus (β-HPV) and cutaneous squamous cell carcinoma (cSCC) in immunocompetent individuals.

Objective  We aimed to clarify this association and evaluate type-specific β-HPV involvement.

Data Sources  We performed a systematic literature search of MEDLINE and EMBASE for studies in humans through June 18, 2014, with no restriction on publication date or language. The following search terms were used: “human papillomavirus” and “cutaneous squamous cell carcinoma or skin squamous cell carcinoma or cSCC or nonmelanoma skin neoplasms.”

Study Selection  Articles were independently assessed by 2 reviewers. We only included case-control or cohort studies, in immunocompetent individuals, that calculated the odds ratio (OR) for cSCC associated with overall and type-specific β-HPV.

Data Extraction and Synthesis  We first assessed the heterogeneity among study-specific ORs using the Q statistic and I2 statistic. Then, we used the random-effects model to obtain the overall OR and its 95% CI for all studies as well as for each type of HPV. We also tested and corrected for publication bias by 3 funnel plot–based methods. The quality of each study was assessed with the Newcastle Ottawa Scale.

Main Outcomes and Measures  Pooled ORs and 95% CIs for overall β-HPV and HPV types 5, 8, 15, 17, 20, 24, 36, and 38 association with skin biopsy proven cSCC.

Results  Seventy-nine articles were assessed for eligibility; 14 studies met inclusion criteria for the meta-analysis and included 3112 adult immunocompetent study participants with cSCC 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. Our subgroup analysis in studies using only serology for HPV detection showed a significant association between overall β-HPV and HPV subtypes 5, 8, 17, 20, 24, and 38 with an increased risk of cSCC development.

Conclusions and Relevance  This study serves as added evidence supporting β-HPV as a risk factor for cSCC in healthy individuals. The subgroup analysis highlights this significant association for HPV 5, 8, 17, 20, and 38, which may help to direct future prevention efforts.