Tim Waterboer

Publications (65)336.56 Total impact

• Article: Prospective study of genital human papillomaviruses and non-melanoma skin cancer.

  Kristin Andersson, Tapio Luostarinen, Anna Söderlund Strand, Hilde Langseth, Randi E Gislefoss, Ola Forslund, Michael Pawlita, Tim Waterboer, Joakim Dillner
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  ABSTRACT: Genital high-risk Human Papillomaviruses (HPVs) cause cervical cancer and are also found in a small proportion of non-melanoma skin cancers (NMSC). We used cancer registry linkages to follow the 856,000 serum donors included in the Southern Sweden Microbiology Biobank or the Janus Biobank in Norway, for incident skin cancers occurring up to 30 years after serum donation. Serum samples taken before diagnosis of squamous cell carcinoma (SCC) (N=633), basal cell carcinoma (BCC) (N=1990) or other NMSC (N=153) and matched samples from control donors were tested for antibodies to the genital HPV types 16 and 18. Both HPV 16 and 18 were associated with increased risk for SCC (OR 1.6, 95% CI 1.1-2.6 and OR 1.7, 95% CI 1.1-2.5, respectively) and other NMSC (OR 2.3, 95% CI 1.0-5.2 and OR 3.5, 95% CI 1.4-8.7, respectively), but not for BCC. Tumor blocks from HPV16 or 18 seropositive cases were tested with real time PCR for presence of HPV16 or 18 DNA. No HPV18 DNA was found and only 4/79 SCC cases (two of which were from the perineum/perianal area), 1/221 BCC cases and 0/5 cases with other NMSC contained HPV16 DNA. In conclusion, we found prospective evidence that HPV16 and 18 antibodies associate with SCC and other NMSC risk, but not with BCC risk. As only a small proportion of seropositive subjects had evidence of the corresponding HPV DNA in the tumor, most of this excess risk is likely to be due to confounders associated with genital HPV infection. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 04/2013; · 5.44 Impact Factor
• Article: Cutaneous alpha, beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: A population-based study.

  Shohreh F Farzan, Tim Waterboer, Jiang Gui, Heather H Nelson, Zhongze Li, Kristina M Michael, Ann E Perry, Steven K Spencer, Eugene Demidenko, Adele C Green, Michael Pawlita, Margaret R Karagas
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  ABSTRACT: Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n=1408), histologically-confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2-5, 7-10, 15, 17, 20, 23, 24, 27b, 36, 38, 48-50, 57, 65, 75-77, 88, 92, 95, 96, 101, 103, and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (P for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07-3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies, (meta odds ratio = 1.45, CI = 1.27-1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 03/2013; · 5.44 Impact Factor
• Article: Human Papillomavirus Infections and Upper Aero-Digestive Tract Cancers: The ARCAGE Study.

  Devasena Anantharaman, Tarik Gheit, Tim Waterboer, Behnoush Abedi-Ardekani, Christine Carreira, Sandrine McKay-Chopin, Valerie Gaborieau, Manuela Marron, Pagona Lagiou, Wolfgang Ahrens, [......], Anne-Marie Biggs, Nalin Thakker, Ariana Znaor, Peter Thomson, Cristina Canova, David I Conway, Claire M Healy, Massimo Tommasino, Michael Pawlita, Paul Brennan
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  ABSTRACT: Background Human papillomavirus (HPV) is causally implicated in a subset of cancers of the upper aero-digestive tract (UADT).Methods Associations between type-specific HPV antibodies were examined among 1496 UADT cancer case subjects and 1425 control subjects by estimating odds ratios (ORs) in logistic regression analyses adjusted for potential confounders. The agreement between serology and tumor markers of HPV infection, including presence of HPV DNA and p16 expression, were examined in a subset of tumors.ResultsHPV16 L1 seropositivity was associated with increased risk of oral cavity and oropharyngeal cancer (OR = 1.94, 95% confidence interval [CI] = 1.03 to 3.65; OR = 8.60, 95% CI = 5.21 to 14.20, respectively). HPV16 E6 antibodies were present in 30.2% of oropharyngeal case subjects and only 0.8% of control subjects (OR = 132.0, 95% CI = 65.29 to 266.86). Combined seropositivity to HPV16 E6 and E7 was rare (n = 1 of 1425 control subjects). An agreement of 67% was observed between HPV16 E6 serology and the corresponding presence of an HPV-related cancer: four of six HPV DNA-positive/p16-overexpressing tumors were HPV16 E6 antibody positive. An HPV16 independent association was observed for HPV18 and oropharyngeal cancer (OR = 8.14, 95% CI = 2.21 to 29.99 for HPV18 E6 seropositivity) and HPV6 and laryngeal cancer (OR = 3.25, 95% CI = 1.46 to 7.24 for HPV6 E7 seropositivity). Conclusions These results confirm an important role for HPV16 infection in oropharyngeal cancer. HPV16 E6 antibodies are strongly associated with HPV16-related oropharyngeal cancers. Continuing efforts are needed to consider both HPV serology and p16 staining as biomarkers relevant to the etiology and natural history of HPV16-related oropharyngeal tumors. These results also support a marginal role for HPV18 in oropharyngeal cancer and HPV6 in laryngeal cancer.
  CancerSpectrum Knowledge Environment 03/2013; · 14.07 Impact Factor
• Article: Human Papilloma Virus load in eyebrow hair follicles and risk of cutaneous squamous cell carcinoma.

  Rachel E Neale, Soenke Weissenborn, Damiano Abeni, Jan Nico Bouwes Bavinck, Sylvie Euvrad, Mariet C Feltkamp, Adele C Green, Catherine A Harwood, Maurits Nc de Koning, Luigi Naldi, Ingo Nindl, Michael Pawlita, Charlotte Proby, Wim Quint, Tim Waterboer, Ulrike Wieland, Herbert J Pfister
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  ABSTRACT: BACKGROUND: Beta HPV (betaPV) may play a role in the development of cutaneous squamous cell carcinoma (SCC). However betaPV is highly prevalent, and it may only be people with a higher viral load that have increased risk of SCC. We therefore examined the association between betaPV load and SCC. METHODS: We recruited 448 immunocompetent cases with SCC and 464 controls from Italy and Australia, and 497 immunosuppressed organ transplant recipients (OTR) (179 cases and 318 controls) from Europe. We used reverse hybridization to genotype 25 betaPV types in eyebrow hair follicles, and determined the viral load for 8 selected types using quantitative PCR. We used logistic regression to assess associations between type-specific and cumulative viral load and SCC. RESULTS: Australian and OTR participants in the highest cumulative load tertile were at significantly higher risk of SCC than those in the lowest tertile. Those with more than 4 betaPV types in the high load tertile were at approximately three-fold increased risk of SCC. In Australia HPV23 and 36 loads were significantly associated with SCC, with borderline associations for HPV5 and 38. In OTR HPV8 and 38 loads were significantly associated and HPV20 and 36 were borderline. We found little evidence for an association between load and SCC in Italy. CONCLUSIONS: High viral load may be associated with risk of cutaneous SCC, with total load seemingly more important than the load of any specific type. Impact: Our findings lend weight to the hypothesis that HPV plays a role in skin carcinogenesis.
  Cancer Epidemiology Biomarkers &amp Prevention 02/2013; · 4.12 Impact Factor
• Article: Case-Control Study of Cutaneous Human Papillomavirus Infection in Basal Cell Carcinoma of the Skin.

  Michelle R Iannacone, Tarik Gheit, Tim Waterboer, Anna R Giuliano, Jane L Messina, Neil A Fenske, Basil S Cherpelis, Vernon K Sondak, Richard G Roetzheim, Sandra Ferrer-Gil, Kristina M Michael, Sandrine McKay-Chopin, Michael Pawlita, Massimo Tommasino, Dana E Rollison
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  ABSTRACT: Genus-β human papillomavirus (HPV) DNA has been detected in basal cell carcinoma (BCC) tumors, but most epidemiologic studies have not observed associations between genus-β HPV seropositivity and BCC. A clinic-based case-control study was conducted to investigate cutaneous HPV infection in BCC. BCC cases (n=224) were recruited from a dermatology clinic, and controls (n=300) were patients who were screened negative for skin cancer. Antibodies against cutaneous HPV types in genera α, β, γ, mu, and nu were measured, and tumors from a subset of BCC cases (n=195) were tested for HPV DNA. Overall associations were observed between BCC and seropositivity for HPV types in genus-α (odds ratio (OR)=1.61; 95% confidence interval (CI)=1.11-2.35), γ (OR=1.78; 95% CI=1.22-2.60), and mu (OR=1.56; 95% CI=1.06-2.30). BCC cases with β-HPV DNA in their tumors were more likely to be β-HPV seropositive than controls (OR=1.76; 95% CI=1.03-3.01), with type-specific associations observed for HPV8 and HPV23, whereas no association was observed between β-HPV seropositivity and β-HPV DNA-negative BCC. No concordance between seropositivity and tumor DNA status was observed for HPV types in genera α and γ. In conclusion, the combined serology and tumor DNA results suggest that β HPV types may have a role in BCC. Additional studies of BCC that assess HPV types in multiple genera are needed.Journal of Investigative Dermatology advance online publication, 10 January 2013; doi:10.1038/jid.2012.478.
  Journal of Investigative Dermatology 01/2013; · 6.31 Impact Factor
• Article: Longitudinal study of seroprevalence and serostability of the human polyomaviruses JCV and BKV in organ transplant recipients.

  Annika Antonsson, Michael Pawlita, Mariet C W Feltkamp, Jan N Bouwes Bavinck, Sylvie Euvrard, Catherine A Harwood, Luigi Naldi, Ingo Nindl, Charlotte M Proby, Rachel E Neale, Tim Waterboer
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  ABSTRACT: The human polyomaviruses BKV and JCV cause mostly subclinical infections in childhood. Systemical immunosuppression after organ transplantation can lead to reactivation of persistent polyomavirus infections which may cause rejection of the transplanted organ. BKV and JCV seroprevalence and serostability was measured in 441 European solid organ transplanted recipients. Baseline samples were collected on average 24 days post-transplantation and sera were then collected over an 18 months follow-up period on up to six different time points. The overall seroprevalence at baseline for BKV was 97% with very little change over time. Prevalence for JCV was 76% at baseline and increased to 80% at the end of follow-up. BKV seroprevalence was highest in the youngest age group (100%) and decreased with increasing age (92% in the oldest age group; P < 0.0001), while JCV increased with age (69% vs. 81%; P = 0.020). Antibody reactivities for both BKV and JCV increased significantly with time (P = 0.0002 and P < 0.0001, respectively). Among the 406 patients with several samples, 94% were stably seropositive for BKV and 1% remained seronegative during the follow-up. JCV antibody stability was somewhat lower: 67% remained stably seropositive and 13% seronegative. While seroprevalence of BKV and JCV decrease and increase with age, respectively, both polyomaviruses showed significant increasing antibody reactivity over time in organ transplanted recipients at the onset of immunosuppression. J. Med. Virol. © 2012 Wiley Periodicals, Inc.
  Journal of Medical Virology 11/2012; · 2.82 Impact Factor
• Article: Longitudinal study of seroprevalence and serostability of 34 human papillomavirus types in European organ transplant recipients.

  Annika Antonsson, Tim Waterboer, Jan N Bouwes Bavinck, Damiano Abeni, Maurits de Koning, Sylvie Euvrard, Mariet C W Feltkamp, Adèle C Green, Catherine A Harwood, Luigi Naldi, Ingo Nindl, Herbert J Pfister, Charlotte M Proby, Wim G Quint, Eggert Stockfleth, Sönke J Weissenborn, Michael Pawlita, Rachel E Neale
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  ABSTRACT: Organ transplant recipients (OTR) are at increased risk of cutaneous squamous cell carcinoma, which may be related to reactivation of human papillomavirus (HPV) infections. Measurement of change in HPV antibodies after transplantation would help to explore this hypothesis. We measured antibodies to 34 HPV types on up to six occasions over 18 months in 441 OTRs from five European countries. At baseline (mean 24 days after transplantation), 80% of all OTRs were seropositive to at least one HPV type. The beta HPV genus had the highest seroprevalence (45%). For most HPV genera baseline seroprevalence peaked between 40 and 59 years old. Most OTRs retained their serostatus over time and antibody levels were stable. Seroprevalence in immunosuppressed OTRs is stable in the 18 months immediately after transplantation. Thus there is no short-term evidence that immunosuppression leads to new or reactivated skin infection with HPV sufficient to induce antibodies.
  Virology 11/2012; · 3.35 Impact Factor
• Article: Biomarkers of HPV in Head and Neck Squamous Cell Carcinoma.

  Caihua Liang, Carmen J Marsit, Michael D McClean, Heather H Nelson, Brock C Christensen, Robert I Haddad, John R Clark, Richard O Wein, Gregory A Grillone, E Andres Houseman, Gordana Halec, Tim Waterboer, Michael Pawlita, Jeffrey F Krane, Karl T Kelsey
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  ABSTRACT: Human papillomavirus (HPV) is an accepted cause of head and neck squamous cell carcinoma (HNSCC), and patients with HPV-associated HNSCC have a favorable prognosis. Currently, there is no general guidance on the most appropriate biomarkers for clinical assessment of HPV in these malignancies. We compared PCR-based and serologic HPV assays, as well as p16 immunohistochemistry, individually and in combination in a single population-based study to assess their associations with overall survival among patients with HNSCC, and thus their potential value as biomarkers. HPV16 serology was determined for 488 patients; immunohistochemical detection of p16 expression in tumors was conducted in a subset of 233 cases, and PCR-based methods to assess the presence of HPV16 DNA in a subset of 179 cases of tumors. Considering each biomarker individually in the subset of patients studied for all endpoints, seropositivity for the E6 and E7 proteins was significantly associated with enhanced all-cause survival in oropharyngeal disease [HR(E6/E7+) = 0.1, 95% confidence interval (CI) = 0.02-0.3]. Neither the presence of HPV16 DNA nor p16 immunostaining was associated with significant enhanced overall survival in oropharyngeal disease (HR(DNA) = 0.9, 95% CI = 0.3-2.9; HR(p16) = 0.3, 95% CI = 0.1-1.1). However, the combination of HPV-positive DNA and E6 or E7 serology was associated with enhanced overall survival in oropharyngeal disease (HR(DNA+/E6/E7+) = 0.1, 95% CI = 0.02-1.0), whereas E6/E7 seronegative patients with evidence of HPV in tumor DNA did not show any evidence of favorable survival (HR(DNA+/E6-/E7-) = 3.4, 95% CI = 0.6-18.1). Furthermore, patients with p16 staining and E6 or E7 seropositivity had favorable survival from oropharyngeal disease (HR(p16+/E6/E7+) = 0.1, 95% CI = 0.02-0.4), whereas patients who were p16 positive and E6/E7 seronegative had significantly increased hazard of all causes of death (HR(p16+/E6-/E7-) = 3.1, 95% CI = 1.2-7.7). A stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when "HPV-associated" HNSCC is defined using tumor status (HPV DNA status or P16) and HPV E6/E7 serology in combination rather using tumor HPV status alone. Cancer Res; 72(19); 5004-13. ©2012 AACR.
  Cancer Research 09/2012; 72(19):5004-5013. · 7.86 Impact Factor
• Article: Case-control study of cutaneous human papillomaviruses in squamous cell carcinoma of the skin.

  Michelle R Iannacone, Tarik Gheit, Tim Waterboer, Anna R Giuliano, Jane L Messina, Neil A Fenske, Basil S Cherpelis, Vernon K Sondak, Richard G Roetzheim, Kristina M Michael, Massimo Tommasino, Michael Pawlita, Dana E Rollison
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  ABSTRACT: Cutaneous human papillomavirus (HPV) infection may be a risk factor for squamous cell carcinoma (SCC) of the skin. To investigate the association between cutaneous HPV and SCC, a case-control study was conducted, including 173 SCC cases from a university dermatology clinic and 300 controls that screened negative for skin cancer. Serum antibodies against cutaneous HPV types in genera alpha, beta, gamma, mu, and nu were measured. Tumor tissue from 159 SCC cases was tested for the presence of DNA for genus-beta HPV types. Using logistic regression ORs and 95% confidence intervals (CI) were estimated for the associations between SCC and cutaneous HPV infection, adjusting for age and sex. The Bonferroni method was used to account for multiple comparisons. SCC was positively associated with seropositivity to any genus-beta HPV type (OR, 1.93; 95% CI, 1.23-3.02), particularly with types in species-1 (OR, 1.86; 95% CI, 1.22-2.85). Type-specific associations with SCC were observed for HPV 8 (OR, 1.80; 95% CI, 1.14-2.84), 17 (OR, 1.59; 95% CI, 1.02-2.49) and HPV 10 from genus-alpha (OR, 2.24; 95% CI, 1.04-4.85). None of the type-specific associations remained statistically significant after correction for multiple comparisons. When DNA-positive SCC cases were compared with controls, strong serologic associations were observed for HPVs 5 (OR, 3.48; 95% CI, 1.27-9.59), 17 (OR, 3.36; 95% CI, 1.29-8.72), and 24 (OR, 3.79; 95% CI, 1.24-11.5). Genus-beta HPV infections were associated with SCC in our study population. Identifying the role of cutaneous HPV infection in SCC may lead to improved characterization of high-risk individuals and the development of novel prevention strategies.
  Cancer Epidemiology Biomarkers &amp Prevention 06/2012; 21(8):1303-13. · 4.12 Impact Factor
• Article: Sunlight exposure and cutaneous human papillomavirus seroreactivity in basal cell and squamous cell carcinomas of the skin.

  Michelle R Iannacone, Wei Wang, Heather G Stockwell, Kathleen O'Rourke, Anna R Giuliano, Vernon K Sondak, Jane L Messina, Richard G Roetzheim, Basil S Cherpelis, Neil A Fenske, Kristina M Michael, Tim Waterboer, Michael Pawlita, Dana E Rollison
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  ABSTRACT: Ultraviolet radiation exposure may interact synergistically with cutaneous human papillomavirus (HPV) infection in the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. To investigate differences in the risk of sunlight-associated BCC and SCC by cutaneous genus-specific HPV serostatus, a case-control study was conducted among 204 BCC and 156 SCC cases who were recruited from a university dermatology clinic and 297 controls who had no history of cancer and screened negative for current skin cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between measures of sunlight exposure and BCC/SCC, stratified by genus-specific HPV serostatus, with adjustment for age and sex. Sunburn due to cutaneous sensitivity to sunlight exposure (P = .006) and poor tanning ability (P = .003) were associated with a higher seroprevalence for genus beta HPV types. Poor or no tanning ability was more strongly associated with SCC among individuals who were seropositive for antibodies to cutaneous HPV types in genera alpha (OR, 15.60; 95% CI, 5.40-45.1; P = .01 for interaction) and beta (OR, 6.86; 95% CI, 3.68-12.80; P = .001 for interaction), compared with individuals who were seronegative for these HPV types. Seropositivity for HPV types in genera alpha or beta increased the risk of SCC associated with poor tanning ability.
  The Journal of Infectious Diseases 06/2012; 206(3):399-406. · 6.41 Impact Factor
• Article: Prospective study of human papillomavirus seropositivity and risk of nonmelanoma skin cancer.

  Kristin Andersson, Kristina M Michael, Tapio Luostarinen, Tim Waterboer, Randi Gislefoss, Timo Hakulinen, Ola Forslund, Michael Pawlita, Joakim Dillner
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  ABSTRACT: Cutaneous human papillomaviruses (HPVs) have been associated with squamous cell carcinoma (SCC) in case-control studies, but there are limited data from prospective studies assessing whether virus exposure predicts risk of future cancer development. Two major biobanks, the Southern Sweden Microbiology Biobank (1971-2003) and the Janus Biobank (1973-2003) in Norway, containing samples from 850,000 donors, were searched for incident skin cancer for up to 30 years using registry linkages. Altogether, 2,623 donors with samples taken before diagnosis of SCC or basal cell carcinoma (BCC) of the skin were identified. Prediagnostic samples and samples from 2,623 matched controls were tested for antibodies against 33 types of HPV. Baseline seropositivity to HPV types in genus β species 2 was associated with SCC risk (odds ratio = 1.3, 95% confidence interval: 1.1, 1.7); this was also the case for samples taken more than 18 years before diagnosis (odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). Type-specific persistent seropositivity entailed elevated point estimates for SCC risk for 29 HPV types and decreased point estimates for only 3 types. After multiple hypothesis adjustment, HPV 76 was significantly associated with SCC risk and HPV 9 with BCC risk. In summary, seropositivity for certain HPV types was associated with an increased risk for future development of SCC and BCC.
  American journal of epidemiology 03/2012; 175(7):685-95. · 5.59 Impact Factor
• Source

  Available from: Reza Malekzadeh

  Article: InterSCOPE study: Associations between esophageal squamous cell carcinoma and human papillomavirus serological markers.

  Freddy Sitas, Sam Egger, Margaret I Urban, Philip R Taylor, Christian C Abnet, Paolo Boffetta, Dianne L O'Connell, David C Whiteman, Paul Brennan, Reza Malekzadeh, Michael Pawlita, Sanford M Dawsey, Tim Waterboer
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  ABSTRACT: The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case-control studies conducted in regions with differing background risks of esophageal cancer. We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case-control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided. We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036). We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers.
  CancerSpectrum Knowledge Environment 01/2012; 104(2):147-58. · 14.07 Impact Factor
• Article: Case-control study of Merkel cell polyomavirus infection and cutaneous squamous cell carcinoma.

  Dana E Rollison, Anna R Giuliano, Jane L Messina, Neil A Fenske, Basil S Cherpelis, Vernon K Sondak, Richard G Roetzheim, Michelle R Iannacone, Kristina M Michael, Tarik Gheit, Tim Waterboer, Massimo Tommasino, Michael Pawlita
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  ABSTRACT: Merkel cell polyomavirus (MCV) DNA has been reported in 0% to 25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. We conducted the first serologic case-control study of MCV and SCC. Patients with histologically confirmed cutaneous SCC (n = 173) were recruited from a university dermatology clinic. Controls were individuals who screened negative for and had no history of skin or other cancers (n = 300). Levels of antibodies against capsid antigens for MCV and another polyomavirus, JC virus (JCV), were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases and tested for MCV DNA by multiplexed PCR. Associations between MCV seroreactivity and SCC were estimated by ORs and 95% CIs calculated using logistic regression with adjustment for age and sex. MCV DNA was detected in SCC tumor tissues from 55 (38%) of 145 cases. A statistically significant association was observed between MCV seropositivity and MCV DNA-positive SCC (OR = 2.49, 95% CI = 1.03-6.04), with an almost four-fold association observed when comparing those with MCV antibodies in the fourth versus first quartiles (OR = 3.93, 95% CI = 1.43-10.76, P(trend) = 0.01). No significant associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR = 1.38, 95% CI = 0.76-2.48) or between JCV seropositivity and MCV DNA-positive or DNA-negative SCC. Past exposure to MCV may be a risk factor for SCC. Understanding the role of viral infections in the development of nonmelanoma skin cancer could lead to novel prevention strategies.
  Cancer Epidemiology Biomarkers &amp Prevention 01/2012; 21(1):74-81. · 4.12 Impact Factor
• Article: Dried blood spot samples for seroepidemiology of infections with human papillomaviruses, Helicobacter pylori, Hepatitis C Virus, and JC Virus.

  Tim Waterboer, Bolormaa Dondog, Kristina M Michael, Angelika Michel, Markus Schmitt, Salvatore Vaccarella, Silvia Franceschi, Gary Clifford, Michael Pawlita
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  ABSTRACT: To establish antibody analysis from dried blood spots (DBS) on filter paper for seroepidemiologic infection and cancer association studies, we analyzed data from a population-based study in Mongolia. Using multiplex serology, we analyzed 985 paired DBS and serum samples from the same donors for antibodies to 12 different proteins from four groups of infectious agents: human papillomaviruses (HPV), Helicobacter pylori (H. pylori), hepatitis C virus (HCV), and JC polyomavirus (JCV). Quantitative antibody reactivities in serum and DBS showed good correlation, with median correlation coefficients (Pearson R(2)) of 0.88 (range, 0.80-0.90) for high-titer (i.e., H. pylori, HCV, JCV) and 0.79 (range, 0.72-0.85) for low-titer antibodies (i.e., HPV). For high-titer antibodies, serum and DBS data were comparable (median slope of linear trend line, 1.14; range, 1.09-1.21), whereas for low-titer antibodies, DBS reactivities were lower than in serum (median slope, 0.54; range, 0.50-0.80). By extrapolating seropositivity cutoff points previously defined for serum to DBS, we found high agreement (>89% for all antigens) of dichotomized DBS and serum results and median kappa values for high- and low-titer antibodies of 0.86 and 0.78 (range, 0.78-0.92 and 0.55-0.86), respectively. Epidemiologic associations with known risk factors for HPV antibodies were as strong for DBS as for serum. DBS provide a reliable alternative to serum or plasma for detection of antibodies against various pathogens by multiplex serology. Impact: DBS do not require blood centrifugation and allow storage and shipment at ambient temperature, thus facilitating field work for seroepidemiologic studies especially in environments with limited technical infrastructure.
  Cancer Epidemiology Biomarkers &amp Prevention 12/2011; 21(2):287-93. · 4.12 Impact Factor
• Article: Human papillomavirus genotypes present in the oral mucosa of newborns and their concordance with maternal cervical human papillomavirus genotypes.

  Hanna-Mari Koskimaa, Tim Waterboer, Michael Pawlita, Seija Grénman, Kari Syrjänen, Stina Syrjänen
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  ABSTRACT: To elucidate the concordance of human papillomavirus (HPV) genotypes between the mother and her newborn and to identify risk factors for the vertical transmission of HPV. HPV genotypes present in 329 pregnant women, their newborns, cord blood, and placenta samples were determined by molecular techniques, including using pure DNA for nested polymerase chain reaction. HPV antibodies were tested using multiplex HPV serology. Kappa statistics and the Wilcoxon test were used to assess concordance, and regression analysis was used to calculate ORs and 95% CIs. HPV DNA was detected in 17.9% of oral samples from newborns and in 16.4% of the cervical samples of the mothers. At delivery, mother-newborn pairs had similar HPV-genotype profiles, but this concordance disappeared in 2 months. Oral HPV carriage in newborns was most significantly associated with the detection of HPV in the placenta (OR=14.0; 95% CI, 3.7-52.2; P=.0001). The association between status of the cord blood and oral HPV was also significant at delivery (OR=4.7; 95% CI, 1.4-15.9; P=.015) but disappeared within 1 month. HPV antibodies in infants were of maternal origin (OR=68; 95% CI, 20.1-230.9; P=.0001). HPV is prevalent in oral samples from newborns. The genotype profile of newborns was more restricted than that of the maternal cervical samples. The close maternal-newborn concordance could indicate that an infected mother transmits HPV to her newborn via the placenta or cord blood.
  The Journal of pediatrics 11/2011; 160(5):837-43. · 4.02 Impact Factor
• Source

  Available from: José Eluf-Neto

  Article: Genome-wide association study of HPV seropositivity.

  Dan Chen, James D McKay, Gary Clifford, Valérie Gaborieau, Amélie Chabrier, Tim Waterboer, David Zaridze, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, [......], Victor Wünsch-Filho, José Eluf-Neto, Leticia Fernández Garrote, Elena Matos, Diana Zelenika, Anne Boland, Paolo Boffetta, Michael Pawlita, Mark Lathrop, Paul Brennan
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  ABSTRACT: High-risk α mucosal types of human papillomavirus (HPV) cause anogenital and oropharyngeal cancers, whereas β cutaneous HPV types (e.g. HPV8) have been implicated in non-melanoma skin cancer. Although antibodies against the capsid protein L1 of HPV are considered as markers of cumulative exposure, not all infected persons seroconvert. To identify common genetic variants that influence HPV seroconversion, we performed a two-stage genome-wide association study. Genome-wide genotyping of 316 015 single nucleotide polymorphisms was carried out using the Illumina HumanHap300 BeadChip in 4811 subjects from a central European case-control study of lung, head and neck and kidney cancer that had serology data available on 13 HPV types. Only one association met genome-wide significance criteria, namely that between HPV8 seropositivity and rs9357152 [odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.24-1.50 for the minor allele G; P=1.2 × 10(-10)], a common genetic variant (minor allele frequency=0.33) located within the major histocompatibility complex (MHC) II region at 6p21.32. This association was subsequently replicated in an independent set of 2344 subjects from a Latin American case-control study of head and neck cancer (OR=1.35, 95% CI=1.18-1.56, P=2.2 × 10(-5)), yielding P=1.3 × 10(-14) in the combined analysis (P-heterogeneity=0.87). No heterogeneity was noted by cancer status (controls/lung cancer cases/head and neck cancer cases/kidney cancer cases). This study provides a proof of principle that genetic variation plays a role in antibody reactivity to HPV infection.
  Human Molecular Genetics 09/2011; 20(23):4714-23. · 7.64 Impact Factor
• Article: Factors associated with the seroprevalence of 26 cutaneous and two genital human papillomavirus types in organ transplant patients.

  F Sampogna, J N Bouwes Bavinck, M Pawlita, D Abeni, C A Harwood, C M Proby, M C W Feltkamp, S Euvrard, L Naldi, R E Neale, I Nindl, H Pfister, W G V Quint, T Waterboer
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  ABSTRACT: Viral skin infections are commonly present in organ transplant recipients (OTR). In this study, we aimed to identify factors associated with human papillomavirus (HPV) infections in OTR. Patients with solid-organ transplants were recruited from the outpatient nephrology and dermatology clinics in five European countries. Only patients with no current or past skin cancer were included in this analysis. Serum samples were analysed for antibodies to the L1 proteins of 26 cutaneous and two genital HPV types from five phylogenetic genera (α, β, γ, μ and ν). The most consistent association was found between recreational sun exposure and the seroprevalence of all tested genera, except α. The antibody presence of any β type was higher among people who had been transplanted at least 23 years prior to participation than in those who had been transplanted for less than 7 years. The prevalence of two γ-HPV types (60 and 65) and three β-HPV types (15, 38 and 49) was associated with time since transplantation. The presence of a high number of warts was associated with the presence of any μ-PV or ν-PV types, and having greater than 50 keratotic skin lesions was almost significantly associated with the presence of antibodies to two or more γ-PV. Discrepancies in the results of the present study, as well as in previous reports, may depend on different methodologies and on geographical variations. Our results also indicate that further research with more standardized methods is needed to clarify the role of cutaneous HPV in OTR.
  Journal of General Virology 09/2011; 93(Pt 1):165-74. · 3.36 Impact Factor
• Article: Risk of seropositivity to multiple oncogenic human papillomavirus types among human immunodeficiency virus-positive and -negative Ugandan women.

  P B Namujju, T Waterboer, C Banura, R Muwonge, E K Mbidde, R Byaruhanga, M Muwanga, H-M Surcel, M Pawlita, M Lehtinen
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  ABSTRACT: To understand the prospects for human papillomavirus (HPV) mass vaccination in the setting of a developing country, we studied the co-occurrence of seropositivity to multiple high-risk (hr) HPV types among HIV-positive and HIV-negative Ugandan women. Our seroepidemiological study was conducted among 2053 women attending antenatal clinics. Sera were analysed for antibodies to eight hrHPV types of the α-7 (18/45) and α-9 (16/31/33/35/52/58) species of HPV by using a multiplex serology assay. Our results show that seropositivity for greater than one hrHPV type was as common (18 %) as for a single type (18 %). HIV-positive women had higher HPV16, HPV18 and HPV45 seroprevalences than HIV-negative women. In multivariate logistic regression analysis, age (>30 years) and level of education (secondary school and above) reduced the risk, whereas parity (>5) and HIV-positivity increased the risk for multiple hrHPV seropositivity. However, in stepwise logistic regression analyses, HIV-status remained the only independent, stand-alone risk factor [odds ratio (OR) 1.7, 95 % confidence interval (CI) 1.0-2.8). On the other hand, the risk of HPV16 or HPV18 seropositive women, as compared to HPV16 or HPV18 seronegative women, for being seropositive to other hrHPV types was not significantly different when they were grouped by HIV-status (ORHPV16/HIV+ 12, 95 % CI 4.5-32 versus ORHPV16/HIV- 22, 95 % CI 15-31 and ORHPV18/HIV+ 58, 95 % CI 14-242 versus ORHPV18/HIV- 45, 95 % CI 31-65). In conclusion, seropositivity to HPV16, HPV18 and to non-vaccine hrHPV types is common in Ugandan women, suggesting that there is little natural cross-protective immunity between the types. HIV-positivity was an independent, stand-alone, albeit moderate risk factor for multiple hrHPV seropositivity. HPV mass vaccination may be the most appropriate method in the fight against cervical cancer in the Ugandan population.
  Journal of General Virology 08/2011; 92(Pt 12):2776-83. · 3.36 Impact Factor
• Article: Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients.

  Sönke Weissenborn, Rachel E Neale, Tim Waterboer, Damiano Abeni, Jan Nico Bouwes Bavinck, Adele C Green, Catherine A Harwood, Sylvie Euvrard, Mariet C W Feltkamp, Maurits N C de Koning, Luigi Naldi, Wim G V Quint, Gianpaolo Tessari, Charlotte M Proby, Ulrike Wieland, Herbert Pfister
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  ABSTRACT: There is increasing evidence of an association between human papillomaviruses (HPV) of the beta-genus (beta-PV) and the development of cutaneous squamous cell carcinoma (SCC). The viral DNA load may be an important determinant of pathogenicity, but there are currently no baseline epidemiological data relating to load in people without SCC. We investigated DNA-loads of eight beta-PV types previously associated with risk of SCC. We collected eyebrow hairs from immunocompetent people (ICP) and organ transplant recipients (OTR), determined load by quantitative PCR and obtained demographic, phenotypic, and sun exposure information. Viral loads for ICP from Australia (n = 241) and Italy (n = 223) and OTR from across Europe (n = 318) spanned seven orders of magnitude. The median loads for all types were below one viral DNA copy per 60 cells and were highest for HPV5, HPV8 and HPV20. None of the populations had consistently higher viral loads for all 8 types. However, a higher proportion of OTR were in the top deciles of viral load distributions for six of the eight beta-PV types examined. In a nested analysis of Italian OTR and ICP, this finding was significant for six beta-PV types and cumulative load. Increasing age was significantly associated with higher viral loads in Australia, and there was a weak trend for higher loads with the time elapsed since transplantation in the OTR. We observed a wide distribution of beta-PV loads with OTR significantly more likely to have the highest viral loads. Thus, viral loads may be an important contributor to the higher risk of SCC in OTR.
  Medical Microbiology and Immunology 07/2011; 201(2):117-25. · 3.83 Impact Factor
• Article: The HPV16 transcriptome in cervical lesions of different grades.

  Markus Schmitt, Véronique Dalstein, Tim Waterboer, Christine Clavel, Lutz Gissmann, Michael Pawlita
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  ABSTRACT: Infections with high-risk human papillomaviruses (HPV), mainly HPV type 16, can cause malignant transformation of the human cervical epithelium and cervical cancer (CxCa). Very little is known about the quantitative expression of HPV16 transcripts in cervical lesions of different grades. We have analysed the viral transcriptome in 80 HPV16 DNA positive cervical smears including lesions of different cytological grades, using nucleic acid sequence-based amplification (NASBA)-Luminex hybridisation assays quantifying spliced and unspliced HPV16 transcripts. Based on the quantitative analysis of single transcripts, highly significant changes in transcript levels were observed between different grades of cervical lesions. In conclusion, quantitative expression changes of HPV16 transcript markers may be involved in tumour progression. This study provides a basis for selection of candidate RNA markers for diagnostics of HPV16-related disease.
  Molecular and Cellular Probes 06/2011; 25(5-6):260-5. · 2.08 Impact Factor