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A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)–based approaches to screen for early stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.

The recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women.Participants received at age 10-18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women.The dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination.Our study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination.

Background Humoral immune responses may be critical for preventing, controlling, and/or eliminating human papillomavirus (HPV) infection. We analyzed humoral response to natural HPV infection considering phylogenetic relatedness among unvaccinated women. Methods We included 399 young women attending university/college in Montreal, Canada who were participants of the HITCH cohort. Participants provided blood samples at baseline and 5 follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase (GST) fusion proteins, and virus-like particles (VLP-L1) of Alphapapillomavirus types were measured using multiplex serology. We assessed correlations and associations between HPV types at baseline using Pearson correlation coefficients (r) and univariable linear regressions. Results At baseline, > 40% were seropositive for GST-L1 antibodies of at least 1 HPV type. Strong correlations between GST-L1 were observed for α9 HPV types: 58–52 (r = 0.86), 58–33 (r = 0.75), 33–52 (r = 0.72), and between GST-E6: 52–11 (r = 0.84), 52–18 (r = 0.79), 58–33 (r = 0.78), 35–11 (r = 0.76). HPV16 VLP-L1 moderately explained variability in HPV16 GST-L1 (regression coefficient [b] = 0.38, R2 = 43.1%), and HPV45 GST-L1 in HPV18 GST-L1 (b = 0.68, R2 = 42.8%). GST-E6 antibodies accounted for a low to moderate proportion of variability in HPV16 and HPV18 GST-E6 (R2 = 6.4%–62.2%). Conclusions Associations between naturally induced HPV-specific antibodies depend on phylogenetic relatedness.

South Africa's HIV epidemic has evolved over time in terms of numbers of people living with HIV, access to antiretroviral treatment (ART) and age. These changes have profoundly influenced local cancer patterns. The Johannesburg Cancer Study has, over a period of 22 years (1995-2016), recruited over 20 000 incident black cancer patients who consented to provide answers to a questionnaire and blood samples (serum, DNA). This has presented a unique opportunity to examine the evolving association of HIV with cancer in Africa. We used logistic regression models to explore case-control associations between specific cancers and HIV, using participants with non-infection related cancers as controls. Using data of 20 835 cancer patients with confirmed HIV status, we found the following cancers to be associated with HIV: Kaposi's sarcoma (OR

Background Sexually transmitted infections, specifically Chlamydia trachomatis (CT), may be associated with epithelial ovarian cancer (EOC) risk. The association between CT and EOC subtypes is unclear. Our aim was to investigate whether history of CT and other infections (M. genitalium (MG), herpes simplex virus type 2, and human papillomaviruses) are associated with EOC risk by histotype. Methods We measured antibodies (Ab) to CT, MG, HSV2, and HPV-16 and 18 in serum samples in a nested case-control study in the Finnish Maternity Cohort (n= 484 cases 1:1 matched to controls). Logistic Regression was used to calculate relative risks (RRs) and 95% confidence intervals [CIs] in seropositive vs. seronegative individuals in all cases, as well as serous (n=249), clear cell and endometrioid (n=91), and mucinous (n=142) EOC. Results CT-seropositivity was not associated with EOC risk (e.g., CT pGP3-Ab RR=0.92 [0.72- 1.19]), regardless of disease subtype. We observed a positive association between MG-seropositivity and mucinous EOC (RR=1.66 [1.09-2.54]; p­het_histotype≤0.001), but not other subtypes. No associations were observed with seropositivity to multiple STIs. Conclusions CT infection was not associated with EOC risk, with associations observed only for MG and mucinous EOC. Mechanisms linking MG to mucinous EOC remain to be elucidated.

Human papillomavirus (HPV) infections drive one in twenty new cancer cases. Despite the potential for improving treatment, screening, and vaccination strategies, little is known as to why most HPV infections clear spontaneously within two years. To untangle the dynamics of these non-persisting infections, we performed a combined quantitative analysis of virological, immunological, and clinical data from an original longitudinal cohort of 189 women with high temporal resolution. We find that HPV viral load reaches a plateau within two months, and clears within a median time of 14 months. Furthermore, we identify immune correlates associated with infection clearance, especially TCR-gamma-delta cells. Our results open new perspectives for understanding the frontier between acute and chronic infections and for controlling HPVassociated diseases.

Supplementary Table 1

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 “at-risk” people (screening) and 133 “high-risk” people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P < 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88% for DEIA, Cobas, and E6 antibodies, respectively), but specificity was reduced (93%–97%). Aptima had poor sensitivity (23%). Sensitivity decreased when cotesting HPV16 oral rinse DNA and E6 antibodies (37%–48%), or multiple E antibodies (69%–72%). HPV16 DNA were detected in ∼2% of the at-risk by either DEIA or Cobas and up to 15% of the high-risk population. HPV16 E6 seroprevalence was 2.3% and 2.4% in the at-risk and high-risk populations, respectively. Oral rinse HPV testing had moderate-to-poor sensitivity for HPV-OPC, suggesting many true positives would be missed in a potential screening scenario. HPV16 E6 serum antibody was the most promising biomarker evaluated.

Supplementary Table S1: Smoking and gastric cancer risk by time between blood draw and diagnosis, the H. pylori Biomarker Cohort Consortium (HpBCC) Supplementary Table S2: Smoking and gastric cancer risk by sex, the H. pylori Biomarker Cohort Consortium (HpBCC) Supplementary Table S3: Smoking and gastric cancer risk by country, the H. pylori Biomarker Cohort Consortium (HpBCC)

Smoking is an established risk factor for gastric cancer development. In this study, we aimed to assess prospectively the association of smoking with gastric cancer risk in 1,446 non-cardia gastric cancer cases and 1,796 controls from China, Japan, and Korea with consideration of Helicobacter pylori infection as a potential effect modifier. Applying logistic regression models stratified by study and adjusted for age and sex we found that current, but not former, smoking was significantly associated with gastric cancer risk [OR = 1.33; 95% confidence interval (CI), 1.07–1.65]. However, the association was significant only in H. pylori sero-positive individuals determined by 3 different sero-markers: overall sero-positivity, sero-positivity to the onco-protein CagA, and sero-positivity to the gastric cancer associated sero-marker HP0305 and HP1564. Specifically, a significant interaction was found when stratifying by HP0305/HP1564 (Pinteraction = 0.01) with a 46% increased risk of gastric cancer among HP0305/HP1564 sero-positive current smokers (95% CI, 1.10–1.93) as opposed to no increased gastric cancer risk among HP0305/HP1564 sero-negative current smokers (OR = 0.93; 95% CI, 0.65–1.33). We confirmed that current smoking is associated with an increased gastric cancer risk, however, only among individuals that are simultaneously sero-positive for the leading causal factor for gastric cancer, H. pylori.

Background: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted.Methods: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and Results: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2–51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3–15.4); E2 (OR, 7.7; 95% CI, 1.4–29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6–119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9–81.8). No associations were observed with moderate HPV16 E6 seroreactivity.Conclusions: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors.Impact: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection. Cancer Epidemiol Biomarkers Prev; 24(4); 683–9. ©2015 AACR.

Supplementary methods, tables and figures.

PDF file - 45K, Associations between cumulative HPV load and SCC, stratified by skin type and time since transplantation (for OTR). In each case the reference category is HPV negative combined with the lowest load tertile.

Background: Beta-human papillomavirus (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 who have increased risk of SCCs. We therefore examined the association between betaPV load and SCCs.Methods: We recruited 448 immunocompetent cases with SCCs 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 eight selected types using quantitative PCR. We used logistic regression to assess associations between type-specific and cumulative viral load and SCCs.Results: Australian and OTR participants in the highest cumulative load tertile were at significantly higher risk of SCCs than those in the lowest tertile. Those with more than four betaPV types in the high load tertile were at approximately three-fold increased risk of SCCs. In Australia, HPV23 and 36 loads were significantly associated with SCCs, 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 SCCs in Italy.Conclusions: High viral load may be associated with risk of cutaneous SCCs, 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 Epidemiol Biomarkers Prev; 22(4); 719–27. ©2013 AACR.

Supplementary Table S1 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

Overall survival by HPV-status. Overall survival stratified by HPV-status based on A) molecular HPV-status, B) seropositivity to HPV-16 E6, C) seropositivity to any high-risk HPV-types and D) by molecular HPV-status if available and seropositivity to any high-risk HPV-types if molecular HPV-status was unavailable. Overall survival was significantly longer regardless of the definition of HPV-status (p

Supplementary Table S5 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

Association of different combinations of four antibodies (CagA, VacA, NapA, and GroEL) with gastric adenocarcinoma and its subtypes.

The reported associations with gastric adenocarcinoma and seropositivity to different Helicobacter pylori antigens using multiplex serology have not been consistent across studies. We aimed to investigate the association between 15 different multiplex serology antigens and the risk of gastric cardia (GCA) and gastric noncardia (GNCA) adenocarcinomas in northeastern Iran, a population with high rates of gastric adenocarcinoma. We included 272 cases of gastric adenocarcinoma (142 GCA, 103 GNCA, and 27 unspecified) and 524 controls who were individually matched to cases for age, sex, and place of residence in a population-based case–control study. Seropositivity to H. pylori was assessed using both multiplex serology and H. pylori IgG ELISA. Ninety-five percent of controls were seropositive to H. pylori. Of the 15 antibodies in the multiplex assay, 11 showed no significant association with gastric adenocarcinomas. CagA and VacA were associated with a significantly increased risk of all gastric adenocarcinoma and GNCA in multivariate models. Surprisingly, GroEL and NapA were significantly associated with a reduced risk of these tumors. Only CagA antigen was associated with significantly elevated risk of GCA. We found no associations between H. pylori seropositivity overall either by whole-cell ELISA test or multiplex serology, likely due to the high prevalence of seropositivity. Individual antigen testing showed that CagA positivity was associated with increased risk of both noncardia and cardia adenocarcinoma, which is similar to some other Asian populations, whereas two antigens were associated with lower risk of gastric cancer. This latter result was unexpected and should be retested in other populations. Cancer Res; 75(22); 4876–83. ©2015 AACR.

Supplementary Table S4 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

Patient characteristics (non-oropharyngeal patients)

Supplemental Table 1. Study-specific definitions for categorization of tobacco and alcohol use.

Background: Merkel cell polyomavirus (PyV) is causally related to Merkel cell carcinoma, a rare skin malignancy. Little is known about the serostability of other PyVs over time or associations with cutaneous squamous cell carcinoma (SCC).Methods: As part of a U.S. nested case–control study, antibody response against the PyV VP1 capsid proteins of BK and John Cunningham virus (JC) was measured using multiplex serology on 113 SCC cases and 229 gender, age, and study center–matched controls who had a prior keratinocyte cancer. Repeated serum samples from controls and both pre and postdiagnosis samples from a subset of SCC cases were also tested. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using conditional logistic regression.Results: Among controls, BK and JC seroreactivity was stable over time, with intraclass correlation coefficients of 0.86 for BK and 0.94 for JC. Among cases, there was little evidence of seroconversion following SCC diagnosis. JC seropositivity prior to diagnosis was associated with an elevated risk of SCC (OR = 2.54; 95% CI, 1.23–5.25), and SCC risk increased with increasing quartiles of JC (Ptrend = 0.004) and BK (Ptrend = 0.02) seroreactivity.Conclusions: PyV antibody levels were stable over time and following an SCC diagnosis. A history of PyV infection may be involved in the occurrence of SCC in a population at high risk for this malignancy.Impact: A single measure of PyV seroreactivity appears a reliable indicator of long-term antibody status, and PyV exposure may be a risk factor for subsequent SCC. Cancer Epidemiol Biomarkers Prev; 25(5); 736–44. ©2016 AACR.

Prognostic impact of antibody responses to cancer antigens stratified by HPV-status. Overall survival was significantly shorter for patients with {greater than or equal to}2 AR, AR to c-myc, MAGåE-A1, MAGE-A4 and Rhodopsin E2 in the HPV-negative cohort and IMP-1 in the HPV-positive cohort. Overall survival was calculated using the Kaplan-Meier method and p-values were determined using logrank tests. Results were corrected for multiple testing with a false discovery rate of 15%.

Purpose: The human epigenome is profoundly altered in cancers, with a characteristic loss of methylation in repetitive regions and concomitant accumulation of gene promoter methylation. The degree to which these processes are coordinated is unclear so we investigated both in head and neck squamous cell carcinomas.Experimental Design: Global methylation was measured using the luminometric methylation assay (LUMA) and pyrosequencing of LINE-1Hs and AluYb8 repetitive elements in a series of 138 tumors. We also measured methylation of more than 27,000 CpG loci with the Illumina HumanMethylation27 Microarray (n = 91).Results:LINE-1 methylation was significantly associated with LUMA and Infinium loci methylation (Spearman's ρ = 0.52/ρ = 0.56, both P < 0.001) but not that of AluYb8. Methylation of LINE-1, AluYb8, and Infinium loci differed by tumor site (each Kruskal–Wallis, P < 0.05). Also, LINE-1 and LUMA methylation were associated with HPV16 E6 serology (each Mann–Whitney, P < 0.05). Comparing LINE-1 methylation to gene-associated methylation, we identified a distinct subset of CpG loci with significant hypermethylation associated with LINE-1 hypomethylation. An investigation of sequence features for these CpG loci revealed that they were significantly less likely to reside in repetitive elements (Gene Set Enrichment Analysis, P < 0.02), enriched in CpG islands (P < 0.001) and were proximal to transcription factor–binding sites (P < 0.05). We validated the top CpG loci that had significant hypermethylation associated with LINE-1 hypomethylation (at EVI2A, IFRD1, KLHL6, and PTPRCAP) by pyrosequencing independent tumors.Conclusions: These data indicate that global hypomethylation and gene-specific methylation processes are associated in a sequence-dependent manner, and that clinical characteristics and exposures leading to HNSCC may be influencing these processes. Clin Cancer Res; 17(11); 3579–89. ©2011 AACR.

Purpose:The identification of high-risk patients within human papillomavirus (HPV)-positive and -negative head and neck squamous cell carcinoma (HNSCC) is needed for improved treatment and surveillance strategies. In this study, we set out to discover antibody responses (AR) with prognostic impact in HNSCC stratified by HPV status.Experimental Design:A fluorescent bead–based multiplex serology assay on 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens, and 8 oncogenes) and 29 HPV antigens was performed in samples of 362 patients with HNSCC from five independent cohorts (153 HPV positive, 209 HPV negative). A multivariable Cox proportional hazard model with bootstrapping (M = 1000) was used for validation of prognostic antibody responses.Results:Antibody response to any of the cancer antigens was found in 257 of 362 patients (71%). In HPV-negative patients, antibody responses to c-myc, MAGE-A1, -A4, and Rhodopsin E2 (combined as ARhigh risk) were significantly associated with shorter overall survival. In HPV-positive patients, antibody responses to IMP-1 were discovered as a negative prognostic factor. ARhigh risk (HR = 1.76) and antibody responses to IMP-1 (HR = 3.28) were confirmed as independent markers for a poor prognosis in a multivariable Cox proportional hazard model with bootstrapping (M = 1000).Conclusions:We identified antibody responses to cancer antigens that associate with a dismal prognosis in patients with HNSCC beyond HPV-positive status. ARhigh risk may be used to detect HPV-negative patients with an extraordinarily bad prognosis. Most importantly, antibody response to IMP-1 may serve as a marker for a subgroup of HPV-positive patients who present with a poor prognosis similar to that in HPV-negative patients.

Consort diagram of the study cohort.

Cutaneous human papillomavirus (cuHPV) infections may be novel targets for skin cancer prevention and treatment, but critical information regarding the development of virus-positive skin cancers following cuHPV infection has been lacking. In this study, baseline cuHPV infection was measured by serology and viral DNA detection in eyebrow hairs (EBH) and forearm skin swabs (SSW) among 1,008 individuals undergoing routine skin cancer screening exams and followed for incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC). Baseline β-HPV detection, particularly in SSW, significantly predicted cuSCC (HR = 4.32; 95% confidence interval, 1.00–18.66), whereas serologic evidence of past β-HPV infection was not associated with cuSCC. Less than 5% of baseline β-HPV types detected in SSW were present in subsequent cuSCC tumors, and cuHPV detected in SSW with higher mean fluorescence intensity values were more likely to be present in cuSCC compared with those with lower levels (P < 0.001). β-HPV-positive cuSCC occurred more often in areas of highly sun-damaged skin than did β-HPV-negative cuSCC. Overall, no clear patterns were observed between baseline β-HPV detection and subsequent development of BCC, or between baseline γ-HPV detection and either cuSCC or BCC. Collectively, these results demonstrate that β-HPV detection in SSW is a significant predictor of cuSCC risk, although evidence suggests only a small subset of cuSCC is etiologically linked to β-HPV infection.Significance:β-HPV positivity may be a useful biomarker for identifying individuals who could benefit from increased screening or novel cutaneous squamous cell carcinoma prevention strategies.

Supplementary Table S2 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

Supplementary Figures S1-S4 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

Supplemental Figure 1. Flowchart of the "Skin Cancer Prevention Study" randomized clinical trial (RCT) design from which the study group was derived. Supplemental Figure 2. Robustness of human polyomavirus (PyV) seroprevalence estimates among 229 controls from the Skin Cancer Prevention Study. Supplemental Figure 3. Robustness of odds ratio (OR) estimates obtained from conditional logistic regression analysis for cutaneous squamous cell carcinoma (SCC) by seropositivity for each polyomavirus (PyV) type among 306 study participants from the Skin Cancer Prevention Study. Supplemental Figure 4. Robustness of odds ratio (OR) estimates obtained from unconditional logistic regression analysis for cutaneous squamous cell carcinoma (SCC) by seropositivity for each polyomavirus (PyV) type among 342 study participants from the Skin Cancer Prevention Study, with adjustment for continuous age, gender, and study center. Supplemental Figure 5. Plot of conditional (left) and unconditional (right) odds ratios (95% confidence intervals as whiskers) for cutaneous squamous cell carcinoma (SCC) by seropositivity for each polyomavirus type among study participants from the Skin Cancer Prevention Study. Supplemental Figure 6. Plot of conditional (left) and unconditional (right) odds ratios (95% confidence intervals as whiskers) for cutaneous squamous cell carcinoma (SCC) by seropositivity for each polyomavirus type among study participants from the Skin Cancer Prevention Study. Supplemental Table 1. Distribution of BK and JC human polyomavirus (PyV) seropositivity by selected baseline characteristics among 229 controls from the Skin Cancer Prevention Study. Supplemental Table 2. Unconditional odds ratios (95% confidence intervals) for cutaneous squamous cell carcinoma (SCC) by seropositivity for each polyomavirus (PyV) type and quartiles of PyV seroreactivity at baseline among 342 study participants from the Skin Cancer Prevention Study.

PDF file - 62K, Concordance of the detecting markers in subset of subjects with complete data and HPV16 serological markers, Eastern Massachusetts, 1999-2003

PDF file - 67KB, Antibodies to type-specific HPV proteins and the risk of lung cancer.

Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case–control studies (retrospective) and one nested case–control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer. Cancer Res; 74(13); 3525–34. ©2014 AACR.

PDF file - 35K, ROC curves for HPV assays. AUC=Area under the Curve. P=0.024 from the DeLong's tests comprising the AUCs of E7 and DNA (MPG); P=0.05 comparing the AUCs of E7 and L1 (MS)

Supplementary Appendix, Tables 1-2 from Diagnosing Cervical Cancer and High-Grade Precursors by HPV16 Transcription Patterns

PDF file - 55KB, Association between type-specific HPV antibodies and risk of lung cancer by seropositivity threshold.

PDF file - 63K, The association between selected markers and overall survival of HNSSC patients stratified by tumor sites, Eastern Massachusetts, 1999-2003

PDF file - 52KB, Comparison of HPV16 DNA positivity by sex, smoking status and lung histology.

PDF file - 64K, Characteristics among the whole cases and those with DNA or P16 detected, Eastern Massachusetts, 1999-2003

PDF file - 65K, The association between selected markers and overall survival of HNSSC patients with and without adjustment for tumor stages, Eastern Massachusetts, 1999-2003

PDF file - 74K, The association between presence of HPV DNA detected by varying positive thresholds and overall survival of HNSSC patients stratified by tumor sites, Eastern Massachusetts, 1999-2003

PDF file - 78K, Overall survival among HNSCC patients by HPV markers and tumor sites, Eastern Massachusetts, 1999-2003

This cross-sectional analysis examines whether circulating tumor human papillomavirus DNA is detectable in the plasma of healthy participants at risk for oral human papillomavirus infection and the agreement with oral rinse and serum biomarkers.

Helicobacter pylori infection has been suggested to be associated with lung cancer risk. However, information is lacking on whether the association differs by H. pylori antigen. We conducted a nested case-control study within the Southern Community Cohort Study, including 295 incident lung cancer cases and 295 controls. Helicobacter pylori multiplex serology assay was performed to detect antibodies to 15 H. pylori proteins. Conditional logistic regression was used to estimate odds ratios (ORs) and confidence intervals (95% CIs) after adjustment for covariates. Overall H. pylori+ was associated with a non-statistically significant increased risk of lung cancer (OR: 1.29; 95% CI: 0.85–1.95). Significant associations, however, were observed for H. pylori+ VacA+ (OR: 1.64; 95% CI: 1.02–2.62) and H. pylori+ Catalase+ (OR: 1.75; 95% CI: 1.11–2.77). The positive association of H. pylori+ Catalase+ with lung cancer risk was predominantly seen among African Americans (OR: 2.09; 95% CI: 1.11–3.95) but not European Americans (OR: 1.20; 95% CI: 0.56–2.54). Among participants who smoked ≥ 30 pack-years, overall H. pylori+ (OR: 1.85; 95% CI: 1.02–3.35), H. pylori+ CagA+ (OR: 2.77; 95% CI: 1.35–5.70), H. pylori+ VacA+ (OR: 2.53; 95% CI: 1.25–5.13) and H. pylori+ HP1564+ (OR: 2.01; 95% CI: 1.07–3.77) were associated with increased risk of lung cancer. Our study provides novel evidence that associations of H. pylori infection with lung cancer risk differ by H. pylori biomarker, may be more evident among African Americans and may be modified by smoking habits. Furthermore, studies are warranted to confirm our findings.

Aims/hypothesis The prevalence of type 2 diabetes is increasing worldwide, and previous studies have suggested that it is higher in individuals who are seropositive for herpesviruses. This study examines the prospective association of herpesviruses with (pre)diabetes to evaluate their potential role in diabetes aetiology. Methods Two follow-up examinations of the German population-based KORA cohort (F4 and FF4) were used to identify participants with normal glucose tolerance at baseline, thus being at risk for (pre)diabetes (n = 1257). All participants had repeated OGTTs and antibody measurements for herpes simplex virus (HSV) 1 and 2, varicella-zoster virus, Epstein–Barr virus, cytomegalovirus (CMV) and human herpesvirus 6 and 7. Regression models were used to evaluate the association between serostatus with (pre)diabetes incidence after a 7 year follow-up and HbA1c. Results HSV2 and CMV were associated with (pre)diabetes incidence after adjustment for sex, age, BMI, education, smoking, physical activity, parental diabetes, hypertension, lipid levels, insulin resistance and fasting glucose. Seropositivity of both viruses was also cross-sectionally associated with higher HbA1c at baseline, with the association of HSV2 being independent of confounders, including the prevalence of (pre)diabetes itself. While seropositivity for multiple herpesviruses was associated with a higher incidence of (pre)diabetes, this association was not independent of confounders. Conclusions/interpretation The associations of HSV2 and CMV serostatus with (pre)diabetes incidence indicate that these herpesviruses may contribute to the development of impaired glucose metabolism. Our results highlight the link between viral infection and (pre)diabetes, and the need for more research evaluating viral prevention strategies. Graphical abstract

Glioma is an aggressive neoplasm of the brain with poorly understood etiology. A limited number of pathogens have been examined as glioma risk factors, but data from prospective studies with infection status determined before disease are lacking. Herpesviruses comprise a large family of DNA viruses that infect humans and are linked to a range of chronic diseases. We conducted a prospective evaluation of the association between antibody to six human herpesviruses and glioma risk in the Janus Serum Bank (Janus) and the Cancer Prevention Study-II (CPS-II). In Janus and CPS-II, the risk for glioma was not related to seroprevalence of herpes simplex virus-1, varicella zoster virus, or human herpes viruses 6A or 6B. In Janus, seropositivity to either the Epstein Barr virus (EBV) EA[D] or VCAp18 antigen was associated with a lower risk of glioma (ORs: 0.55 [95% CI 0.32-0.94] and 0.57 [95% CI 0.38-0.85]). This inverse association was consistent by histologic subtype and was observed for gliomas diagnosed up to two decades following antibody measurement. In Janus, seropositivity to at least one of three examined cytomegalovirus (CMV) antigens (pp150, pp52, pp28) was associated with an increased risk of nonglioblastoma (OR: 2.08 [95% CI 1.07-4.03]). This association was limited to tumors diagnosed within 12 years of antibody measurement. In summary, we report evidence of an inverse association between exposure to EBV and glioma. We further report that CMV exposure may be related to a higher likelihood of the nonglioblastoma subtype.

Background: It is unknown whether reactivation of human papillomavirus (HPV) after latency occurs in the anus. We measured incidence and predictors of incident anal HPV in sexually inactive gay and bisexual men (GBM) as a surrogate of HPV reactivation. Methods: The Study of the Prevention of Anal Cancer collected data on sexual behavior, anal cytology, HPV DNA, histology and HPV serology. HPV incidence during periods when zero sexual partners were reported in the last six months at both the current and previous annual visit (“no sexual activity”) was analyzed by Cox regression using the Wei-Lin-Weissfeld method to determine univariable predictors. Results: Of 617 men enrolled, 525 had results for ≥2 visits, of whom 58 (11%) had ≥ one period of “no sexual activity”. During sexually inactive periods, there were 29 incident high risk HPV infections in 20 men, which occurred more commonly in older men (Ptrend = 0.010), HIV-positive men (HR = 3.12; 95% CI, 0.91–16.65), longer duration of HIV (Ptrend = 0.028), history of AIDS defining illness (P = 0.010), lower current (P = 0.010) and nadir CD4 count (P = 0.014). For 18 of 29 infections with available results, 12 men remained type-specific HRHPV L1 seronegative. None were consistently seropositive. A new diagnosis of HSIL occurred in only two men, caused by an HPV type other than the incident type. Conclusions: Our findings suggest that in sexually inactive GBM, anal HRHPV incidence is relatively common, and is associated with increasing age and immune dysfunction, a pattern consistent with HPV reactivation. Impact: Reactivation of anal HPV may occur.