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1.  Time since first sexual intercourse and the risk of cervical cancer 
Young age at first sexual intercourse is an important risk factor for cervical cancer, but no simple statistical model of its influence has been established. We investigated the relationship between risk of cervical carcinoma and time since first intercourse using data on monogamous women (5,074 cases and 16,137 controls) from the International Collaboration of Epidemiological Studies of Cervical Cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from pooled data on 20 studies using conditional logistic regression. The OR for invasive cervical carcinoma is approximately proportional to the square of time since first intercourse (exponent 1.95, 95% CI: 1.76–2.15) up to age 45. First cervical infection with human papillomavirus (HPV) often occurs soon after first sexual intercourse, so early age at first sexual intercourse is a reasonable proxy for early age at first exposure to HPV. In addition, age-specific incidence rates of cervical cancer in unscreened populations remain fairly constant above age 45. Cervical cancer thus resembles other cancers caused by strong early-stage carcinogens, with incidence rates proportional to a power of time since first exposure and also resembles cancers of the breast and other hormone-dependent epithelia where a similar flattening of age-specific incidence rates is seen at the time menopausal changes start. Taken together, these observations suggest that HPV vaccination may prevent the majority of cervical cancers by delaying HPV infection without necessarily providing lifetime protection against HPV.
doi:10.1002/ijc.26250
PMCID: PMC3982220  PMID: 21702036
cervical carcinoma; cervical intraepithelial neoplasia; age at first sexual intercourse; multi-stage carcinogenesis
2.  Hepatitis C and Non-Hodgkin Lymphoma Among 4784 Cases and 6269 Controls From the International Lymphoma Epidemiology Consortium 
Background & Aims
Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin’s lymphoma (NHL) subtypes after HCV infection.
Methods
The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded.
Results
HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40–2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44–4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68–2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14–5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65–1.60).
Conclusions
These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma).
doi:10.1016/j.cgh.2008.02.011
PMCID: PMC3962672  PMID: 18387498
3.  Genetic Variants in Nicotine Addiction and Alcohol Metabolism Genes, Oral Cancer Risk and the Propensity to Smoke and Drink Alcohol: A Replication Study in India 
PLoS ONE  2014;9(2):e88240.
Background
Genetic variants in nicotinic acetylcholine receptor and alcohol metabolism genes have been associated with propensity to smoke tobacco and drink alcohol, respectively, and also implicated in genetic susceptibility to head and neck cancer. In addition to smoking and alcohol, tobacco chewing is an important oral cancer risk factor in India. It is not known if these genetic variants influence propensity or oral cancer susceptibility in the context of this distinct etiology.
Methods
We examined 639 oral and pharyngeal cancer cases and 791 controls from two case-control studies conducted in India. We investigated six variants known to influence nicotine addiction or alcohol metabolism, including rs16969968 (CHRNA5), rs578776 (CHRNA3), rs1229984 (ADH1B), rs698 (ADH1C), rs1573496 (ADH7), and rs4767364 (ALDH2).
Results
The CHRN variants were associated with the number of chewing events per day, including in those who chewed tobacco but never smoked (P =  0.003, P =  0.01 for rs16969968 and rs578776 respectively). Presence of the variant allele contributed to approximately 13% difference in chewing frequency compared to non-carriers. While no association was observed between rs16969968 and oral cancer risk (OR =  1.01, 95% CI =  0.83– 1.22), rs578776 was modestly associated with a 16% decreased risk of oral cancer (OR =  0.84, 95% CI =  0.72– 0.98). There was little evidence for association between polymorphisms in genes encoding alcohol metabolism and oral cancer in this population.
Conclusion
The association between rs16969968 and number of chewing events implies that the effect on smoking propensity conferred by this gene variant extends to the use of smokeless tobacco.
doi:10.1371/journal.pone.0088240
PMCID: PMC3914962  PMID: 24505444
4.  Upscaling human papillomavirus vaccination in high-income countries: impact assessment based on transmission model 
Background
The decrease in human papillomavirus (HPV) vaccine prices may allow upscale already started vaccination programmes but the advantages of different options are unclear.
Methods
Using a mathematical model of HPV16 and 18 transmission and data on vaccination coverage from Italy, we compared 3 options to upscale an already started programme targeting 11-year old girls (coverage 65%): a) coverage improvement (from 65% to 90%); b) addition of 11-year-old boys (coverage 65%); or c) 1-year catch-up of older girls (coverage 50%).
Results
The reduction of cervical HPV16/18 infection as compared to no vaccination (i.e. effectiveness against HPV16/18) increased from 76% to 98% with coverage improvement in girls and to 90% with the addition of boys. With higher coverage in girls, HPV16/18 infection cumulative probability by age 35 decreased from 25% to 8% with a 38% increase in vaccine number. The addition of boys decreased the cumulative probability to 18% with a 100% increase in the number of vaccinees. For any coverage in girls, the number of vaccinees to prevent 1 woman from being infected by HPV16/18 by age 35 was 1.5, whereas it was 2.7 for the addition of boys. Catch-up of older girls only moved forward the vaccination effectiveness by 2–5 years.
Conclusions
Increasing vaccination coverage among girls is the most effective option for decreasing HPV16/18. If not achievable, vaccinating boys is justifiable if vaccine cost has at least halved, because this option would almost double the number of vaccinees.
doi:10.1186/1750-9378-9-4
PMCID: PMC3901332  PMID: 24438317
Human papillomavirus; Vaccination; High-income; Mathematical model
5.  Clustering patterns of human papillomavirus infections among HIV-positive women in Kenya 
Background
HIV-positive women are at increased risk of human papillomavirus (HPV) infection, and, especially, multiple infections compared to HIV-negative women. Whether certain HPV types have a tendency to cluster in multiple infections beyond or below what would be expected by shared risk factors (e.g., sexual behavior and the degree of immunosuppression) is unclear. We, therefore, investigated clustering patterns of 44 HPV types in HIV-positive women from Kenya.
Findings
HPV status was assessed on cervical scrapings from 498 women using GP5+/6+ PCR and reverse line blot. Logistic regression was used to model type-specific HPV positivity, adjusted for age, specific HPV type prevalence, CD4, combination antiretroviral therapy, and, in the Full Model, individual-level random effects that represent unobservable risk factors common to all HPV types. We found a modest excess of women with co-infections with 2 HPV types (1.12; 95% credible intervals: 1.03-1.21) in the Full Model but no significant associations of individual types. No significant deviations of observed/expected counts were observed for any 2-way combination of HPV types at either the chosen level of significance, p = 0.00005, or at p = 0.01. Findings were substantially similar when women with CIN2/3 were excluded and when they were stratified by use of anti-retroviral therapy or CD4 count.
Conclusions
HPV co-infections occurred at random in the cervix of HIV-positive women as previously found in HIV-negative women. The removal of HPV types through vaccination should not result, therefore, in an increase or decrease in the prevalence of HPV types not targeted by vaccination in immunosuppressed women.
doi:10.1186/1750-9378-8-50
PMCID: PMC3878246  PMID: 24355034
Human papillomavirus; HIV; Prevalence; Women; Multiple infections
6.  Prevalence of Human Papillomavirus and Cervical Intraepithelial Neoplasia in China: A pooled analysis of 17 Population-based Studies 
High-risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR-HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly inform on the cervical cancer burden in the country. 30,207 women from 17 population-based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen), visual inspection with acetic acid, and liquid-based cytology. Women positive for any test received colposcopy-directed or 4-quadrant biopsies. 29,579 women had HR-HPV testing results, of whom 28,761 had biopsy-confirmed (9019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR-HPV prevalence was 17.7%. HR-HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25–29 years (11.3%) in rural and at age 35–39 (11.3%) in urban women. In rural and urban women, age-standardized CIN2 prevalence was 1.5% (95%CI: 1.4%–1.6%) and 0.7% (95%CI: 0.7%–0.8%), and CIN3+ prevalence was 1.2% (95%CI: 1.2%–1.3%) and 0.6% (95%CI: 0.5%–0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR-HPV positive women steadily increased with age, peaking in 45–49 year-old women. High prevalence of HR-HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group 45–49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is under-reported.
doi:10.1002/ijc.27571
PMCID: PMC3435460  PMID: 22488743
Cervical Cancer; Human Papillomavirus; Cervical Intraepithelial Neoplasia; Prevalence; China
7.  Type-Specific Human Papillomavirus Biological Features: Validated Model-Based Estimates 
PLoS ONE  2013;8(11):e81171.
Infection with high-risk (hr) human papillomavirus (HPV) is considered the necessary cause of cervical cancer. Vaccination against HPV16 and 18 types, which are responsible of about 75% of cervical cancer worldwide, is expected to have a major global impact on cervical cancer occurrence. Valid estimates of the parameters that regulate the natural history of hrHPV infections are crucial to draw reliable projections of the impact of vaccination. We devised a mathematical model to estimate the probability of infection transmission, the rate of clearance, and the patterns of immune response following the clearance of infection of 13 hrHPV types. To test the validity of our estimates, we fitted the same transmission model to two large independent datasets from Italy and Sweden and assessed finding consistency. The two populations, both unvaccinated, differed substantially by sexual behaviour, age distribution, and study setting (screening for cervical cancer or Chlamydia trachomatis infection). Estimated transmission probability of hrHPV types (80% for HPV16, 73%-82% for HPV18, and above 50% for most other types); clearance rates decreasing as a function of time since infection; and partial protection against re-infection with the same hrHPV type (approximately 20% for HPV16 and 50% for the other types) were similar in the two countries. The model could accurately predict the HPV16 prevalence observed in Italy among women who were not infected three years before. In conclusion, our models inform on biological parameters that cannot at the moment be measured directly from any empirical data but are essential to forecast the impact of HPV vaccination programmes.
doi:10.1371/journal.pone.0081171
PMCID: PMC3882251  PMID: 24400036
8.  Vitamin or mineral supplement intake and the risk of head and neck cancer: pooled analysis in the INHANCE consortium 
To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual-level pooled data from 12 case-control studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, and 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta-carotene, iron, selenium, and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, and pack-years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR=0.76, 95% CI=0.59-0.96) and with ever use of calcium supplement (OR=0.64, 95% CI=0.42-0.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR=0.72, 95% CI=0.54-0.97) and more than 365 tablets of cumulative calcium intake (OR=0.36, 95% CI=0.16-0.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of head and neck cancer.
doi:10.1002/ijc.27405
PMCID: PMC3376697  PMID: 22173631
vitamin supplement; mineral supplement; head and neck cancer
9.  Characteristics and survival of head and neck cancer by HPV status: a cancer registry-based study 
Elucidation of the role of human papillomavirus (HPV) in the etiology and prognosis of squamous carcinomas of the head and neck (HNSCC) is essential to optimize prevention and treatment strategies for this disease. We analyzed 385 HNSCC tissue blocks identified through a population-based cancer registry in Metropolitan Detroit for HPV DNA using a broad-spectrum PCR technique (SPF10-LiPA25) to correlate with patient and tumor characteristics and overall survival. Overall, HPV DNA (any type) was detected in 29.4% of all HNSCC, but it was significantly more prevalent (50.6%) in oropharyngeal sites (N=81), where 90% of HPV were type 16, than in other sites. HPV prevalence (any type) in oropharyngeal sites was highest in patients with a negative smoking indicator, Caucasians, and in regional tumor stage. Likewise, only in oropharyngeal sites did patients overall positive to HPV show significantly better survival compared with HPV-negative patients, notably among those who had been irradiated. The best and the worst survival from cancer in oropharyngeal sites were found, respectively, among HPV-positive patients with negative smoking indicator and among HPV-negative patients with positive smoking indicator. The results of the present study revealed that the presence of HPV DNA was associated with patients’ specific characteristics and better overall survival exclusively in oropharyngeal sites. To define the fraction of HNSCC preventable by HPV vaccination or amenable to less aggressive treatment, however, tobacco exposure and HPV markers other than DNA presence need to be taken into account.
doi:10.1002/ijc.26500
PMCID: PMC3319485  PMID: 22020866
Human papillomavirus (HPV); PCR; Surveillance, Epidemiology and End Results; Head and neck cancer; Survival
10.  Patterns of Human Papillomavirus Types in Multiple Infections: An Analysis in Women and Men of the High Throughput Human Papillomavirus Monitoring Study 
PLoS ONE  2013;8(8):e71617.
Background
To evaluate the pattern of co-infection of human papillomavirus (HPV) types in both sexes in Sweden.
Methods
Cell samples from genital swabs, first-void urine, and genital swabs immersed in first-void urine were collected in the present cross-sectional High Throughput HPV Monitoring study. Overall, 31,717 samples from women and 9,949 from men (mean age 25) were tested for 16 HPV types using mass spectrometry. Multilevel logistic regression was used to estimate the expected number of multiple infections with specific HPV types, adjusted for age, type of sample, and accounting for correlations between HPV types due to unobserved risk factors using sample-level random effects. Bonferroni correction was used to allow for multiple comparisons (120).
Results
Observed-to-expected ratio for any multiple infections was slightly above unity in both sexes, but, for most 2-type combinations, there was no evidence of significant departure from expected numbers. HPV6/18 was found more often and HPV51/68 and 6/68 less often than expected. However, HPV68 tended to be generally underrepresented in co-infections, suggesting a sub-optimal performance of our testing method for this HPV type.
Conclusions
We found no evidence for positive or negative clustering between HPV types included in the current prophylactic vaccines and other untargeted oncogenic types, in either sex.
doi:10.1371/journal.pone.0071617
PMCID: PMC3747214  PMID: 23977090
11.  FAMILY HISTORY OF CANCER: POOLED ANALYSIS IN THE INTERNATIONAL HEAD AND NECK CANCER EPIDEMIOLOGY (INHANCE) CONSORTIUM 
Alcohol and tobacco consumption are well recognized risk factors for head and neck cancer (HNC). Evidence suggests that genetic predisposition may also play a role. Only a few epidemiologic studies, however, have considered the relation between HNC risk and family history of HNC and other cancers. We pooled individual- level data across 12 case-control studies including 8,967 HNC cases and 13,627 controls. We obtained pooled odds ratios (OR) using fixed and random effect models, and adjusting for potential confounding factors. All statistical tests were two-sided. A family history of HNC in first-degree relatives increased the risk of HNC (OR=1.7, 95% confidence interval, CI, 1.2-2.3). The risk was higher when the affected relative was a sibling (OR=2.2, 95% CI 1.6-3.1) rather than a parent (OR=1.5, 95% CI 1.1-1.8), and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher, or limited to, subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5-9.5) among subjects with family history, who were alcohol and tobacco users. A weak but significant association (OR=1.1, 95% CI 1.0-1.2) emerged for family history of other tobacco-related neoplasms, particularly with laryngeal cancer (OR=1.3, 95% CI 1.1-1.5). No association was observed for family history of non-tobacco related neoplasms and the risk of HNC (OR=1.0, 95% CI 0.9-1.1). Familial factors play a role in the etiology of HNC. In both subjects with and without family history of HNC, avoidance of tobacco and alcohol exposure may be the best way to avoid HNC.
doi:10.1002/ijc.23848
PMCID: PMC3711193  PMID: 18814262
Head and neck cancer; family history; pooled analysis; tobacco; alcohol
12.  Difference in overall and age-specific prevalence of high-risk human papillomavirus infection in Italy: evidence from NTCC trial 
BMC Infectious Diseases  2013;13:238.
Background
Although among women a decreasing prevalence of human papillomavirus (HPV) infection with increasing age has been consistently observed in high-resource countries, different age profiles have been reported elsewhere.
Methods
We compared the age profile of high-risk (HR)-HPV prevalence in nine different areas of Northern and Central Italy by studying the women recruited in the intervention arm of the New Technologies in Cervical Cancer study and tested by Hybrid Capture 2. Differences in the age-distribution of HPV infection were investigated in each centre by the joinpoint approach in a logistic model. 46,900 women aged 25 to 60 years were included in the analysis.
Results
The HR-HPV age-standardised (on Italian population) prevalence ranged from 5.7% (Trento) to 10.3% (Ravenna). HR-HPV prevalence decreased as a logistic function of increasing age in 6 of 9 centres (Trento, Verona, Florence, Bologna, Imola, and Viterbo). The effect of age on HR-HPV prevalence slopes did not differ significantly among these 6 centres, whereas significant heterogeneity in intercepts (p < 0.001) was found, reflecting different overall HR-HPV prevalence between centres. One significant joinpoint was observed in 2 centres (Padua and Ravenna), indicating that the decrease in HR-HPV prevalence by age was better described using a function composed with two logistic segments. In Padua HR-HPV prevalence decreased only slightly up to 39 years but showed a steep downturn thereafter. In Ravenna HR-HPV prevalence decreased steeply down to 45 years of age and then showed a plateau. Finally, in Turin two significant joinpoints were observed: prevalence decreased only after age 29 and showed a plateau after age 39.
Conclusions
Our results showed substantial differences in overall and age-specific HR-HPV prevalence across Italian areas. These findings may be related to different timing of changes in sexual behaviours across regions. Age-specific HR-HPV prevalence in Italy does not support an influence of age per se.
doi:10.1186/1471-2334-13-238
PMCID: PMC3669053  PMID: 23706168
Human papillomavirus; Prevalence; Age-specific
13.  Diet and the Risk of Head and Neck Cancer: A Pooled Analysis in the INHANCE Consortium 
Cancer causes & control : CCC  2011;23(1):69-88.
We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake, was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random effects logistic regression model. An inverse association was observed for higher frequency intake of fruit (4th vs. 1st quartile OR=0.52, 95% CI=0.43–0.62, ptrend<0.01) and vegetables (OR=0.66, 95% CI=0.49–0.90, ptrend=0.01). Intake of red meat (OR=1.40, 95% CI=1.13–1.74, ptrend=0.13) and processed meat (OR=1.37, 95% CI=1.14–1.65, ptrend<0.01) were positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR=0.90, 95% CI=0.84–0.97).
doi:10.1007/s10552-011-9857-x
PMCID: PMC3654401  PMID: 22037906
Diet; head and neck cancer; fruit and vegetable; red meat; processed meat
14.  Human papillomavirus type 16 E6 variants in France and risk of viral persistence 
Background
Only a small portion of HPV 16 infections persist and can lead to cervical intraepithelial lesions and cancer. Factors that favour HPV persistence versus clearance are still poorly understood, but several studies have suggested that HPV intra-type variants may influence persistence and clinical outcome. The aim of this study was to assess the possible association between HPV 16 variants and the risk for viral persistence in the general population of France.
Methods
One hundred and forty two women infected with HPV 16 with normal cytology, without previous treatment for cervical lesions, and with a valid second follow-up visit 4 to 16 months later, were selected from patients participating in routine cervical cancer screening in the Reims HPV Primary Screening Cohort Study. HPV intra-type variants were determined by sequencing the HPV 16 E6 open reading frame, and were compared for viral persistence at the second visit using odds ratios (OR) to estimate relative risk.
Results
Although no statistically significant differences in risk for persistence were observed by the HPV 16 variant lineage, European variants containing the polymorphism 350 T (EUR-350 T) appeared to persist more often than those containing 350 G (EUR-350 G) (OR = 1.6, 95% CI = 0.8-3.4).
Conclusions
No strong differences were observed in the risk of viral persistence for the HPV 16 variants that predominate in France.
doi:10.1186/1750-9378-8-4
PMCID: PMC3562255  PMID: 23343041
Cervical cancer screening; Cohort; Polymorphism; HPV; Variants; Persistence
15.  Human Papillomavirus Type 16 Genetic Variants: Phylogeny and Classification Based on E6 and LCR 
Journal of Virology  2012;86(12):6855-6861.
Naturally occurring genetic variants of human papillomavirus type 16 (HPV16) are common and have previously been classified into 4 major lineages; European-Asian (EAS), including the sublineages European (EUR) and Asian (As), African 1 (AFR1), African 2 (AFR2), and North-American/Asian-American (NA/AA). We aimed to improve the classification of HPV16 variant lineages by using a large resource of HPV16-positive cervical samples collected from geographically diverse populations in studies on HPV and/or cervical cancer undertaken by the International Agency for Research on Cancer. In total, we sequenced the entire E6 genes and long control regions (LCRs) of 953 HPV16 isolates from 27 different countries worldwide. Phylogenetic analyses confirmed previously described variant lineages and subclassifications. We characterized two new sublineages within each of the lineages AFR1 and AFR2 that are robustly classified using E6 and/or the LCR. We could differentiate previously identified AA1, AA2, and NA sublineages, although they could not be distinguished by E6 alone, requiring the LCR for correct phylogenetic classification. We thus provide a classification system for HPV16 genomes based on 13 and 32 phylogenetically distinguishing positions in E6 and the LCR, respectively, that distinguish nine HPV16 variant sublineages (EUR, As, AFR1a, AFR1b, AFR2a, AFR2b, NA, AA1, and AA2). Ninety-seven percent of all 953 samples fitted this classification perfectly. Other positions were frequently polymorphic within one or more lineages but did not define phylogenetic subgroups. Such a standardized classification of HPV16 variants is important for future epidemiological and biological studies of the carcinogenic potential of HPV16 variant lineages.
doi:10.1128/JVI.00483-12
PMCID: PMC3393538  PMID: 22491459
16.  Clustering of Human Papillomavirus (HPV) Types in the Male Genital Tract: The HPV in Men (HIM) Study 
The Journal of Infectious Diseases  2011;204(10):1500-1504.
Objective. To evaluate clustering patterns of prevalent infection with multiple human papillomavirus (HPV) types in 3677 men from the HPV in Men (HIM) study.
Methods. HPV testing was performed in samples combined from the glans penis/coronal sulcus, the shaft, and the scrotum by Linear Array methodology. Linear Array uses a mixed probe to assess HPV52 positivity, which limits the assay’s ability to determine HPV52 status in the presence of HPV33, 35, or 58. Logistic regression was used to model type-specific HPV positivity, adjusted for age, study area, lifetime number of sexual partners, and specific HPV type prevalence. Participant-level random effects were added to represent unobservable risk factors common to all HPV types.
Results. The observed-to-expected ratio for infections with ≥ 3 types was 1.09 (95% credible interval, 1.04–1.14). For the majority of 2-type combinations, no evidence was found of a significant departure of the observed from the expected number. An apparent clustering of HPV52 with HPV35 or 58 was observed, because of limitation in the ability of Linear Array to define HPV52 positivity.
Conclusions. Our study showed that, despite obvious anatomical differences, HPV coinfections do seem to occur at random in the male external genitalia as in the female cervix.
doi:10.1093/infdis/jir595
PMCID: PMC3222106  PMID: 21908729
17.  Testing of human papillomavirus in lung cancer and non-tumor lung tissue 
BMC Cancer  2012;12:512.
Background
Risk factors for lung cancer, such as cigarette smoking, environmental pollution, asbestos, and genetic determinants, are well-known, whereas involvement of the human papillomavirus (HPV) is still unclear.
Methods
We examined a series of 100 lung cancer patients from Italy and the UK for the presence of HPV DNA in both lung tumor specimens and adjacent non-tumoral specimens from the same patients. Thirty-five of the most clinically relevant HPV types were assayed using PCR amplification of the highly conserved L1 region of the viral genome followed by hybridization with specific probes.
Results
No HPV was detected in tumor specimens nor in normal lung tissue of any patient.
Conclusions
These data indicate that, in this Western series, HPV is not associated with the risk of lung cancer. Our findings will help refine estimates of lung cancer risk in patients affected by a common viral infection involved in other types of human cancer.
doi:10.1186/1471-2407-12-512
PMCID: PMC3537645  PMID: 23140419
Biomarker; Cancer; HPV; Lung
18.  An Examination of Male and Female Odds Ratios by BMI, Cigarette Smoking and Alcohol Consumption for Cancers of the Oral Cavity, Pharynx and Larynx in Pooled Data from 15 Case-Control Studies 
Cancer causes & control : CCC  2011;22(9):1217-1231.
Background
Greater tobacco smoking and alcohol consumption and lower body mass index (BMI) increase odds ratios (OR) for oral cavity, oropharyngeal, hypopharyngeal and laryngeal cancers; however, there are no comprehensive sex-specific comparisons of ORs for these factors.
Methods
We analyzed 2,441 oral cavity (925 females and 1,516 males), 2,297 oropharynx (564 females and 1,733 males), 508 hypopharynx (96 females and 412 males) and 1,740 larynx (237 females and 1,503 males) cases from the INHANCE consortium of 15 head and neck cancer case-control studies. Controls numbered from 7,604 to 13,829 subjects, depending on analysis. Analyses fitted linear-exponential excess ORs models.
Results
ORs were increased in underweight (<18.5 BMI) relative to overweight and obese categories (≥25 BMI) for all sites and were homogeneous by sex. ORs by smoking and drinking in females compared to males were significantly greater for oropharyngeal cancer (p<0.01 for both factors), suggestive for hypopharyngeal cancer (p=0.05 and p=0.06, respectively), but homogeneous for oral cavity (p=0.56 and p=0.64) and laryngeal (p=0.18 and p=0.72) cancers.
Conclusions
The extent that OR modifications of smoking and drinking by sex for oropharyngeal and, possibly, hypopharyngeal cancers represent true associations, or derive from unmeasured confounders or unobserved sex-related disease subtypes (e.g., human papillomavirus positive oropharyngeal cancer) remains to be clarified.
doi:10.1007/s10552-011-9792-x
PMCID: PMC3304584  PMID: 21744095
Alcohol consumption; cigarette smoking; interactions; odds ratio models
19.  Clustering of Multiple Human Papillomavirus Infections in Women From a Population-Based Study in Guanacaste, Costa Rica 
The Journal of Infectious Diseases  2011;204(3):385-390.
Objective. To evaluate clustering patterns of prevalent infection with multiple human papillomavirus (HPV) types in 8365 nonhysterectomized women from the Guanacaste Study of HPV Natural History.
Methods. HPV testing was performed on cervical cells by MY09/M11 L1 degenerate consensus primer polymerase chain reaction method, with dot-blot hybridization for genotyping. Logistic regression was used to model type-specific HPV positivity, adjusted for age, lifetime number of sexual partners, and specific HPV type prevalence. Woman-level random effects were added to represent unobservable risk factors common to all HPV types.
Results. The observed-to-expected ratio for infections with 2 types was 1.16 (95% credible interval: 1.11–1.21) and for ≥3 types was 1.04 (95% credible interval: .96–1.13). The tendency of HPV types to cluster increased significantly with the genetic similarity of L1 regions. P value < .01 was observed for 2 HPV pairs: HPV-62 and -81 were found together more, while HPV-51 and -71 were found together less often than expected.
Conclusions. We found a small degree of aggregation between any HPV types and lack of clustering between specific carcinogenic types. Our data indirectly provide reassurance on lack of misclassification for the large majority of HPV types in multiple infections detected by the MY09/11 method and genotyped using dot-blot hybridization.
doi:10.1093/infdis/jir286
PMCID: PMC3132145  PMID: 21742837
20.  Using Prior Information from the Medical Literature in GWAS of Oral Cancer Identifies Novel Susceptibility Variant on Chromosome 4 - the AdAPT Method 
PLoS ONE  2012;7(5):e36888.
Background
Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility of automatically retrieving information from the medical literature and leveraging this information in GWAS.
Methods
We developed a method that searches through PubMed abstracts for pre-assigned keywords and key concepts, and uses this information to assign prior probabilities of association for each single nucleotide polymorphism (SNP) with the phenotype of interest - the Adjusting Association Priors with Text (AdAPT) method. Association results from a GWAS can subsequently be ranked in the context of these priors using the Bayes False Discovery Probability (BFDP) framework. We initially tested AdAPT by comparing rankings of known susceptibility alleles in a previous lung cancer GWAS, and subsequently applied it in a two-phase GWAS of oral cancer.
Results
Known lung cancer susceptibility SNPs were consistently ranked higher by AdAPT BFDPs than by p-values. In the oral cancer GWAS, we sought to replicate the top five SNPs as ranked by AdAPT BFDPs, of which rs991316, located in the ADH gene region of 4q23, displayed a statistically significant association with oral cancer risk in the replication phase (per-rare-allele log additive p-value [ptrend] = 2.5×10−3). The combined OR for having one additional rare allele was 0.83 (95% CI: 0.76–0.90), and this association was independent of previously identified susceptibility SNPs that are associated with overall UADT cancer in this gene region. We also investigated if rs991316 was associated with other cancers of the upper aerodigestive tract (UADT), but no additional association signal was found.
Conclusion
This study highlights the potential utility of systematically incorporating prior knowledge from the medical literature in genome-wide analyses using the AdAPT methodology. AdAPT is available online (url: http://services.gate.ac.uk/lld/gwas/service/config).
doi:10.1371/journal.pone.0036888
PMCID: PMC3360735  PMID: 22662130
22.  A sex-specific association between a 15q25 variant and upper aerodigestive tract cancers 
Background
Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35).
Methods
In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies.
Results
rs16969968 was again associated with UADT cancers in women (OR=1.21, 95% confidence interval(CI)=1.08–1.36, P=0.001) and a similar lack of observed effect in men (OR=1.02, 95%CI=0.95–1.09, P=0.66) (P-heterogeneity=0.01). In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR=1.22, 95%CI=1.12–1.34, P=7×10−6) but not males (OR=1.02, 95%CI=0.97–1.08, P=0.35) (P-heterogeneity=6×10−4). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P-heterogeneity=0.86).
Conclusions
This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.
Impact
Further research is warranted to elucidate the mechanisms underlying these observations.
doi:10.1158/1055-9965.EPI-10-1008
PMCID: PMC3070066  PMID: 21335511
genetic variants; 15q25; nicotinic acetylcholine receptor; upper aerodigestive tract cancers; cigarettes per day
23.  Variations in Helicobacter pylori Cytotoxin-Associated Genes and Their Influence in Progression to Gastric Cancer: Implications for Prevention 
PLoS ONE  2012;7(1):e29605.
Helicobacter pylori (HP) is a bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa. Persistent Hp infection often induces gastritis and is associated with the development of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Virulent HP isolates harbor the cag (cytotoxin-associated genes) pathogenicity island (cagPAI), a 40 kb stretch of DNA that encodes components of a type IV secretion system (T4SS). This T4SS forms a pilus for the injection of virulence factors into host target cells, such as the CagA oncoprotein. We analyzed the genetic variability in cagA and other selected genes of the HP cagPAI (cagC, cagE, cagL, cagT, cagV and cag Gamma) using DNA extracted from frozen gastric biopsies or from clinical isolates. Study subjects were 95 cagA+ patients that were histologically diagnosed with chronic gastritis or gastric cancer in Venezuela and Mexico, areas with high prevalence of Hp infection. Sequencing reactions were carried out by both Sanger and next-generation pyrosequencing (454 Roche) methods. We found a total of 381 variants with unambiguous calls observed in at least 10% of the originally tested samples and reference strains. We compared the frequencies of these genetic variants between gastric cancer and chronic gastritis cases. Twenty-six SNPs (11 non-synonymous and 14 synonymous) showed statistically significant differences (P<0.05), and two SNPs, in position 1039 and 1041 of cagE, showed a highly significant association with cancer (p-value = 2.07×10−6), and the variant codon was located in the VirB3 homology domain of Agrobacterium. The results of this study may provide preliminary information to target antibiotic treatment to high-risk individuals, if effects of these variants are confirmed in further investigations.
doi:10.1371/journal.pone.0029605
PMCID: PMC3250449  PMID: 22235308
24.  High-risk HPV infection after five years in a population-based cohort of Chilean women 
Background
The need to review cervical cancer prevention strategies has been triggered by the availability of new prevention tools linked to human papillomavirus (HPV): vaccines and screening tests. To consider these innovations, information on HPV type distribution and natural history is necessary. This is a five-year follow-up study of gynecological high-risk (HR) HPV infection among a Chilean population-based cohort of women.
Findings
A population-based random sample of 969 women from Santiago, Chile aged 17 years or older was enrolled in 2001 and revisited in 2006. At both visits they answered a survey on demographics and sexual history and provided a cervical sample for HPV DNA detection (GP5+/6+ primer-mediated PCR and Reverse line blot genotyping). Follow-up was completed by 576 (59.4%) women; 45 (4.6%) refused participation; most losses to follow-up were women who were unreachable, no longer eligible or had missing samples. HR-HPV prevalence increased by 43%. Incidence was highest in women < 20 years of age (19.4%) and lowest in women > 70 (0%); it was three times higher among women HR-HPV positive versus HPV negative at baseline (25.5% and 8.3%; OR 3.8, 95% CI 1.8-8.0). Type-specific persistence was 35.3%; it increased with age, from 0% in women < 30 years of age to 100% in women > 70. An enrollment Pap result ASCUS or worse was the only risk factor for being HR-HPV positive at both visits.
Conclusions
HR-HPV prevalence increased in the study population. All HR-HPV infections in women < 30 years old cleared, supporting the current recommendation of HR-HPV screening for women > 30 years.
doi:10.1186/1750-9378-6-21
PMCID: PMC3269983  PMID: 22087645
25.  Birth Order and Risk of Non-Hodgkin Lymphoma—True Association or Bias? 
American Journal of Epidemiology  2010;172(6):621-630.
There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983–2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.
doi:10.1093/aje/kwq167
PMCID: PMC2950815  PMID: 20720098
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class

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