Cancer incidence in indigenous populations of Western Amazon, Brazil.

OBJECTIVES: This study aims to estimate a population-based cancer incidence among indigenous populations in the State of Acre, Brazilian Western Amazon, to provide knowledge about cancer epidemiological profiles contributing to healthcare policies and service planning. Although cancer epidemiology in Brazil is well described through incidence and mortality estimate in the general population, cancer estimates among indigenous peoples are still unknown. DESIGN: This is a descriptive study of cancer incidence among the indigenous population (2000-2012) in the State of Acre, Brazil. The sources used were population-based cancer registries of Goiânia, hospital-based cancer registry of Acre, São Paulo, and Porto Velho; Special Indigenous Health Districts databases of Acre, Goiânia, and São Paulo; Mortality Information System, and Rio Branco's public and private laboratories' reports. Standardized Incidence Ratio (SIR) was calculated using cancer incidence rates of Goiânia as reference. RESULTS: From 137 cancer cases, 51.8% occurred in women and 32.1% in people aged 70 + . Among men, the most frequent cancer sites were stomach (25.8%), liver (15.1%), colorectal (7.6%), leukemia (7.6%), and prostate (6.1%). Among women, the most frequent were cervical (50.7%), stomach (8.5%), leukemia (5.6%), liver (4.3%), and breast (4.3%). Among men, there was an excess of cancer cases for stomach (SIR=1.75; 95%CI:1.67-1.83), liver (SIR=1.77; 95%CI:1.66-1.88), and leukemia (SIR=1.64; 95%CI:1.49-1.78). In women, an excess of cancer cases was observed for cervical (SIR=4.49; 95%CI:4.34-4.64) and liver (SIR=2.11; 95%CI:1.88-2.34). A lower cancer incidence for prostate (SIR=0.06; 95%CI:0.05-0.07) and female breast (SIR=0.12; 95%CI:0.11-0.14) was observed. CONCLUSIONS: Cervical, stomach, and liver cancers corresponded to 52% of the cases and were highly incident among the Brazilian indigenous population of Western Amazon compared to non-indigenous counterparts. Despite the low frequency of breast and prostate cancer, the fact they were present among indigenous peoples suggests a complex epidemiological transition framework in these populations.

Pesticide exposure and thyroid function in an agricultural population in Brazil.

Although numerous pesticides may interfere with thyroid function, however, epidemiological evidence supporting this relationship is limited, particularly regarding modern non-persistent pesticides. We sought to evaluate the association of agricultural work practices, use of contemporary-use pesticides, and OC pesticides residue levels in serum with circulating thyroid hormone levels in an agricultural population. A cross-sectional study was conducted with a random sample of 275 male and female farm residents in Farroupilha, South of Brazil. Information on sociodemographics, lifestyle and agricultural work was obtained through questionnaire. Blood samples were collected on all participants and analyzed for cholinesterase activity, serum residues of OC pesticides, and levels of free T4 (FT4), total T3 (TT3) and TSH. Non-persistent pesticides exposure assessment was based on questionnaire information on current use of pesticides, and frequency and duration of use, among others. Associations were explored using multivariate linear regression models. Total lifetime years of use of fungicides, herbicides and dithiocarbamates in men was associated with increased TSH accompanied by decrease in FT4, with evidence of a linear trend. In addition, there was an association between being sampled in the high pesticide-use season and increased TSH levels. Conversely, farm work and lifetime use of all pesticides were related with slight decrease in TSH and increased TT3 and FT4, respectively. In general, pesticide use was not associated with thyroid hormones in women. Subjects with detected serum concentrations of ß-hexachlorocyclohexane, endrin, dieldrin, heptachlor epoxide B, γ-chlordane, transnonachlor, heptachlor, p,p'-dichlorodiphenylethane and endosulfan II experienced slight changes in TT3; however, associations were weak and inconsistent. These findings suggest that both cumulative and recent occupational exposure to agricultural pesticides may affect the thyroid function causing hypothyroid-like effects, particularly in men.

Prevalence of very low birthweight, malformation, and low Apgar score among newborns in Brazil according to maternal urban or rural residence at birth.

AIM: Adverse birth outcomes are a major public health issue in rural areas, where several environmental risk factors, including pesticides, may endanger the health of women of reproductive age. We investigated the prevalence of selected birth outcomes among newborns from mothers living in urban and rural areas of a Brazilian municipality. METHODS: Information about all live births that occurred between 2004 and 2006 in the Municipality of Nova Friburgo, Brazil, was retrieved from the Live Birth Information System. Newborns were classified as rural or urban, according to the mother's residence address. RESULTS: Newborns from rural areas had a higher prevalence of very low-birthweight, low Apgar score, and malformation. On Poisson regression with adjustment for several confounders, rural offspring were more likely to have the aforementioned outcomes. CONCLUSIONS: Women in rural areas are at higher risk of giving birth to an infant with very low-birthweight, low 5-min Apgar score and malformations detectable at birth, regardless of socioeconomic and gestational conditions.

Estimating and explaining the effect of education and income on head and neck cancer risk: INHANCE consortium pooled analysis of 31 case-control studies from 27 countries.

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

Hematological and hepatic alterations in Brazilian population heavily exposed to organochlorine pesticides.

The aim of this study was to investigate the frequency of hematological and hepatic alterations and possible association with serum levels of beta-hexachlorocyclohexane (beta-HCH), p,p'-DDE, and hexachlorobenzene (HCB) among residents in an area heavily contaminated with organochlorine (OC) pesticides. A cross-sectional study was conducted in 415 male and 432 female residents aged >14 years. Serum samples were collected and analyzed for OC pesticides concentrations and biochemical parameters. Frequencies of hematological and hepatic alterations were calculated for each gender. Association between beta-HCH, p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene), and HCB levels and presence of alterations was determined by logistic regression stratified by gender and controlling for confounders. Highest frequencies were observed for eosinophilia (23% men and 18% women), low hemoglobin (12% men and 15% women), and low erythrocyte count (12% men). High levels of bilirubin, glutamic-oxaloacetic transaminase (GOT), and glutamic-pyruvic transaminase (GPT) were observed, respectively, in 10, 11, and 12% of men and <10% of women. Gamma-glutamyl transferase (GGT) was elevated in 26 and 25% of males and females, respectively. Multivariate analysis revealed associations between eosinophilia and beta-HCH in men (OR = 1.06, 95%CI = 1.01-1.12) and women (OR = 1.05, 96%CI = 0.99-1.11), p,p'-DDE in men (OR = 1.03, 95%CI = 0.99-1.06) and women (OR = 1.02, 95%CI = 0.99-1.06), and HCB in women (OR = 1.54, 95%IC = 0.85-4.45). Beta-HCH was found to be associated with increased risk of elevated bilirubin in females (OR = 1.18, 95%CI = 1.07-1.29) and males (OR = 4.21, 95%CI = 1.87-9.47 for fourth vs. first quintile). Thus, OC pesticides may exert adverse effects on hematopoietic tissue and liver in populations chronically exposed to high levels of these compounds.

Echocardiography in sickle cell anaemia patients under 20 years of age: a descriptive study in the Brazilian Western Amazon.

INTRODUCTION: Cardiac abnormalities in sickle cell anaemia are frequent and early, despite being more evident in adulthood. The study on cardiac abnormalities is essential in the current context, as, owing to improved health, children are increasingly able to reach adulthood and suffering the consequences of chronic cardiac injury. OBJECTIVE: The aim of this study was to determine the prevalence of echocardiographic changes in patients under 20, suffering from sickle cell disease in Rio Branco, Brazilian Western Amazon. METHODS: The descriptive epidemiological study compare two sets of children and adolescents, one including sickle cell anaemia patients (n=45), and other one (n=109) without sickle cell anaemia or heart disease. The echocardiographic measurements were indexed according to body surface using z-scores, and the prevalence of echocardiographic changes in both groups, with their respective 95% confidence intervals, ascertained and compared. RESULTS: Compared with the non-sickle cell anaemia series, the sickle cell anaemia group showed z-scores 13.1-fold higher for the diastolic diameter of the left ventricle, 5.2 times higher for the thickness of the posterior wall, 4.9 higher for the left atrium, 2.5 times higher for the right ventricle and 2.0 times higher for the septum thickness. Also the rate of left ventricular mass, systolic pressure of the right ventricle and the relative wall thickness were significantly higher in sickle cell anaemia set. CONCLUSIONS: Cardiac abnormalities were observed in 93.5% of patients. Early detection of cardiac abnormalities and quantifying them using the indexation of echocardiographic measurements according to body surface will allow proper identification and attendance of these children.

Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection.

BACKGROUND: The role of human papillomavirus (HPV) on head and neck squamous cell carcinoma (HNSCC) survival in regions with low HPV prevalence is not yet clear. We evaluated the HPV16 infection on survival of HNSCC Brazilian patient series. METHODS: This cohort comprised 1,093 HNSCC cases recruited from 1998 to 2008 in four Brazilian cities and followed up until June 2009. HPV16 antibodies were analyzed by multiplex Luminex assay. In a subset of 398 fresh frozen or paraffin blocks of HNSCC specimens, we analyzed for HPV16 DNA by L1 generic primer polymerase chain reaction. HNSCC survival according to HPV16 antibodies was evaluated through Kaplan-Meier method and Cox regression. RESULTS: Prevalence of HPV16 E6 and E6/E7 antibodies was higher in oropharyngeal cancer than in other head and neck tumor sites. HPV16 DNA positive in tumor tissue was also higher in the oropharynx. Seropositivity for HPV16 E6 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer. The presence of HPV16 E6/E7 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer survival. The death risk of oropharyngeal squamous cell carcinoma patients HPV16 E6/E7 antibodies positive was 78 % lower than to those who test negative. CONCLUSION: Oropharyngeal squamous cell carcinoma is less aggressive in the HPV16 E6/E7 positive serology patients. HPV16 E6/E7 antibody is a clinically sensible surrogate prognostic marker of oropharyngeal squamous cell carcinoma.

Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study.

BACKGROUND: Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype. METHODS: We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child's age, sex, ethnicity, parental education, and study center. RESULTS: Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78-0.92) for vitamin use and 0.80 (0.71-0.89) for folic acid use. The reduced risk was more pronounced in children whose parents' education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75-1.14) and 0.68 (0.48-0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester). CONCLUSIONS: Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

Brain cancer mortality in an agricultural and a metropolitan region of Rio de Janeiro, Brazil: a population-based, age-period-cohort study, 1996-2010.

BACKGROUND: Individuals who live in rural areas are at greater risk for brain cancer, and pesticide exposure may contribute to this increased risk. The aims of this research were to analyze the mortality trends and to estimate the age-period-cohort effects on mortality rates from brain cancer in two regions in Rio de Janeiro, Brazil. METHODS: This descriptive study examined brain cancer mortality patterns in individuals of both sexes, >19 years of age, who died between 1996 and 2010. They were residents of a rural (Serrana) or a non-rural (Metropolitan) area of Rio de Janeiro, Brazil. We estimated mortality trends using Joinpoint Regression analysis. Age-period-cohort models were estimated using Poisson regression analysis. RESULTS: The estimated annual percentage change in mortality caused by brain cancer was 3.8% in the Serrana Region (95% confidence interval (CI): 0.8-5.6) and -0.2% (95% CI: -1.2-0.7) in the Metropolitan Region. The results indicated that the relative risk was higher in the rural region for the more recent birth cohorts (1954 and later). Compared with the reference birth cohort (1945-49, Serrana Region), the relative risk was four times higher for individuals born between 1985 and 1989. CONCLUSIONS: The results of this study indicate that there is an increasing trend in brain cancer mortality rates in the rural Serrana Region in Brazil. A cohort effect occurred in the birth cohorts born in this rural area after 1954. At the ecological level, different environmental factors, especially the use of pesticides, may explain regional disparities in the mortality patterns from brain cancers.

Epidermal growth factor receptor gene polymorphisms are associated with prognostic features of breast cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile. METHODS: The study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed. RESULTS: (CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40-0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19-0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 - 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17-0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19-0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes. CONCLUSIONS: The data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors.

Adult height and head and neck cancer: a pooled analysis within the INHANCE Consortium.

Several epidemiological studies have shown a positive association between adult height and cancer incidence. The only study conducted among women on mouth and pharynx cancer risk, however, reported an inverse association. This study aims to investigate the association between height and the risk of head and neck cancer (HNC) within a large international consortium of HNC. We analyzed pooled individual-level data from 24 case-control studies participating in the International Head and Neck Cancer Epidemiology Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated separately for men and women for associations between height and HNC risk. Educational level, tobacco smoking, and alcohol consumption were included in all regression models. Stratified analyses by HNC subsites were performed. This project included 17,666 cases and 28,198 controls. We found an inverse association between height and HNC (adjusted OR per 10 cm height = 0.91, 95% CI 0.86-0.95 for men; adjusted OR = 0.86, 95% CI 0.79-0.93 for women). In men, the estimated OR did vary by educational level, smoking status, geographic area, and control source. No differences by subsites were detected. Adult height is inversely associated with HNC risk. As height can be considered a marker of childhood illness and low energy intake, the inverse association is consistent with prior studies showing that HNC occur more frequently among deprived individuals. Further studies designed to elucidate the mechanism of such association would be warranted.

Reference values of lead in blood and related factors among blood donors in the Western Amazon, Brazil.

The aim of this study was to (1) determine the reference value of blood lead levels (BLL) in a sample of blood donors of Rio Branco, the capital city of Acre, in the Western Brazilian Amazon, and (2) explore factors influencing lead (Pb) exposure levels. Between 2010 and 2011, blood samples were collected from universal blood donors attending the Central Hemotherapic Unit in Rio Branco with a total number of 1196. Information on characteristics of 1183 donors was obtained through questionnaires. Blood Pb concentrations were determined by inductively coupled plasma-mass spectrometry with detection limit of 0.003 µg/L. Association between BLL and participant characteristics was examined by linear regression analysis. Reference values of BLL were calculated as the upper limit of the 95% confidence interval of the 95th percentile. Reference values of BLL were 109.5 µg/L for men, 70.7 µg/L for women, 88.9 µg/L for younger individuals (18-29 yr), 115.3 µg/L for older ones (≥30 yr), 94.2 µg/L for nonsmokers, and 164.5 µg/L for smokers. Levels of BLL were significantly higher in males, subjects older than 29 yr, non-whites, smokers, regular consumers of manioc flour, and donors practicing any activity related to paints, ceramics, pottery, fishing, or firearms. Subjects with higher education, higher income, vitamin intake use, and drinkers of bottled water displayed lower BLL. In general, BLL in men and women from Rio Branco were higher than those described in other adult populations. Prevention of exposure of this population to local sources of Pb needs to be addressed.

Cancer mortality among Brazilian dentists.

BACKGROUND: Previous studies have variably shown excess risks of elected cancers among dentists. METHODS: National Brazilian mortality data were used to obtain mortality patterns among dentists between 1996 and 2004. Cancer mortality odds ratios (MORs) and cancer proportional mortality ratios for all cancer sites were calculated, using the general population and physicians and lawyers as comparison groups. RESULTS: Female dentists from both age strata showed higher risks for breast, colon-rectum, lung, brain, and non-Hodgkin lymphoma. Compared to physicians and lawyers, higher MOR estimates were observed for brain cancer among female dentists 20-49 yr. Among male dentists, higher cancer mortality was found for colon-rectum, pancreas, lung, melanoma, and non-Hodgkin lymphoma. Higher risk estimates for liver, prostate, bladder, brain, multiple myeloma and leukemia were observed among 50-79 yr old male dentists. DISCUSSION: If confirmed, these results indicate the need for limiting occupational exposures among dentists in addition to establishing screening programs to achieve early detection of selected malignant tumors.

A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻8); rs1229984-ADH1B, p = 7 × 10⁻9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Fetal growth and childhood acute lymphoblastic leukemia: findings from the childhood leukemia international consortium.

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC.

Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.

Genome-wide association study of HPV seropositivity.

High-risk α mucosal types of human papillomavirus (HPV) cause anogenital and oropharyngeal cancers, whereas ß 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.

Long-term exposure to organochlorine pesticides and thyroid status in adults in a heavily contaminated area in Brazil.

Organochlorine (OC) pesticides are endocrine disruptors altering the thyroid hormonal system. The aim of this study is to investigate the relationship between exposure to OC pesticides and thyroid status in adults from a rural area in Rio de Janeiro, Brazil, heavily contaminated with OC pesticides. A cross-sectional study was carried out in 303 men and 305 women >14 years old. Concentrations of 19 OC pesticides and levels of free thyroxine (T4), total triiodothyronine (T3), thyroid-stimulating hormone (TSH), anti-thyroperoxidase (TPOAb) and anti-thyroglobulin (TgAg) antibodies were analyzed in serum samples. Associations between OC pesticides concentrations and values of biochemical thyroid parameters were determined using multivariate regression models stratified by gender. Prevalence of subclinical hyperthyroidism and the presence of TPOAb antibodies were higher than those described for euthyroid populations elsewhere. After adjusting for confounders, total T3 levels were associated with lower concentrations of endosulphan 2 in men and with higher alpha-chlordane, p,p'-dichlorodiphenyltrichloroethane (DDT), endosulphan 2, and methoxychlor in women. Levels of free T4 showed inverse association with beta-hexachlorocyclohexane (HCH) and p,p'-DDT in men, and were positively associated with hexachlorobenzene (HCB), heptachlor, o,p'-DDT, and p,p'-DDT in women. TSH levels were associated with higher beta-HCH in men. A positive association was observed between exposure methoxychlor in males and presence of TPOAb, but no association with TPOAb was found in women. These results suggest that OC pesticides can affect the thyroid system through gender-specific mechanisms that may differ among compounds. Further detailed investigations and health monitoring should be warranted for this population.

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers.

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2'deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and haematopoietic malignancy (64% in Burkitt's lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic-based therapy.

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, 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, 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 HNC.