scispace - formally typeset
Search or ask a question

Showing papers by "International Agency for Research on Cancer published in 2008"


Journal ArticleDOI
TL;DR: It is suggested that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing therisk of death.
Abstract: Background Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. Methods We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. Results During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumfer...

1,804 citations


Journal ArticleDOI
03 Apr 2008-Nature
TL;DR: The results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
Abstract: Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

1,226 citations


Journal ArticleDOI
TL;DR: The analysis of heterogeneity showed that study type, gender and adjustment for confounding factors significantly influence the RRs estimates and the reliability of the studies, and pooled RRs for respiratory cancers were greater than the pooled estimates for other sites.
Abstract: We conducted a systematic meta-analysis of observational studies on cigarette smoking and cancer from 1961 to 2003. The aim was to quantify the risk for 13 cancer sites, recognized to be related to tobacco smoking by the International Agency for Research on Cancer (IARC), and to analyze the risk variation for each site in a systematic manner. We extracted data from 254 reports published between 1961 and 2003 (177 case-control studies, 75 cohorts and 2 nested case-control studies) included in the 2004 IARC Monograph on Tobacco Smoke and Involuntary Smoking. The analyses were carried out on 216 studies with reported estimates for 'current' and/or 'former' smokers. We performed sensitivity analysis, and looked for publication and other types of bias. Lung (RR = 8.96; 95% CI: 6.73-12.11), laryngeal (RR = 6.98; 95% CI: 3.14-15.52) and pharyngeal (RR = 6.76; 95% CI: 2.86-15.98) cancers presented the highest relative risks (RRs) for current smokers, followed by upper digestive tract (RR = 3.57; 95% CI: 2.63-4.84) and oral (RR = 3.43; 95% CI: 2.37-4.94) cancers. As expected, pooled RRs for respiratory cancers were greater than the pooled estimates for other sites. The analysis of heterogeneity showed that study type, gender and adjustment for confounding factors significantly influence the RRs estimates and the reliability of the studies.

781 citations


Journal ArticleDOI
TL;DR: The current state of sequence‐based genetic testing is reviewed, other standardized reporting systems used in oncology are described, and a standardized classification system for application to sequence-based results for cancer predisposition genes is proposed.
Abstract: Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.

777 citations


Journal ArticleDOI
19 Aug 2008-Vaccine
TL;DR: The greater sensitivity of HPV DNA testing compared to cytology argues strongly for using HPVDNA testing as the primary screening test in newly implemented programmes, except where resources are extremely limited and only programmes based on visual inspection are affordable.

621 citations


Journal ArticleDOI
TL;DR: Current knowledge on the interplay between DNA methylation and histone modifications during gene silencing and its importance in the integration of environmental and intrinsic stimuli in the control of gene expression is summarized.
Abstract: Knowledge on heritable changes in gene expression that result from epigenetic events is of increasing relevance in the development of strategies for prevention, early diagnosis and treatment of cancer. Histone acetylation and DNA methylation are epigenetic modifications whose patterns can be regarded as heritable marks that ensure accurate transmission of the chromatin states and gene expression profiles over many cell generations. Importantly, patterns and levels of DNA methylation and histone acetylation are profoundly altered in human cancers. Accumulating evidence suggests that an epigenetic cross-talk, i.e. interplay between DNA methylation and histone acetylation, may be involved in the process of gene transcription and aberrant gene silencing in tumours. Although the molecular mechanism of gene activation is relatively well understood, the hierarchical order of events and dependencies leading to gene silencing in the course of cancer development remain largely unknown. While some studies suggest that DNA methylation patterns guide histone modifications (including histone acetylation and methylation) during gene silencing, other studies argue that DNA methylation takes its cues primarily from histone modification states. In this review, we summarize current knowledge on the interplay between DNA methylation and histone modifications during gene silencing and its importance in the integration of environmental and intrinsic stimuli in the control of gene expression. We also discuss the importance of an epigenetic cross-talk in the protection against genetic changes in response to environmental genotoxins as well as the implication for cancer therapy and prevention.

585 citations


Journal ArticleDOI
TL;DR: Use of smokeless tobacco products is common worldwide, with increasing consumption in many countries, and epidemiological data from the USA and Asia show a raised risk of oral cancer, but this is not confirmed in northern European studies.
Abstract: Summary Use of smokeless tobacco products is common worldwide, with increasing consumption in many countries. Although epidemiological data from the USA and Asia show a raised risk of oral cancer (overall relative risk 2·6 [95% CI 1·3–5·2]), these are not confirmed in northern European studies (1·0 [0·7–1·3]). Risks of oesophageal cancer (1·6 [1·1–2·3]) and pancreatic cancer (1·6 [1·1–2·2]) have also increased, as shown in northern European studies. Results on lung cancer have been inconsistent, with northern European studies suggesting no excess risk. In India and Sudan, more than 50% of oral cancers are attributable to smokeless tobacco products used in those countries, as are about 4% of oral cancers in US men and 20% of oesophageal and pancreatic cancers in Swedish men. Smokeless tobacco products are a major source of carcinogenic nitrosamines; biomarkers of exposure have been developed to quantify exposure as a framework for a carcinogenesis model in people. Animal carcinogenicity studies strongly support clinical results. Cancer risk of smokeless tobacco users is probably lower than that of smokers, but higher than that of non-tobacco users.

570 citations


Journal ArticleDOI
TL;DR: The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology, and two uncorrelated disease markers at 5p15.33 are detected.
Abstract: We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P - 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

556 citations


Journal ArticleDOI
TL;DR: A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility.
Abstract: Established guidelines for causal inference in epidemiological studies may be inappropriate for genetic associations. A consensus process was used to develop guidance criteria for assessing cumulative epidemiologic evidence in genetic associations. A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility. In addition, we discuss how additional input and guidance can be derived from biological data. Future empirical research and consensus development are needed to develop an integrated model for combining epidemiological and biological evidence in the rapidly evolving field of investigation of genetic factors.

533 citations


Journal ArticleDOI
TL;DR: Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC, indicating that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.
Abstract: Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau ( VHL ) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.

500 citations


Journal ArticleDOI
15 Apr 2008-Blood
TL;DR: In this paper, the authors performed a pooled analysis of self-reported autoimmune conditions and risk of non-Hodgkin lymphoma (NHL) and subtypes, including 29,423 participants in 12 case-control studies.

Journal ArticleDOI
TL;DR: These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men.
Abstract: Background Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.

Journal ArticleDOI
TL;DR: DIC is shown to be an approximation to a penalized loss function based on the deviance, with a penalty derived from a cross-validation argument, which under-penalizes more complex models.
Abstract: The deviance information criterion (DIC) is widely used for Bayesian model comparison, despite the lack of a clear theoretical foundation. DIC is shown to be an approximation to a penalized loss function based on the deviance, with a penalty derived from a cross-validation argument. This approximation is valid only when the effective number of parameters in the model is much smaller than the number of independent observations. In disease mapping, a typical application of DIC, this assumption does not hold and DIC under-penalizes more complex models. Another deviance-based loss function, derived from the same decision-theoretic framework, is applied to mixture models, which have previously been considered an unsuitable application for DIC.

Journal ArticleDOI
Montserrat Garcia-Closas1, Per Hall2, Heli Nevanlinna3, Karen A. Pooley4, Jonathan J. Morrison4, Douglas A. Richesson1, Stig E. Bojesen5, Børge G. Nordestgaard5, C K Axelsson5, José Ignacio Arias6, Roger L. Milne6, Gloria Ribas6, Anna González-Neira6, Javier Benitez6, P. Zamora7, Hiltrud Brauch8, Hiltrud Brauch9, Christina Justenhoven8, Christina Justenhoven9, Ute Hamann10, Yon Ko, Thomas Bruening11, Susanne Haas12, Thilo Dörk13, Peter Schürmann13, Peter Hillemanns13, Natalia Bogdanova13, Michael Bremer13, Johann H. Karstens13, Rainer Fagerholm3, Kirsimari Aaltonen3, Kristiina Aittomäki3, Karl von Smitten3, Carl Blomqvist3, Arto Mannermaa14, Matti Uusitupa14, Matti Eskelinen14, Maria Tengström14, Veli-Matti Kosma14, V. Kataja14, Georgia Chenevix-Trench15, Amanda B. Spurdle15, Jonathan Beesley15, Xiaoqing Chen15, Peter Devilee16, Christi J. van Asperen16, Catharina E. Jacobi16, Rob A. E. M. Tollenaar16, Petra E A Huijts17, Jan G. M. Klijn17, Jenny Chang-Claude10, Silke Kropp10, Tracy Slanger10, Dieter Flesch-Janys18, Elke Mutschelknauss18, Ramona Salazar, Shan Wang-Gohrke19, Fergus J. Couch20, Ellen L. Goode20, Janet E. Olson20, Celine M. Vachon20, Zachary S. Fredericksen20, Graham G. Giles21, Laura Baglietto21, Gianluca Severi21, John L. Hopper22, Dallas R. English22, Melissa C. Southey22, Christopher A. Haiman23, Brian E. Henderson23, Laurence N. Kolonel24, Loic Le Marchand24, Daniel O. Stram23, David J. Hunter25, Susan E. Hankinson25, David G. Cox25, Rulla M. Tamimi25, Peter Kraft25, Mark E. Sherman1, Stephen J. Chanock1, Jolanta Lissowska26, Louise A. Brinton1, Beata Peplonska27, Maartje J. Hooning17, Han Meijers-Heijboer17, J. Margriet Collée17, Ans M.W. van den Ouweland17, André G. Uitterlinden17, Jianjun Liu28, Yen Lin Low28, Li Yuqing28, Keith Humphreys2, Kamila Czene2, Angela Cox29, Sabapathy P. Balasubramanian29, Simon S. Cross29, Malcolm W.R. Reed29, Fiona M. Blows4, Kristy Driver4, Alison M. Dunning4, Jonathan Tyrer4, Bruce A.J. Ponder30, Suleeporn Sangrajrang, Paul Brennan31, James McKay31, Fabrice Odefrey31, Valerie Gabrieau31, Alice J. Sigurdson1, Michele M. Doody1, J. P. Struewing1, Bruce H. Alexander, Douglas F. Easton4, Paul D.P. Pharoah4 
TL;DR: The findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct.
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

Journal ArticleDOI
TL;DR: Subgroup analyses showed that low SES was significantly associated with increased oral cancer risk in high and lower income‐countries, across the world, and remained when adjusting for potential behavioural confounders.
Abstract: There is uncertainty and limited recognition of the relationship between socioeconomic inequalities and oral cancer. We aimed to quantitatively assess the association between socioeconomic status (SES) and oral cancer incidence risk. A systematic review of case-control studies obtained published and unpublished estimates of the SES risk related to oral cancer. Studies were included which reported odds ratios (ORs) and corresponding 95% CIs of oral cancer with respect to SES, or if the estimates could be calculated or obtained. Meta-analyses were performed on subgroups: SES measure, age, sex, global region, development level, time-period and lifestyle factor adjustments; while sensitivity analyses were conducted based on study methodological issues. Forty-one studies provided 15,344 cases and 33,852 controls which met our inclusion criteria. Compared with individuals who were in high SES strata, the pooled ORs for the risk of developing oral cancer were 1.85 (95%CI 1.60, 2.15; n = 37 studies) for those with low educational attainment; 1.84 (1.47, 2.31; n = 14) for those with low occupational social class; and 2.41 (1.59, 3.65; n = 5) for those with low income. Subgroup analyses showed that low SES was significantly associated with increased oral cancer risk in high and lower income-countries, across the world, and remained when adjusting for potential behavioural confounders. Inequalities persist but are perhaps reducing over recent decades. Oral cancer risk associated with low SES is significant and comparable to lifestyle risk factors. Our results provide evidence to steer health policy which focus on lifestyles factors toward an integrated approach incorporating measures designed to tackle the root causes of disadvantage.

Journal ArticleDOI
TL;DR: This reanalysis of individual patient data from 12 studies of the association between IGFs and IGF binding proteins and prostate cancer suggests that higher levels of serum IGF-I are associated with higher risk for prostate cancer.
Abstract: Insulin-like growth factors, their binding proteins, and prostate cancer risk : analysis of individual patient data from 12 prospective studies.

Journal ArticleDOI
TL;DR: The adverse outcomes of assisted fertilisation that are noted compared with those in the general population could be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology.

Journal ArticleDOI
TL;DR: The results reinforce the evidence of a link between CA frequency and cancer risk and provide novel information on the role of aberration subclass and cancer type.
Abstract: Mechanistic evidence linking chromosomal aberration (CA) to early stages of cancer has been recently supported by the results of epidemiological studies that associated CA frequency in peripheral lymphocytes of healthy individuals to future cancer incidence. To overcome the limitations of single studies and to evaluate the strength of this association, a pooled analysis was carried out. The pooled database included 11 national cohorts and a total of 22 358 cancer-free individuals who underwent genetic screening with CA for biomonitoring purposes during 1965–2002 and were followed up for cancer incidence and/or mortality for an average of 10.1 years; 368 cancer deaths and 675 incident cancer cases were observed. Subjects were classified within each laboratory according to tertiles of CA frequency. The relative risk (RR) of cancer was increased for subjects in the medium [RR = 1.31, 95% confidence interval (CI) = 1.07–1.60] and in the high (RR = 1.41; 95% CI = 1.16–1.72) tertiles when compared with the low tertile. This increase was mostly driven by chromosome-type aberrations. The presence of ring chromosomes increased the RR to 2.22 (95% CI = 1.34–3.68). The strongest association was found for stomach cancer [RRmedium = 1.17 (95% CI = 0.37–3.70), RRhigh = 3.13 (95% CI = 1.17–8.39)]. Exposure to carcinogens did not modify the effect of CA levels on overall cancer risk. These results reinforce the evidence of a link between CA frequency and cancer risk and provide novel information on the role of aberration subclass and cancer type.

Journal ArticleDOI
TL;DR: A major finding was the consistently higher sensitivity but equal specificity of VILI compared with VIA, and some caution is warranted in the interpretation of observed accuracy measures, since a certain degree of gold standard misclassification cannot be excluded.
Abstract: Cervical cancer is the main cancer among women in sub-Saharan Africa, India and other parts of the developing world. Evaluation of screening performance of effective, feasible and affordable early detection and management methods is a public health priority. Five screening methods, naked eye visual inspection of the cervix uteri after application of diluted acetic acid (VIA), or Lugol's iodine (VILI) or with a magnifying device (VIAM), the Pap smear and human papillomavirus testing with the high-risk probe of the Hybrid Capture-2 assay (HC2), were evaluated in 11 studies in India and Africa. More than 58,000 women, aged 25-64 years, were tested with 2-5 screening tests and outcome verification was done on all women independent of the screen test results. The outcome was presence or absence of cervical intraepithelial neoplasia (CIN) of different degrees or invasive cervical cancer. Verification was based on colposcopy and histological interpretation of colposcopy-directed biopsies. Negative colposcopy was accepted as a truly negative outcome. VIA showed a sensitivity of 79% (95% CI 73-85%) and 83% (95% CI 77-89%), and a specificity of 85% (95% CI 81-89%) and 84% (95% CI 80-88%) for the outcomes CIN2+ or CIN3+, respectively. VILI was on average 10% more sensitive and equally specific. VIAM showed similar results as VIA. The Pap smear showed lowest sensitivity, even at the lowest cutoff of atypical squamous cells of undetermined significance (57%; 95% CI 38-76%) for CIN2+ but the specificity was rather high (93%; 95% CI 89-97%). The HC2-assay showed a sensitivity for CIN2+ of 62% (95% CI 56-68%) and a specificity of 94% (95% CI 92-95%). Substantial interstudy variation was observed in the accuracy of the visual screening methods. Accuracy of visual methods and cytology increased over time, whereas performance of HC2 was constant. Results of visual tests and colposcopy were highly correlated. This study was the largest ever done that evaluates the cross-sectional accuracy of screening tests for cervical cancer precursors in developing countries. The merit of the study was that all screened subjects were submitted to confirmatory investigations avoiding to verification bias. A major finding was the consistently higher sensitivity but equal specificity of VILI compared with VIA. Nevertheless, some caution is warranted in the interpretation of observed accuracy measures, since a certain degree of gold standard misclassification cannot be excluded. Because of the correlation between visual screening tests and colposcopy and a certain degree of over-diagnosis of apparent CIN2+ by study pathologists, it is possible that both sensitivity and specificity of VIA and VILI were overestimated. Gold standard verification error could also explain the surprisingly low sensitivity of HC2, which contrasts with findings from other studies.

Journal ArticleDOI
TL;DR: Tobacco use and use of both crude opium and other forms of opium were associated with higher risk of oesophageal squamous cell carcinoma in Golestan Province, northeastern Iran, and all forms of tobacco use (cigarettes, hookah, and nass) wereassociated with higher ESCC risk.
Abstract: The very high incidence of oesophageal squamous cell carcinoma (ESCC) in Golestan Province in northeastern Iran was suggested by studies in the 1970s as partly due to opium use, which is not uncommon in this area, but based on limited numbers. From December 2003 to June 2007, we administered a validated structured questionnaire to 300 ESCC cases and 571 controls, matched on neighbourhood of residence, age (±2 years), and sex. We used conditional logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. Compared with those who used neither tobacco nor opium, risk of ESCC was increased in those who used tobacco only (OR, 95% CI: 1.70, 1.05–2.73), in those who used opium only (2.12, 1.21–3.74), and in those who used both tobacco and opium (2.35, 1.50–3.67). All forms of tobacco use (cigarettes, hookah, and nass) were associated with higher ESCC risk. Similarly, use of both crude opium and other forms of opium were associated with higher risk. Alcohol consumption was seen in only 2% of the cases and 2% of the controls, and was not associated with ESCC risk.

Journal ArticleDOI
TL;DR: Favorable trends were observed in several European countries mainly over the last decade, particularly in women and in young adults, whereas they were more favorable at age 20‐44 years in both sexes.

Journal ArticleDOI
TL;DR: Excess second head and neck cancer risk was observed 10 years after diagnosis with lymphohaematopoietic cancers, and patterns were consistent with the notion that the pattern of cancer in survivors of head andneck cancer is dominated by the effect of tobacco smoking and alcohol drinking.
Abstract: The objective of the study was to assess the risk of second primary cancers (SPCs) following a primary head and neck cancer (oral cavity, pharynx and larynx) and the risk of head and neck cancer as a SPC. The present investigation is a multicenter study from 13 population-based cancer registries. The study population involved 99,257 patients with a first primary head and neck cancer and contributed 489,855 person-years of follow-up. To assess the excess risk of SPCs following head and neck cancers, we calculated standardized incidence ratios (SIRs) by dividing the observed numbers of SPCs by the expected number of cancers calculated from accumulated person-years and the age-, sex- and calendar period-specific first primary cancer incidence rates in each of the cancer registries. During the observation period, there were 10,826 cases of SPCs after head and neck cancer. For all cancer sites combined, the SIR of SPCs was 1.86 (95% CI = 1.83-1.90) and the 20-year cumulative risk was 36%. Lung cancer contributed to the highest proportion of the SPCs with a 20-year cumulative risk of 13%. Excess second head and neck cancer risk was observed 10 years after diagnosis with lymphohaematopoietic cancers. The most common SPC following a first primary head and neck cancer was lung cancer. However, the highest excess of SPCs was in the head and neck region. These patterns were consistent with the notion that the pattern of cancer in survivors of head and neck cancer is dominated by the effect of tobacco smoking and alcohol drinking.

Journal ArticleDOI
TL;DR: In this paper, the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk was analyzed in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident Endometrial Cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection and, for premenopausal women, phase of menstrual cycle.
Abstract: Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50-4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20-3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98-2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88-2.36; P=0.05) and 2.05 (95% CI 1.23-3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34-0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

Journal ArticleDOI
TL;DR: Assessment of baseline status of paediatric cancer care in ten countries receiving support and postulated 5-year survival showed that alliances between public, private, and international agencies might rapidly improve the outcome of children with cancer in these countries.
Abstract: Summary Background Childhood-cancer survival is dismal in most low-income countries, but initiatives for treating paediatric cancer have substantially improved care in some of these countries. The My Child Matters programme was launched to fund projects aimed at controlling paediatric cancer in low-income and mid-income countries. We aimed to assess baseline status of paediatric cancer care in ten countries that were receiving support (Bangladesh, Egypt, Honduras, Morocco, the Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam). Methods Between Sept 5, 2005, and May 26, 2006, qualitative face-to-face interviews with clinicians, hospital managers, health officials, and other health-care professionals were done by a multidisciplinary public-health research company as a field survey. Estimates of expected numbers of patients with paediatric cancer from population-based data were used to project the number of current and future patients for comparison with survey-based data. 5-year survival was postulated on the basis of the findings of the interviews. Data from the field survey were statistically compared with demographic, health, and socioeconomic data from global health organisations. The main outcomes were to assess baseline status of paediatric cancer care in the countries and postulated 5-year survival. Findings The baseline status of paediatric oncology care varied substantially between the surveyed countries. The number of patients reportedly receiving medical care (obtained from survey data) differed markedly from that predicted by population-based incidence data. Management of paediatric cancer and access to care were poor or deficient (ie, nonexistent, unavailable, or inconsistent access for most children with cancer) in seven of the ten countries surveyed, and accurate baseline data on incidence and outcome were very sparse. Postulated 5-year survival were: 5–10% in Bangladesh, the Philippines, Senegal, Tanzania, and Vietnam; 30% in Morocco; and 40–60% in Egypt, Honduras, Ukraine, and Venezuela. Postulated 5-year survival was directly proportional to several health indicators (per capita annual total health-care expenditure [Pearson's r 2 =0·760, p=0·001], per capita gross domestic product [ r 2 =0·603, p=0·008], per capita gross national income [ r 2 =0·572, p=0·011], number of physicians [ r 2 =0·560, p=0·013] and nurses [ r 2 =0·506, p=0·032] per 1000 population, and most significantly, annual government health-care expenditure per capita [ r 2 =0·882, p Interpretation Detailed surveys can provide useful data for baseline assessment of the status of paediatric oncology, but cannot substitute for national cancer registration. Alliances between public, private, and international agencies might rapidly improve the outcome of children with cancer in these countries. Funding National Institutes of Health (grant CA21765; Bethesda, MD, USA), American Lebanese Syrian Associated Charities (ALSAC; Memphis, TN, USA), and Sanofi-Aventis Sponsorship Department (Paris, France).

Journal ArticleDOI
TL;DR: High BMI was the lifestyle risk factor that most consistently modified breast cancer prognosis in this study, and no significant relationship with survival after breast cancer emerged for several other major lifestyle factors, including physical activity, alcohol drinking, exogenous hormones use and fat intake.
Abstract: A few lifestyle characteristics before cancer diagnosis have been suggested to modify the prognosis of breast cancer. Follow-up information from 1,453 women with incident invasive breast cancer, diagnosed between 1991 and 1994 and interviewed within the framework of an Italian multicenter case-control study, was used to assess the effect of obesity and of a large spectrum of other factors on breast cancer mortality. Five hundred and three deaths, including 398 breast cancer deaths, were identified. Hazard ratios (HR) for all-cause and breast cancer mortality and corresponding 95% confidence intervals (CI), were calculated using Cox proportional hazards models and adjusted for age and breast cancer characteristics (stage and receptor status). Increased risk of death for breast cancer emerged for body mass index (BMI) >/= 30 kg/m(2) (HR = 1.38; 95% CI: 1.02-1.86), compared to /= 0.85 (HR = 1.27; 95% CI: 0.98-1.64), compared to /=30 and high WHR (>/=0.85), compared to women with BMI /=55 years of age, whereas it was stronger in women with I-II stage than III-IV stage breast cancer. Low vegetable and fruit consumption and current or past smoking were also associated to marginally worse breast cancer survival. No significant relationship with survival after breast cancer emerged for several other major lifestyle factors, including physical activity, alcohol drinking, exogenous hormones use and fat intake. High BMI was the lifestyle risk factor that most consistently modified breast cancer prognosis in our study.

Journal ArticleDOI
TL;DR: The findings support the current state of evidence from general population studies that the protective potential of vegetable and fruit intake is larger for CVD than for cancer and suggest that diabetes patients may benefit from a diet high in vegetables and fruits.
Abstract: We examined the associations of intake of vegetables, legumes and fruit with all-cause and cause-specific mortality in a population with prevalent diabetes in Europe. A cohort of 10,449 participants with self-reported diabetes within the European Prospective Investigation into Cancer and Nutrition study was followed for a mean of 9 y. Intakes of vegetables, legumes, and fruit were assessed at baseline between 1992 and 2000 using validated country-specific questionnaires. A total of 1346 deaths occurred. Multivariate relative risks (RR) for all-cause mortality were estimated in Cox regression models and RR for cause-specific mortality were derived in a competing risk model. An increment in intake of total vegetables, legumes, and fruit of 80 g/d was associated with a RR of death from all causes of 0.94 [95% CI 0.90-0.98]. Analyzed separately, vegetables and legumes were associated with a significantly reduced risk, whereas nonsignificant inverse associations for fruit intake were observed. Cardiovascular disease (CVD) mortality and mortality due to non-CVD/non-cancer causes were significantly inversely associated with intake of total vegetables, legumes, and fruit (RR 0.88 [95% CI 0.81-0.95] and 0.90 [0.82-0.99], respectively) but not cancer mortality (1.08 [0.99-1.17]). Intake of vegetables, legumes, and fruit was associated with reduced risks of all-cause and CVD mortality in a diabetic population. The findings support the current state of evidence from general population studies that the protective potential of vegetable and fruit intake is larger for CVD than for cancer and suggest that diabetes patients may benefit from a diet high in vegetables and fruits.

Journal ArticleDOI
TL;DR: This paper summarises a proposal, and the considerations that led to it, developed by a joint International Agency for Research on Cancer and WHO working group, and approved by TobReg, which presents performance standards for cigarettes and a strategy to use them to mandate a reduction in the toxicant yields for cigarette smoke.
Abstract: Preventing initiation of tobacco product use, promoting cessation of tobacco use, and protecting the public from exposure to second hand smoke are recognised by the World Health organization (WHO) Framework Convention on Tobacco Control (FCTC) and by the WHO Study Group on Tobacco Product Regulation (TobReg) as the most effective approaches to reducing tobacco related morbidity and mortality. However, the FCTC also recognises the need for tobacco product regulation in articles 9 and 10 of the treaty. In order to inform that process TobReg has developed a series of reports that begin to provide a scientific foundation for tobacco product regulation.1–6 This paper summarises a proposal, and the considerations that led to it, developed by a joint International Agency for Research on Cancer (IARC) and WHO working group, and approved by TobReg, which presents performance standards for cigarettes and a strategy to use them to mandate a reduction in the toxicant yields for cigarette smoke. The most common measurements used historically to categorise cigarette smoke have been machine measured tar, nicotine and carbon monoxide (TNCO) yields per cigarette based on the US Federal Trade Commission (FTC)/International Standards Organization (ISO) testing regimen. There is a current scientific consensus that these per cigarette yields do not provide valid estimates of human exposure or of relative human exposure when smoking different brands of cigarettes.1 7–9 Communication of these measures to smokers as estimates of their exposure or risk creates harm by misleading smokers to believe that differences in exposures and risk are likely to occur with switching to cigarette brands with different machine-measured yields. This ongoing harm precludes continued acceptance of current regulatory strategies based on per cigarette machine measured TNCO levels and necessitates development of new regulatory approaches. Machine smoking regimens other than the FTC/ISO regimen …

Journal ArticleDOI
TL;DR: The Align‐GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiological problem of analyzing rare missens substitution observed during case‐control mutation screening studies of candidate susceptibility genes.
Abstract: Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2 However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk The grades were validated internally using a third, personal and family history-based, measure of risk The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes

Journal ArticleDOI
TL;DR: It is concluded that carefully validated computational algorithms, in the context of other evidence, can be an important tool for classification of missense variants.
Abstract: Genetic testing for mutations in high-risk cancer susceptibility genes often reveals missense substitutions that are not easily classified as pathogenic or neutral. Among the methods that can help in their classification are computational analyses. Predictions of pathogenic vs neutral, or the probability that a variant is pathogenic, can be made based on 1) inferences from evolutionary conservation using protein multiple sequence alignments (PMSAs) of the gene of interest for almost any missense sequence variant, and 2) for many variants, structural features of wild type and variant proteins. These in silico methods have improved considerably in recent years. In this paper, we review and/or make suggestions with respect to 1) the rationale for using in silico methods to help predict the consequences of missense variants, 2) important aspects of creating PMSAs that are informative for classification, 3) specific features of algorithms that have been used for classification of clinically observed variants, 4) validation studies demonstrating that computational analyses can have predictive values of ~75–95%, 5) current limitations of data sets and algorithms that need to be addressed in order to improve the computational classifiers, and 6) how in silico algorithms can be a part of the “integrated analysis” of multiple lines of evidence to help classify variants. We conclude that carefully validated computational algorithms, in the context of other evidence, can be an important tool for classification of missense variants.

Journal ArticleDOI
TL;DR: Evidence is provided that obesity and DM increase HCC risk and that these factors may explain a relevant proportion of cases among subjects without markers of HBV/HCV infection.