Rôle des facteurs de risque familiaux, individuels et environnementaux dans les cancers de la thyroïde (Analyse d'études cas-témoins)

Objectifs : Les cancers de la thyroïde représentent environ 2% de l ensemble des cancers dans les pays développés mais sont les cancers les plus fréquents des glandes endocrines. L incidence des cancers de la thyroïde se caractérise par de fortes variations géographiques dans le monde, les taux les plus élevés étant observés en Nouvelle-Calédonie, et par une augmentation régulière au cours des dernières décennies dans les pays occidentaux. Cette augmentation d incidence est en grande partie attribuée à l évolution des pratiques médicales mais pourrait aussi être en partie liée à une évolution des modes de vie et/ou à des expositions environnementales. En dehors de l exposition aux radiations ionisantes dans l enfance, les facteurs de risque de cancer de la thyroïde restent très mal connus. L objectif de ce travail était d étudier le rôle des antécédents familiaux de pathologie de la thyroïde, des caractéristiques de la vie hormonale et reproductive, des caractéristiques anthropométriques et des expositions environnementales et professionnelles dans l étiologie des cancers de la thyroïde. Méthode : Les analyses reposent principalement sur une étude cas-témoins en population menée en France métropolitaine (étude CATHY). Nous avons également utilisé les données d une étude cas-témoins menée en Nouvelle-Calédonie pour étudier le rôle des antécédents familiaux dans cette zone géographique de forte incidence. L étude CATHY repose sur 621 cas diagnostiqués dans trois départements français (Calvados, Marne, Ardennes) entre 2002 et 2007 et sur 706 témoins, appariés par fréquence aux cas sur l âge, le sexe et le département de résidence. L étude cas-témoins en Nouvelle-Calédonie repose sur 332 cas diagnostiqués entre 1985 et 1999, et sur 412 témoins appariés par fréquence aux cas sur l âge et le sexe. Résultats : Les résultats montrent une augmentation du risque de cancer de la thyroïde chez les individus ayant des apparentés de premier degré atteints de cancer de la thyroïde ou de goitre multinodulaire, en France métropolitaine comme en Nouvelle-Calédonie. Parmi les facteurs hormonaux et reproductifs, un âge tardif aux premières règles, une ménopause précoce et une parité élevée étaient associés à une augmentation du risque de cancer de la thyroïde. Une relation dose-effet inverse était observée entre la durée cumulée des cycles menstruels au cours de la vie et le risque de cancer de la thyroïde. La prise d une contraception orale était associée à une diminution du risque de cancer de la thyroïde, avec une relation dose-effet inverse entre la durée de la contraception orale et le risque de cancer de la thyroïde. La taille, l indice de masse corporelle et la surface corporelle étaient positivement associés au risque de cancer de la thyroïde. Une augmentation du risque de cancer de la thyroïde était observée dans certains secteurs d activité professionnelle comme l industrie du papier, l industrie du caoutchouc et des plastiques, le travail du bois, la réparation automobile et la métallurgie.Objectives: Thyroid cancer accounts for 2% of all cancers in industrialized countries but is the most common endocrine cancer. There is a marked worldwide geographic variation in thyroid cancer incidence, the highest incidence rates being observed in New Caledonia, and a constant increase of thyroid cancer incidence has been observed during the past several decades. Although the evolution in medical practice probably accounts for some of the increase, other factors such as environmental and/or lifestyle factors may also play a role. However, there are few established risk factors of thyroid cancer apart from ionizing radiation exposure in childhood. We aimed to investigate the etiologic role of a family history of thyroid cancer, of hormonal and reproductive factors, anthropometric factors and environmental and occupational exposures in thyroid cancer. Methods: Analyses mainly rely on a population-based case-control study conducted in metropolitan France ( CATHY study ). Data of a case-control study conducted in New-Caledonia were also used to investigate the role of a family history of thyroid cancer as a risk factor for thyroid cancer in this area where thyroid cancer incidence is very high. The CATHY study is based on 621 cases diagnosed from 2002 to 2007 in three administrative areas: the Calvados, the Marne and the Ardennes, and 705 controls matched to cases by age, sex and residence area. The New Caledonian case-control study is based on 332 cases diagnosed form 1985 to 1999 and 412 controls matched to cases by age and sex. Results: A family history of thyroid cancer or multinodular goiter in first degree relatives was associated with an increased risk of thyroid cancer in France as well as in New Caledonia. Among hormonal and reproductive factors, a later age at menarche, a younger age at menopause and a elevated number of full-term pregnancies were associated with an increased risk of thyroid cancer. An inverse relationship was observed between the cumulative number of menstrual cycles and risk of thyroid cancer. Oral contraceptive use was associated with a lower risk of thyroid cancer, and an inverse relationship was observed between oral contraceptive use duration and risk of thyroid cancer. Height, body mass index and body surface area were positively associated with thyroid cancer risk. Analyses by occupation showed a higher risk of thyroid cancer for workers in leather industry, in plastics and rubber industry, in papermaking, in wood manufacturing, in automotive repair and in metallurgy.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertilit

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

notes: PMCID: PMC3976329This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.UK Medical Research CouncilWellcome Trus

Application of two job indices for general occupational demands in a pooled analysis of case-control studies on lung cancer

International audienceObjectives We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer. Methods In 13 case-control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands - each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman's Standard International Occupational Prestige Scale) were affected by adjustment for the job indices. Results In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56-1.93), PSI 1.33 (95% CI 1.17-1.51)] and women [PHI 1.62 (95% CI 1.24-2.11), PSI 1.31 (95% CI 1.09-1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32-1.58) to 1.30 (95% CI 1.17-1.45)], but not PSI. Conclusions Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Genetically Predicted Body Mass Index and Breast Cancer Risk : Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Background Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m(2) increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 x 10(-10)). The associations were similar for both premenopausal (OR = 0.44, 95% CI: 0.31-0.62, p = 9.91x10(-8)) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88x10(-8)). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 x 10(-7)). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p <0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.Peer reviewe

Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Peer reviewe

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.The Breast Cancer Association Consortium (BCAC), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), and the Ovarian Cancer Association Consortium (OCAC) that contributed breast, prostate, and ovarian cancer data analyzed in this study were in part funded by Cancer Research UK [C1287/A10118 and C1287/A12014 for BCAC; C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, and C16913/A6135 for PRACTICAL; and C490/A6187, C490/A10119, C490/A10124, C536/A13086, and C536/A6689 for OCAC]. Funding for the Collaborative Oncological Gene-environment Study (COGS) infrastructure came from: the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the US National Institutes of Health (CA128978) and the Post-Cancer GWAS Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112), the US Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund [with donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07)]. Additional financial support for contributing studies is documented under Supplementary Financial Support.This is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/2159-8290.CD-15-122

Epidémiologie des cancers de la thyroïde en Nouvelle-Calédonie (facteurs de variation des taux d'incidence et étude des facteurs de risque dans la population multiethnique des femmes calédoniennes)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Professions, expositions professionnelles aux solvants et cancer du sein analyse de deux études épidémiologiques sur les cancers du sein chez l'homme et chez la femme

Notre avons étudié le rôle de la profession et des expositions professionnelles aux solvants pétroliers et chlorés dans deux études épidémiologiques sur les facteurs de risque professionnels des cancers du sein chez l'homme et chez la femme. A l inverse du cancer du sein féminin (50000 nouveaux cas par an en France), le cancer du sein chez l homme est un cancer rare (<500 cas par an). Il constitue cependant un modèle intéressant pour l étude des expositions professionnelles qui sont généralement plus élevées chez l homme que chez la femme. Chez les hommes, nos résultats suggèrent un risque de cancer augmenté chez les mécaniciens de véhicules à moteur et un rôle cancérogène des solvants tels que le benzène et le trichloréthylène. Chez les femmes, malgré des risques élevés mais non significatifs dans plusieurs professions, aucune association avec les expositions aux solvants n était mise en évidence pour les faibles niveaux d exposition observés.We have investigated the role of the occupation and of occupational exposures to petroleum andchlorinated solvents using the data of two epidemiological studies on occupational risk factors ofbreast cancers in men and in women. Unlike female breast cancer (50,000 new cases per year inFrance), cancer of male breast cancer is a rare disease (<500 cases per year). It should be seen asan interesting model for studying the effects of occupational exposures in the disease as theseexposure are generally much higher in men than in women. For men, our results suggest that therisk of cancer is increased among motor vehicle mechanics and support the hypothesis of acarcinogenic effect of solvents such as benzene and trichloroethylene in disease occurrence. Inwomen, several occupations were at increased risk of breast cancer, but results were generallynot statistically significant. No association of female breast cancer incidence with exposure tosolvents was observed.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF