Survival of 86,690 patients with thyroid cancer: A population-based study in 29 European countries from EUROCARE-5

Background Incidence rates of thyroid cancer (TC) increased in several countries during the last 30 years, while mortality rates remained unchanged, raising important questions for treatment and follow-up of TC patients. This study updates population-based estimates of relative survival (RS) after TC diagnosis in Europe by sex, country, age, period and histology. Methods Data from 87 cancer registries in 29 countries were extracted from the EUROCARE-5 dataset. One- and 5-year RS were estimated using the cohort approach for 86,690 adult TC patients diagnosed in 2000â\u80\u932007 and followed-up to 12/31/2008. RS trends in 1999â\u80\u932007 and 10-year RS in 2005â\u80\u932007 were estimated using the period approach. Results In Europe 2000â\u80\u932007, 5-year RS after TC was 88% in women and 81% in men. Survival rates varied by country and were strongly correlated (Pearson Ï\u81 = 75%) with country-specific incidence rates. Five-year RS decreased with age (in women from >95% at age 15â\u80\u9354 to 57% at age 75+), from 98% in women and 94% in men with papillary TC to 14% in women and 12% in men with anaplastic TC. Proportion of papillary TC varied by country and increased over time, while survival rates were similar across areas and periods. In 1999â\u80\u932007, 5-year RS increased by five percentage points for all TCs but only by two for papillary and by four for follicular TC. Ten-year RS in 2005â\u80\u932007 was 89% in women and 79% in men. Conclusions The reported increasing TC survival trend and differences by area are mainly explained by the varying histological case-mix of cases

Erratum to "Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2)" [Gynecol. Oncol. 144 (2017) 396-404]

Objective. Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival. Methods. The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15\u201399 years) diagnosed with ovarian cancer during 1995\u20132009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated agestandardised 5-year net survival by stage at diagnosis (localised or advanced). Results. Survival fromtype I epithelial ovarian tumours for women diagnosed during 2005\u201309 ranged from40 to 70%. Survival from type II epithelial tumours was much lower (20\u201345%). Survival fromgermcell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%). Conclusions. There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology

Erratum to "The histology of ovarian cancer: Worldwide distribution and implications for international survival comparisons (CONCORD-2)" [Gynecol. Oncol. 144 (2017) 405-413]

Objective. Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods. The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995\u20132009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included.We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results. During 2005\u20132009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions. The distribution of ovarian cancer histology varieswidely worldwide. Type I epithelial, germcell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired \u3b2-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of 3c2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 7 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 7 10(-4)), improved \u3b2-cell function (P = 1.1 7 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 7 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

<p>Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.</p>

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (|r^g| ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance