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1.  Sequence variant on 8q24 confers susceptibility to urinary bladder cancer 
Nature genetics  2008;40(11):1307-1312.
We conducted a genome wide SNP association study on 1,803 Urinary Bladder Cancer (UBC) cases and 34,336 controls from Iceland and the Netherlands and follow up studies in seven additional case control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30kb upstream of the c-Myc gene (allele specific OR=1.22; P=9.34×10−12). Approximately 20% of individuals of European ancestry are homozygous for rs9642880 (T) and their estimated risk of developing UBC is 1.49 times that of non-carriers with population attributable risk (PAR) of 17%. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome wide significance, was captured by rs710521 (A) located near the TP63 gene on chromosome 3q28 (allele specific OR=1.19; P=1. 15× 10−7).
PMCID: PMC4539560  PMID: 18794855
2.  Sequence variants at the TERT- CLPTM1L locus associate with many cancer types 
Rafnar, Thorunn | Sulem, Patrick | Stacey, Simon N. | Geller, Frank | Gudmundsson, Julius | Sigurdsson, Asgeir | Jakobsdottir, Margret | Helgadottir, Hafdis | Thorlacius, Steinunn | Aben, Katja K.H. | Blöndal, Thorarinn | Thorgeirsson, Thorgeir E. | Thorleifsson, Gudmar | Kristjansson, Kristleifur | Thorisdottir, Kristin | Ragnarsson, Rafn | Sigurgeirsson, Bardur | Skuladottir, Halla | Gudbjartsson, Tomas | Isaksson, Helgi J. | Einarsson, Gudmundur V. | Benediktsdottir, Kristrun R. | Agnarsson, Bjarni A. | Olafsson, Karl | Salvarsdottir, Anna | Bjarnason, Hjordis | Asgeirsdottir, Margret | Kristinsson, Kari T. | Matthiasdottir, Sigurborg | Sveinsdottir, Steinunn G. | Polidoro, Silvia | Höiom, Veronica | Botella-Estrada, Rafael | Hemminki, Kari | Rudnai, Peter | Bishop, D. Timothy | Campagna, Marcello | Kellen, Eliane | Zeegers, Maurice P. | de Verdier, Petra | Ferrer, Ana | Isla, Dolores | Vidal, Maria Jesus | Andres, Raquel | Saez, Berta | Juberias, Pablo | Banzo, Javier | Navarrete, Sebastian | Tres, Alejandro | Kan, Donghui | Lindblom, Annika | Gurzau, Eugene | Koppova, Kvetoslava | de Vegt, Femmie | Schalken, Jack A. | van der Heijden, Henricus F.M. | Smit, Hans J. | Termeer, René A. | Oosterwijk, Egbert | van Hooij, Onno | Nagore, Eduardo | Porru, Stefano | Steineck, Gunnar | Hansson, Johan | Buntinx, Frank | Catalona, William J. | Matullo, Giuseppe | Vineis, Paolo | Kiltie, Anne E. | Mayordomo, José I. | Kumar, Rajiv | Kiemeney, Lambertus A. | Frigge, Michael L. | Jonsson, Thorvaldur | Saemundsson, Hafsteinn | Barkardottir, Rosa B. | Jonsson, Eirikur | Jonsson, Steinn | Olafsson, Jon H. | Gulcher, Jeffrey R. | Masson, Gisli | Gudbjartsson, Daniel F. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2009;41(2):221-227.
The common sequence variants that have recently been associated with cancer risk are particular to a single, or at most two, cancer types. Following up on our genome-wide scan of basal cell carcinoma1, we identified rs401681(C) on chromosome 5p15.33 satisfying our threshold for genome-wide significance (OR=1.25, P=3.7×10−12). We tested rs401681 for association with sixteen additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR=1.15, P=7.2×10−8) and urinary bladder, prostate and cervix cancer (ORs 1.07–1.31, all P<4×10−4). However, rs401681(C) appears to confer protection against cutaneous melanoma (OR=0.88, P=8.0×10−4). Interestingly, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098(A), that showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. Rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein while rs401681 is in an intron of the CLPTM1L gene.
PMCID: PMC4525478  PMID: 19151717
3.  European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene 
Rafnar, Thorunn | Vermeulen, Sita H. | Sulem, Patrick | Thorleifsson, Gudmar | Aben, Katja K. | Witjes, J. Alfred | Grotenhuis, Anne J. | Verhaegh, Gerald W. | Hulsbergen-van de Kaa, Christina A. | Besenbacher, Soren | Gudbjartsson, Daniel | Stacey, Simon N. | Gudmundsson, Julius | Johannsdottir, Hrefna | Bjarnason, Hjordis | Zanon, Carlo | Helgadottir, Hafdis | Jonasson, Jon Gunnlaugur | Tryggvadottir, Laufey | Jonsson, Eirikur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Bishop, D. Timothy | Chung-Sak, Sei | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H. | Knowles, Margaret A. | de Verdier, Petra J. | Ryk, Charlotta | Lindblom, Annika | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Panadero, Angeles | Sanz-Velez, José I. | Sanchez, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D. | Hengstler, Jan G. | Selinski, Silvia | Gerullis, Holger | Ovsiannikov, Daniel | Khezri, Abdolaziz | Aminsharifi, Alireza | Malekzadeh, Mahyar | van den Berg, Leonard H. | Ophoff, Roel A. | Veldink, Jan H. | Zeegers, Maurice P. | Kellen, Eliane | Fostinelli, Jacopo | Andreoli, Daniele | Arici, Cecilia | Porru, Stefano | Buntinx, Frank | Ghaderi, Abbas | Golka, Klaus | Mayordomo, José I. | Matullo, Giuseppe | Kumar, Rajiv | Steineck, Gunnar | Kiltie, Anne E. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | Kiemeney, Lambertus A.
Human Molecular Genetics  2011;20(21):4268-4281.
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC.
PMCID: PMC3188988  PMID: 21750109
4.  Epidemiology of Chronic Pain in Denmark and Sweden 
Pain Research and Treatment  2012;2012:371248.
Introduction. Estimates on the epidemiology of chronic pain vary widely throughout Europe. It is unclear whether this variation reflects true differences between populations or methodological factors. Information on the epidemiology of chronic pain can support decision makers in allocating adequate health care resources. Methods. In order to obtain epidemiological data on chronic pain in Denmark and Sweden, we conducted a literature review of epidemiological data primarily on chronic noncancer pain, prioritising studies of highest quality, recency, and validity by conducting a systematic search for relevant studies. Following quality assessment, data were summarised and assigned to the research questions. Results. The prevalence of moderate to severe noncancer pain was estimated at 16% in Denmark and 18% in Sweden. Chronic pain impacts negatively on perceived health status, quality of life and is associated with increased cost. Despite using pain medications, a large proportion of chronic pain sufferers have inadequate pain control. There was a lack of high-quality and low-bias studies with clear inclusion criteria. Conclusions. In both Denmark and Sweden, chronic pain is a common health problem which is potentially undertreated and warrants attention of health care workers, policy makers and researchers. Future research should utilise clear reporting guidelines to assist decision and policy makers, in this important area.
PMCID: PMC3366230  PMID: 22693667
5.  Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer 
Nature Genetics  2009;41(9):991-995.
We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 × 10−10 and the allelic odds ratio was 1.15 (95% confidence interval 1.10–1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
PMCID: PMC3313685  PMID: 19648920
6.  Designing the selenium and bladder cancer trial (SELEBLAT), a phase lll randomized chemoprevention study with selenium on recurrence of bladder cancer in Belgium 
BMC Urology  2012;12:8.
In Belgium, bladder cancer is the fifth most common cancer in males (5.2%) and the sixth most frequent cause of death from cancer in males (3.8%). Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of bladder cancer. This suggests that selenium may also be suitable for chemoprevention of recurrence.
The SELEBLAT study opened in September 2009 and is still recruiting all patients with non-invasive transitional cell carcinoma of the bladder on TURB operation in 15 Belgian hospitals. Recruitment progress can be monitored live at Patients are randomly assigned to selenium yeast (200 μg/day) supplementation for 3 years or matching placebo, in addition to standard care. The objective is to determine the effect of selenium on the recurrence of bladder cancer. Randomization is stratified by treatment centre. A computerized algorithm randomly assigns the patients to a treatment arm. All study personnel and participants are blinded to treatment assignment for the duration of the study.
The SELEnium and BLAdder cancer Trial (SELEBLAT) is a phase III randomized, placebo-controlled, academic, double-blind superior trial.
This is the first report on a selenium randomized trial in bladder cancer patients.
Trial registration identifier: NCT00729287
PMCID: PMC3352119  PMID: 22436453
Selenium; Bladder cancer; Transitional Cell Carcinoma; Chemoprevention; Randomized clinical trial; Urology
7.  Genetic Evidence Supporting the Association of Protease and Protease Inhibitor Genes with Inflammatory Bowel Disease: A Systematic Review 
PLoS ONE  2011;6(9):e24106.
As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.
PMCID: PMC3169567  PMID: 21931648
8.  Dietary intake of micronutrients and the risk of developing bladder cancer: results from the Belgian case–control study on bladder cancer risk 
Cancer Causes & Control  2011;22(3):469-478.
We aimed to investigate the effect of dietary intake of micronutrients that are metabolized and excreted via the urinary tract on bladder cancer risk.
A semi-quantitative 322 item food frequency questionnaire (FFQ) was used to collect dietary data from 200 bladder cancer cases and 386 control subjects participating in the Belgian case–control study on bladder cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, sex, smoking characteristics, occupational exposures, and energy intake.
We observed a positive association between calcium intake and bladder cancer (OR: 1.77; 95% CI: 1.00–3.15; p-trend = 0.049) and increased odds, although not statistically significant, for highest tertile of phosphorus intake (OR: 1.82; 95% CI: 0.95–3.49; p-trend = 0.06). We identified possible modification of the effects of both calcium and phosphorus by level of magnesium intake. Increased odds of bladder cancer were also observed for participants with highest intake of phosphorus and lowest intake of vitamin D (OR: 4.25; 95% CI: 1.44–12.55) and among older participants with the highest intakes of calcium (OR: 1.90; 95% CI: 1.08–3.36) and phosphorus (OR: 2.02; 95% CI: 1.05–3.92).
The positive associations we observed between bladder cancer and intake of calcium and phosphorus require confirmation by other studies. The balances between inter-related micronutrients also warrant further examination.
PMCID: PMC3042097  PMID: 21203820
Bladder cancer; Micronutrients; Calcium; Vitamin D
9.  A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer 
Kiemeney, Lambertus A | Sulem, Patrick | Besenbacher, Soren | Vermeulen, Sita H | Sigurdsson, Asgeir | Thorleifsson, Gudmar | Gudbjartsson, Daniel F | Stacey, Simon N | Gudmundsson, Julius | Zanon, Carlo | Kostic, Jelena | Masson, Gisli | Bjarnason, Hjordis | Palsson, Stefan T | Skarphedinsson, Oskar B | Gudjonsson, Sigurjon A | Witjes, J Alfred | Grotenhuis, Anne J | Verhaegh, Gerald W | Bishop, D Timothy | Sak, Sei Chung | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H | Hurst, Carolyn D | de Verdier, Petra J | Ryk, Charlotta | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Campagna, Marcello | Placidi, Donatella | Arici, Cecilia | Zeegers, Maurice P | Kellen, Eliane | Gutierrez, Berta Saez | Sanz-Velez, José I | Sanchez-Zalabardo, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D | Hengstler, Jan G | Blaszkewicz, Meinolf | Dietrich, Holger | Ophoff, Roel A | van den Berg, Leonard H | Alexiusdottir, Kristin | Kristjansson, Kristleifur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Kong, Augustine | Thorgeirsson, Thorgeir | Mungan, N Aydin | Lindblom, Annika | van Es, Michael A | Porru, Stefano | Buntinx, Frank | Golka, Klaus | Mayordomo, José I | Kumar, Rajiv | Matullo, Giuseppe | Steineck, Gunnar | Kiltie, Anne E | Aben, Katja K H | Jonsson, Eirikur | Thorsteinsdottir, Unnur | Knowles, Margaret A | Rafnar, Thorunn | Stefansson, Kari
Nature genetics  2010;42(5):415-419.
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
PMCID: PMC2923020  PMID: 20348956
10.  A meta-analysis on depression and subsequent cancer risk 
The authors tested the hypothesis that depression is a possible factor influencing the course of cancer by reviewing prospective epidemiological studies and calculating summary relative risks.
Studies were identified by computerized searches of Medline, Embase and PsycINFO. as well as manual searches of reference lists of selected publications. Inclusion criteria were cohort design, population-based sample, structured measurement of depression and outcome of cancer known for depressed and non-depressed subjects
Thirteen eligible studies were identified. Based on eight studies with complete crude data on overall cancer, our summary relative risk (95% confidence interval) was 1.19 (1.06–1.32). After adjustment for confounders we pooled a summary relative risk of 1.12 (0.99–1.26).
No significant association was found between depression and subsequent breast cancer risk, based on seven heterogeneous studies, with or without adjustment for possible confounders. Subgroup analysis of studies with a follow-up of ten years or more, however, resulted in a statistically significant summary relative risk of 2.50 (1.06–5.91).
No significant associations were found for lung, colon or prostate cancer.
This review suggests a tendency towards a small and marginally significant association between depression and subsequent overall cancer risk and towards a stronger increase of breast cancer risk emerging many years after a previous depression.
PMCID: PMC2235847  PMID: 18053168

Results 1-10 (10)