1. |
- Stacey, Simon N, et al.
(författare)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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2. |
- Anantharaman, Devasena, et al.
(författare)
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No causal association identified for human papillomavirus infections in lung cancer
- 2014
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:13, s. 3525-3534
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer. (C) 2014 AACR.
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3. |
- Brenner, Darren R, et al.
(författare)
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Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 36:11, s. 1314-1326
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
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4. |
- Carreras-Torres, Robert, et al.
(författare)
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Obesity, metabolic factors and risk of different histological types of lung cancer : a Mendelian randomization study
- 2017
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.
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5. |
- Furberg, Helena, et al.
(författare)
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Genome-wide meta-analyses identify multiple loci associated with smoking behavior
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441
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Tidskriftsartikel (refereegranskat)abstract
- Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
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6. |
- Heath, Simon C., et al.
(författare)
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Investigation of the fine structure of European populations with applications to disease association studies
- 2008
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 16:12, s. 1413-1429
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Tidskriftsartikel (refereegranskat)abstract
- An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East-West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North-South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.
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7. |
- Hung, Rayjean J, et al.
(författare)
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A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
- 2008
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 452:7187, s. 633-637
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Tidskriftsartikel (refereegranskat)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.
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8. |
- Johansson, Mattias, et al.
(författare)
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The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
- 2019
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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9. |
- Laskar, Ruhina S, et al.
(författare)
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Sex specific associations in genome wide association analysis of renal cell carcinoma.
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27:10, s. 1589-1598
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Tidskriftsartikel (refereegranskat)abstract
- Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
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10. |
- Lesseur, Corina, et al.
(författare)
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Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:12, s. 1544-1550
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers.
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11. |
- Machiela, Mitchell J, et al.
(författare)
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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 72:5, s. 747-754
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
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12. |
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13. |
- McKay, James D., et al.
(författare)
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Lung cancer susceptibility locus at 5p15.33
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:12, s. 1404-1406
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Tidskriftsartikel (refereegranskat)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.
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14. |
- Muller, David C, et al.
(författare)
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Circulating 25-hydroxyvitamin D3 and survival after diagnosis with kidney cancer
- 2015
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:8, s. 1277-1281
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Tidskriftsartikel (refereegranskat)abstract
- Prospective cohort studies have provided some evidence that circulating vitamin D is associated with risk of, and survival from, renal cell carcinoma (RCC), but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis. We conducted a case-cohort study of 630 RCC cases, including 203 deaths, from a multicenter case-control study in Eastern Europe. Vitamin D was assessed as 25-hydroxyvitamin D3 [25(OH)D3], and we used weighted Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) by categories of season-adjusted 25(OH)D3. Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage, age, sex, and country (HR highest vs. lowest category 0.57; 95% CI, 0.34-0.97). The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease. In summary, 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates, but not specifically with RCC outcome.
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15. |
- Scelo, Ghislaine, et al.
(författare)
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Genome-wide association study identifies multiple risk loci for renal cell carcinoma.
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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16. |
- Wang, Yufei, et al.
(författare)
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Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:7, s. 736-741
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Tidskriftsartikel (refereegranskat)abstract
- We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 x 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 x 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 x 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
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17. |
- Wu, Xifeng, et al.
(författare)
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A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:2, s. 456-462
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Tidskriftsartikel (refereegranskat)abstract
- Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 x 10(-10) and P = 6.07 x 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.
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