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Sex specific associations in genome wide association analysis of renal cell carcinoma.
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
Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
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, p0.5) 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
Prognostic impact of Wilms’ tumour gene 1 (<i>WT1</i>) single nucleotide polymorphism (SNP) rs16754 in ccRCC.
<p>(A) Overall Survival (OS) for patients with rs16754 wild-type, heterozygous and homozygous minor allele and (B) Disease-specific survival (DSS) for patients with rs16754 wild-type, heterozygous and homozygous minor allele.</p
Prognostic impact of Wilms’ tumour gene 1 (<i>WT1</i>) single nucleotide polymorphisms (SNPs) in exon 1 in ccRCC.
<p>(A) Overall Survival (OS) for patients with wild-type, heterozygous and homozygous minor allele in exon 1 and (B) Disease-specific survival (DSS) for patients with wild-type, heterozygous and homozygous minor allele in exon 1.</p
Descriptive data regarding relative telomere length and % Tregs estimated in peripheral blood from 51 patients with RCC (Study 2).
<p>Descriptive data regarding relative telomere length and % Tregs estimated in peripheral blood from 51 patients with RCC (Study 2).</p
Flow cytometric plots for Treg evaluation.
<p>Gating on CD3+/CD4+ cells (left panel) was followed by subsequent gating according to the CD25 and CD127 expression (right panel). Tregs were defined as the CD4<sup>+</sup>CD25<sup>high</sup>CD127<sup>low/-</sup> -cells (P3). (A) A patient with high Tregs/long T cell telomere length. % Tregs of total PBL: 1.7; % Tregs of CD4+ cells: 7.7; T cell telomere length: 0.65. (B) A patient with low Tregs/short T cell telomere length. % Tregs of total PBL: 0.2; % Tregs of CD4+ cells: 4.8; T cell telomere length: 0.33.</p
No correlation between <i>WT1</i> SNP genotypes and clinical and pathologic characteristics in patients with ccRCC.
<p>DSS, disease specific survival; OS, overall survival;</p><p><i>p</i>*, significance compared between patients with <i>WT1</i> SNP homozygous or heterozygous for the minor allele versus wild-type.</p
No correlation between <i>WT1</i> SNP genotypes and <i>WT1</i> RNA expression in ccRCC.
<p><i>WT1</i>, Wilms’ tumour gene 1; −, homozygous minor allele was not identified in tumour-free tissues.</p
Survival analysis of Wilms’ tumour gene 1 (<i>WT1</i>) single nucleotide polymorphism (SNP) in ccRCC based on genotypes.
<p>(A) Kaplan-Meier curves of Overall Survival (OS) for patients with SNP genotypes in <i>WT1</i> and (B) Disease-specific survival (DSS) for patients with <i>WT1</i> SNP genotype.</p
Tumor telomere length and telomerase activity in relation to IL-7.
<p>Comparison of (A) tumor RTL and (B) tumor TA between patients with IL-7 levels below vs. above median (79 pg/ml). Differences between the groups were compared by ANCOVA with age-adjustment.</p