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PDF file - 99K, LocusZoom plots of the top two loci using stage 1 P values.

Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer.Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb).Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5).Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.

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PDF file - 70K, Candidate inflammation genes selected for stage 1 study, Annotation of potentially functional SNPs in linkage disequilibrium (r2 > 0.2) with rs352038 (CXCL3) or rs3918249 (MMP9)

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Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.

PDF file, 123KB, Detailed Description of the Case and Control Sample Sets.

Introduction: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized by increased susceptibility to infections, immune dysregulation, and/or malignancy. Genetic studies, especially during the last decade, led to a better understanding of the pathogenesis of primary immunodeficiencies and contributed to their classification into distinct monogenic disorders falling under one of the >430 currently known inborn errors of immunity (IEI). The growing availability of molecular genetic testing resulted in the increasing identification of patients with IEI. Here, we evaluated the diagnostic yield and the clinical consequences of targeted next-generation sequencing (tNGS) in a cohort of 294 primary immunodeficiency patients, primarily consisting of cases with sporadic primary antibody deficiency. Method: We have custom designed a tNGS panel to sequence a cohort of PID patients. Agilent’s HaloPlex Target Enrichment System for Illumina was used for DNA target enrichment. Results: tNGS identified a definite or predicted pathogenic variant in 15.3% of patients. The highest diagnostic rate was observed among patients with combined immunodeficiency or immune dysregulation, for whom genetic diagnosis may affect therapeutic decision-making. Conclusion: Next-generation sequencing has changed diagnostic assignment and paved the way for targeted therapeutic intervention with agents directed at reverting the disease-causing molecular abnormality or its pathophysiological consequences. Therefore, such targeted therapies and identifying the genetic basis of PID can be essential for patients with manifested immune dysregulation as conventional immunomodulatory regimens may exert an immunosuppressive effect, aggravating their immunodeficiency or may only inadequately control autoimmune or lymphoproliferative manifestations.

Background DNA methylation is frequently observed in the development and progression of many human tumors as well as renal cell cancer (RCC). Tumor Associated Calcium Signal Transducer 2 (TACSTD2) participates in cell cycle progression through MAPK signalling pathway activation. Moreover, tumor-specific hypermethylation and association with aggressive cancer characteristics has been found for lung adenocarcinoma, hepatocellular carcinoma and cholangiocarcinoma. Whether TACSTD2 is tumor specifically hypermethylated in RCC or shows association of methylation with adverse clinicopathological parameters and survival of patients has not been investigated at yet. Methods Quantitative methylation-specific PCR (qMSP) analysis of a locus in the intron 1 region of TACSTD2 gene was carried out in a cross-sectional study of 127 paired RCC and normal samples. In silico analysis of TACSTD2 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) dataset of 280 patients served as validation cohort. Statistical analyses were carried out using the two-sided paired t-test for matched tumor and normal sample comparisons, logistic regression for subgroup comparisons, Cox regression for analysis of recurrence free survival (RFS) and Pearson correlation analysis for correlation of TACSTD2 methylation and TACSTD2 mRNA in KIRC data. Results Higher methylation levels in RCC were significantly associated with advanced disease (p p = 0.003), tumor differentiation (p = 0.033) and presence of lymph node (p = 0.021) or distant metastases (p = 0.008). TACSTD2 hypermethylation was associated with a shorter RFS of patients and demonstrate statistical independency from clinical parameters as state of metastasis, tumor stage, grade and state of advanced disease. In silico validation using TCGA KIRC data also demonstrated association of TACSTD2 loci with adverse clinicopathology and shortened RFS of patients. In addition, in silico analyses of TCGA KIRC data showed an inverse correlation between DNA methylation levels of TACSTD2 and mRNA expression. Conclusions Our results suggest an association between TACSTD2 methylation and disease progression and clinical course of RCC.

In addition to susceptibility to infections, conventional primary immunodeficiency disorders (PIDs) and inborn errors of immunity (IEI) can cause immune dysregulation, manifesting as lymphoproliferative and/or autoimmune disease. Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases, such as arthritis, systemic lupus erythematosus (SLE), and Sjogren’s syndrome (SjS). Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms. Here, we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency, highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.

ObjectivesTreatment of rheumatic diseases requires immunomodulatory agents which can compromise antibody production. However, even in case of agents directly targeting B cells, a minority of patients develop hypogammaglobulinaemia, suggesting a genetic predisposition, which has not been investigated so far. The phenotypic overlap between primary immunodeficiency disorders (PIDs) and rheumatic diseases suggests a shared genetic basis, especially in case of patients with rheumatic diseases with hypogammaglobulinaemia.Methods1008 patients with rheumatic diseases visiting the outpatient clinics of the Hannover University Hospital were screened for hypogammaglobulinaemia. Those with persistent hypogammaglobulinaemia and an equal number of patients without it underwent targeted next-generation sequencing, searching for variations in genes linked with hypogammaglobulinaemia in the context of PIDs.ResultsWe identified 33 predicted pathogenic variants in 30/64 (46.9%) patients with persistent secondary hypogammaglobulinaemia. All 33 variants were monoallelic and 10 of them in 10/64 (15.6%) patients were found in genes associated with autosomal dominant PIDs. 2/64 (3.1%) patients harboured variants which were previously reported to cause PIDs. In the group without hypogammaglobulinaemia we identified seven monoallelic variants in 7/64 (10.9%), including a variant in a gene associated with an autosomal dominant PID.ConclusionsApproximately half of patients with persistent secondary hypogammaglobulinaemia harboured at least a variant in a PID gene. Despite the fact that previous immunomodulatory treatment is an exclusion criterion in the diagnosis of PIDs, we identified genetic variants that can account for PID in patients with clear rheumatic phenotypes who developed hypogammaglobulinaemia after the introduction of immunomodulatory treatment. Our data suggest the common genetic causes of primary and secondary hypogammaglobulinaemia.

Simple Summary Early prediction of aggressive cancer using biomarkers is thought to be important for future improvements in the personalized treatment of renal cell carcinoma (RCC). Epigenetic alterations, such as DNA methylation, are promising candidates because they are frequently associated with distant metastasis of tumors and combinations of them offer greater informativity. Here, we describe the indication of the metastatic disease state of renal cell tumors by the methylation of three new candidate genes, INA, NHLH2, and THBS4. The inclusion of the methylation status of these genes could improve the early detection of metastatic tendency in renal tumors and help identify patients who will benefit from adjuvant treatments. Abstract The detection of DNA methylation in primary tumor tissues could be relevant for early stratification of aggressive renal cell carcinomas (RCCs) as a basis for future personalized adjuvant therapy. Methylated TCGA KIRC based candidate CpG loci in INA, NHLH2, and THBS4 that are possibly associated with RCC metastasis were evaluated by pyrosequencing in 154 paired normal adjacent and primary tumor tissues, as well as in 202 metastatic tissues. Statistical analysis was carried out by bivariate logistic regression for group comparisons, log rank survival analysis, and unsupervised and supervised analysis for the classification of tumors. Increased methylation of INA, NHLH2, and THBS4 loci were significantly associated with distant metastasis in primary tumors (p < 0.05), tissue-specific hypermethylation in metastatic (p = 7.88 × 10−8, 5.57 × 10−10, 2.06 × 10−7) and tumor tissues (p = 3.72 × 10−24, 3.17 × 10−13, 1.58 × 10−19), and shortened progression free survival in patients (p = 0.03). Combined use of CpG site-specific methylation permits the discrimination of tissues with metastatic disease and reveals a significant contribution of CpG sites in all genes to the statistical classification model. Thus, metastasis in RCC is significantly associated with methylation alterations in INA, NHLH2, and THBS4 loci, providing independent information for the potential early detection of aggressive renal cancers as a rationale for stratifying patients to adjuvant therapies.

Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.

Background While a considerable number of tumor-specific hypermethylated loci have been identified in renal cell cancer (RCC), DNA methylation of loci showing successive increases in normal, tumoral, and metastatic tissues could point to genes with high relevance both for the process of tumor development and progression. Here, we report that DNA methylation of a locus in a genomic region corresponding to the 3′UTR of the transcription factor T-box brain 1 (TBR1) mRNA accumulates in normal renal tissues with age and possibly increased body mass index. Moreover, a further tissue-specific increase of methylation was observed for tumor and metastatic tissue samples. Results Biometric analyses of the TCGA KIRC methylation data revealed candidate loci for age-dependent and tumor-specific DNA methylation within the last exon and in a genomic region corresponding to the 3′UTR TBR1 mRNA. To evaluate whether methylation of TBR1 shows association with RCC carcinogenesis, we measured 15 tumor cell lines and 907 renal tissue samples including 355 normal tissues, 175 tissue pairs of normal tumor adjacent and corresponding tumor tissue as well 202 metastatic tissues samples of lung, bone, and brain metastases by the use of pyrosequencing. Statistical evaluation demonstrated age-dependent methylation in normal tissue (R = 0.72, p < 2 × 10−16), association with adiposity (P = 0.019) and tumor-specific hypermethylation (P = 6.1 × 10−19) for RCC tissues. Comparison of tumor and metastatic tissues revealed higher methylation in renal cancer metastases (P = 2.65 × 10−6). Conclusions Our analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.

Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T&gt, G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4+ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27+ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

DNA methylation plays an important role in the genesis and progression of tumor diseases. To identify new DNA methylation markers possibly associated with the clinical characteristics of renal cell carcinoma (RCC), we investigated loci in the sarcosine dehydrogenase (SARDH) gene. SARDH is involved in the metabolism of the glycine‑derivative sarcosine and is closely linked through a functional control loop. Statistical evaluation of methylation data and clinical characteristics of patients showed that kidney tumors with clinically aggressive features such as a high tumor stage, positive lymph nodes, distant metastases or a previously advanced tumor status exhibited significantly lower methylation of a locus in the SARDH gene. Moreover, SARDH methylation was found to be a significant prognostic factor for recurrence‑free survival in RCC patients showing statistical independence from the clinical prognosticators, grade, stage and state of metastasis. In conclusion, the methylation status of the SARDH‑CGI was identified as an independent prognostic candidate marker for RCC.

Recent studies have shown that NELL1 expression is silenced epigenetically in human renal cell cancer (RCC) tissues and in RCC cell lines. However, it remains unknown whether NELL1 promoter methylation observed in clinical specimens might be associated with the clinicopathology or survival of patients with RCC. We analyzed NELL1 DNA methylation in tissues from patients with RCC and in adjacent normal renal tissues. In addition, we evaluated NELL1 methylation in cell lines derived from different urogenital tumors (prostate cancer, urothelial cancer and RCC). We performed regression analyses to determine whether NELL1 methylation is associated with clinicopathological parameters and recurrence‑free survival (RFS). This cross‑sectional study included 98 patients with RCC and 63 paired tumor and adjacent normal tissue samples. We analyzed a locus in the intron 1 region of NELL1 with pyrosequencing. We performed in silico analysis of NELL1 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) data set (n=284 patients), which served as a validation study. Statistical analyses were performed with the two‑sided paired t‑test for paired tumor and adjacent normal samples. We used logistic regression for subgroup comparisons and Cox regression for RFS comparisons. The mean methylation level was 6.8% higher in RCC tissues compared to paired adjacent normal tissues (paired t‑test, P

Rho GDP dissociation inhibitor-β (ARHGDIB) is an important mediator of cell signaling. The expression of ARHGDIB is associated with tumor growth and metastasis in a variety of non-genitourinary cancers; however, the role of ARHGDIB in renal cell carcinoma (RCC) has not yet been evaluated. In the present study, tissue samples from 105 patients undergoing surgery for RCC were obtained. The expression levels of ARHGDIB mRNA in normal kidney tissues and in corresponding cancer tissues were analyzed by reverse transcription-quantitative polymerase chain reaction. Differences in relative mRNA expression levels were assessed using paired two-sample t-tests. Expression levels were analyzed with respect to various clinical parameters, and associations were tested using a bivariate logistic regression model. Relative mRNA expression levels in healthy renal tissues compared with cancerous tissues from the same kidney were assessed using paired t-tests. Expression data were compared with respect to survival data by the Kaplan-Meier method/Cox regression analysis. The results revealed that the relative mRNA expression level of ARHGDIB was significantly higher in the lysates of RCC tumor tissues (P

Background P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. Methods We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. Results P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Conclusions Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0758-5) contains supplementary material, which is available to authorized users.

516 Background: Transition from localized renal cell cancer (RCC) to metastatic disease is associated with an immense mortality. Beside clinicopathological risk estimation, a molecular prediction of metastatic risk from primary cancers with a sufficient diagnostic accuracy is not available. We biometrically identified a candidate metastasis associated methylation signature (MAMS) in a genome-wide in silico DNA methylation analysis of TCGA data and carried out a double evaluation study using tissues from localized RCC, primary metastatic RCC, and distant metastases. Methods: Candidate MAMS was identified by genome-wide random forest analyses of TCGA methylation level 3 data aiming for classification of 230 primary RCC without distant metastases and 52 metastasized tumors. Forty-nine pyrosequencing and/or quantitative methylation specific PCR analyses were established for a total of 20 candidate methylated loci. For evaluation of MAMS, DNA was isolated and bisulfite converted from the primary RCC tissue cohort (n=187) as well as 99 distant metastases. Localized RCCs consisted of 92 pT1a/b tumors (clear cell, 73; papillary, 16; chromophobe, 2; not classified, 1) without lymph node or distant metastases. RCC samples of primary metastatic disease were obtained from 31 patients. Results: Single candidate loci showed specific hypermethylation when metastatic tissues were compared to primary RCC samples. Random forest analysis showed that MAMS including nine methylation loci achieved a sensitivity of 93% and a specificity of 89% (AUC 0.95) for differentiation of localized RCC and metastases (chi square, p = 3.4*10-29). Positive, negative likelihood, and diagnostic odds ratios were 8.6, 0.08, and 108. Using this random forest model for prediction of primary RCCs associated with distant or lymph node metastases revealed a sensitivity of 58% and specificity of 94% (AUC 0.84, p = 1.0*10-9). Positive, negative likelihood, and diagnostic odds ratios were 9.2, 0.45, and 20.5. Conclusions: A negative MAMS test result retrospectively reduced the probability of metastasis 15-fold in the localized disease cohort, suggesting a prospective evaluation for a possible clinical translation of MAMS in handling RCC patients.

The relevance of Corticotropin Releasing Hormone (CRH)-system in human malignancies is a question of growing interest. Here we investigated hypermethylation and epigenetic silencing of the CRH-Binding Protein (CRHBP) gene in clear cell renal cell cancer (ccRCC). Relative methylation of the CRHBP CpG island (CGI) was determined in 17 tumor cell lines as well as 86 ccRCC samples and 66 paired normal tissues using pyrosequencing and quantitative methylation specific PCR of bisulfite converted DNA. Results were statistically compared with relative mRNA expression levels of CRHBP and clinicopathological parameters of patients. Re-expression of CRHBP following 5-aza-2´-deoxycytidine treatment was investigated by quantitative mRNA expression analysis. Real-time impedance analysis was applied for analysis of invasiveness of renal tumor cells following si-RNA knockdown of CRHBP expression or ectopic expression of CRHBP. We found the CRHBP CGI to be frequently methylated in tumor cell lines of renal, prostatic, and bladder cancer. Comparison of methylation in normal and paired renal cancer tissue specimens revealed hypermethylation of the CRHBP CGI in tumors (p

474 Background: Rho GDP dissociation inhibitor 2 (ARHGDIB) is an important mediator of cellular signaling. The expression of ARHGDIB correlates with tumor growth and metastasis in a variety of non genitourinary cancers, however the role of ARHGDIB in renal cell cancer (RCC) has not yet been evaluated. Methods: Tissue samples from 106 patients undergoing surgery for RCC were obtained. The expression of ARHGDIB mRNA in normal kidney tissue and in corresponding cancer tissue was analyzed by means of quantitative real time PCR. Differences in mRNA expression levels were assessed using paired two-sample tests. Associations of relative mRNA expression levels and clinicopathological parameters were statistically analyzed using an univariate logistic regression model. Relative mRNA expression levels in healthy renal tissue compared to cancerous tissue from the same kidney was assessed using a paired t-test. Results: When comparing 74 tissues from kidney tumors with adjacent histologically normal appearing paired tissues, mRNA expression of ARHGDIB was significantly higher in the tumor tissue (p < 0.001). Paired analysis did not only show significantly higher mRNA expression levels for ARHGDIB over all RCC but also for the subgroup with clear cell RCC (ccRCC). The mRNA expression of ARHGDIB was also more pronounced in ccRCC when compared with papillary RCC (p < 0.001). When looking at clinicopathological parameters in univariate logistic regression analysis ccRCC was significantly associated with nodal involvement (p = 0.03) and also with tumor grade (p = 0.05). For all RCC there was no association with clinicopathological parameters. A bivariate Cox regression model, adjusted for metastatic status (p = 0.001), tumor diameter (p = 0.043), state of advanced disease (p = 0.030) and lymph node metastasis (p = 0.006) identified ARHGDIB mRNA expression as a candidate positive prognosticator for RFS. Conclusions: Increased ARHGDIB mRNA expression is significantly associated with RCC tissues. Higher relative expression observed within tumor tissues represents a candidate prognosticator for better RFS of patients.