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International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden 1 . In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence 2 . Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics., (© 2024. The Author(s).)

Identifying causative genes via genetic testing is useful for screening, preventing and treating cancer. Several hereditary syndromes occur in patients with renal cell carcinoma (RCC). However, the evidence is from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to RCC development in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed in 1563 Japanese patients with RCC and 6016 controls. The patients were stratified into clear cell RCC (ccRCC) or non-ccRCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1532 patients with RCC and 5996 controls were analyzed. For ccRCC, 52 of 1283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 × 10-4; OR, 5.8; 95% CI, 2.2-15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 and FH (P = 6.27 × 10-5; OR, Inf; 95% CI, 10.0-Inf). The patients with the pathogenic variants in the associated genes were diagnosed 15.8 years earlier and had a higher proportion of patients with a family history of RCC (OR, 20.0; 95% CI, 1.3-237.4) than the non-carriers. We showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for improved personalized medicine., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Programmed death-ligand 1 (PD-L1) positivity is associated with poor prognosis in renal cell carcinoma (RCC). Because the prognostic impact and effect of confounding factors are less known, we investigated the prognostic significance of PD-L1 expression in Japanese patients with recurrent/metastatic RCC who started systemic therapy in 2010-2015., Methods: This multicenter, retrospective study recruited patients from 29 Japanese study sites who had prior systemic therapy for RCC (November 2018 to April 2019) and stored formalin-fixed paraffin-embedded primary lesion samples. The primary outcome was overall survival (OS) by PD-L1 expression. Secondary outcomes included OS in subgroups and duration of first- and second-line therapies by PD-L1 expression. OS distributions were estimated using Kaplan-Meier methodology., Results: PD-L1 expression (on immune cells [IC] ≥ 1%) was observed in 315/770 (40.9%) patients. PD-L1 positivity was more prevalent in patients with poor risk per both Memorial Sloan Kettering Cancer Center [MSKCC] and International Metastatic RCC Database Consortium, and high-risk pathological features (higher clinical stage, nuclear grade and sarcomatoid features). Median OS for PD-L1-positive patients was 30.9 months (95% CI 25.5-35.7) versus 37.5 months (95% CI 34.0-42.6) for PD-L1-negative patients (HR 1.04 [90% CI 0.89-1.22, p = 0.65]; stratified by MSKCC risk and liver metastases). Propensity score weight (PSW)-adjusted OS was similar between PD-L1-positive and -negative patients (median 34.4 versus 31.5 months; estimated PSW-adjusted HR 0.986)., Conclusions: This study suggests PD-L1 status was not an independent prognostic factor in recurrent/metastatic RCC during the study period because PD-L1 positivity was associated with poor prognostic factors, especially MSKCC risk status., (© 2021. The Author(s).)

Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan (http://www.bhd-net.jp/). Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed., (© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: Long non-coding RNAs (lncRNAs) can be used as prognostic biomarkers in many types of cancer., Objective: We sought to establish an lncRNA signature to improve postoperative risk stratification for patients with localized clear cell renal cell carcinoma (ccRCC)., Design, Setting, and Participants: Based on the RNA-seq data of 444 stage I-III ccRCC tumours from The Cancer Genome Atlas project, we built a four-lncRNA-based classifier using the least absolute shrinkage and selection operation (LASSO) Cox regression model in 222 randomly selected samples (training set) and validated the classifier in the remaining 222 samples (internal validation set). We confirmed this classifier in an external validation set of 88 patients with stage I-III ccRCC from a Japan cohort and using quantitative reverse transcription polymerase chain reaction (RT-PCR) in another three independent sets that included 1869 patients from China with stage I-III ccRCC., Outcome Measurements and Statistical Analysis: Univariable and multivariable Cox regression, Harrell's concordance index (c-index), and time-dependent receiver operating characteristic curves were used to evaluate the association of the classifier with overall survival, disease-specific survival, and disease-free survival., Results and Limitations: Using the LASSO Cox regression model, we built a classifier named RCClnc4 based on four lncRNAs: ENSG00000255774, ENSG00000248323, ENSG00000260911, and ENSG00000231666. In the RNA-seq and RT-PCR data sets, the RCClnc4 signature significantly stratified patients into high-risk versus low-risk groups in terms of clinical outcome across and within subpopulations and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.34 [95% confidence interval {CI}: 1.03-1.75; p=0.028] to 1.89 [95% CI, 1.55-2.31; p<0.001]) after adjusting for clinical and pathologic factors. The RCClnc4 signature achieved a higher accuracy (mean c-index, 0.72) than clinical staging systems such as TNM (mean c-index, 0.62) and the stage, size, grade, and necrosis (SSIGN) score (mean c-index, 0.64), currently reported prognostic signatures and biomarkers for the estimation of survival. When integrated with clinical characteristics, the composite clinical and lncRNA signature showed improved prognostic accuracy in all data sets (TNM + RCClnc4 mean c-index, 0.75; SSIGN + RCClnc4 score mean c-index, 0.75). The RCClnc4 classifier was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients., Conclusions: The RCClnc4 classifier is a promising and potential prognostic tool in predicting the survival of patients with stage I-III ccRCC. Combining the lncRNA classifier with clinical and pathological parameters allows for accurate risk assessment in guiding clinical management., Patient Summary: The RCClnc4 classifier could facilitate patient management and treatment decisions., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To identify key oncogenes and proteins that are controlled by the microRNA miR-29 family (miR-29a, miR-29b and miR-29c) in renal cell carcinoma pathogenesis., Methods: Genome-wide gene expression and in silico database analyses were carried out. The Cancer Genome Atlas database was used to investigate the clinical significance of gene expression data in renal cell carcinoma patients. Loss-of-function assays were applied to investigate the function of target genes., Results: We identified 47 possible target genes that might be regulated by the miR-29 family in renal cell carcinoma cells. Among the targets of the miR-29 family, high expression of 10 genes (ADAMTS14, TRIB13, SERPINH1, FCGR1B, COL1A1, LAIR2, WISP2, TREM1, TNKS1BP1 and GBP2) significantly predicted poor patient prognosis (P < 0.001). SERPINH1 was directly regulated by the miR-29 family, and its overexpression was detected in renal cell carcinoma surgical specimens and tyrosine kinase inhibitor failure autopsy specimens. High expression of SERPINH1 was significantly associated with tumor stage, pathological grade and poor prognosis (P < 0.0001). Knockdown assays showed that its expression enhanced cancer cell migration and invasive abilities., Conclusions: Genes regulated by the anti-tumor miR-29 family are closely involved in the molecular pathogenesis of renal cell carcinoma. Our approach based on anti-tumor microRNAs might contribute to the development of new diagnostic markers and therapeutic strategies., (© 2018 The Japanese Urological Association.)

Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10(-3), odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87x10(-2), OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10(-3), OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects., Case Presentation: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient., Conclusion: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

Unlabelled: What's known on the subject? and What does the study add? Ras association domain family 1A (RASSF1A) is a tumour suppressor and regulates cell cycle, apoptosis and microtubule stability. This is the first study to identify associations between RASSF1A polymorphisms and clinicopathological parameters and survival in patients with clear cell renal cell carcinoma (CCRCC). RASSF1A genotyping may be useful for predicting the prognosis of the clinical course of CCRCC, and this finding might provide a better understanding of the mechanism underlying the development and progression of CCRCC. However, functional and prospective studies with a larger number of patients are needed to confirm the results., Objective: To compare Ras association domain family 1A (RASSF1A) genotypes or haplotypes with clinicopathological characteristics and survival rates of patients with clear cell renal cell carcinoma (CCRCC)., Patients and Methods: The study cohort comprised 224 Japanese patients who underwent radical nephrectomy and had CCRCC confirmed by histopathological analysis. • Three common polymorphisms in the RASSF1A gene, 133Ala/Ser (G/T), -710C/T and -392C/T, were genotyped using TaqMan assays and haplotypes were analysed using appropriate software., Results: Patients with CCRCC with RASSF1A -710TT genotype exhibited a significantly higher tumour stage and higher stage grouping than those with -710CC or -710CT (P = 0.005 and P = 0.032, respectively). • There was no significant association between 133Ala/Ser or -392C/T genotype and clinicopathological characteristics. • RASSF1A 133Ala-710T-392T haplotype and -710TT genotype were significantly associated with poorer recurrence-free survival rates (P = 0.038 and P = 0.007, respectively)., Conclusions: This is the first study to identify associations between RASSF1A polymorphisms and clinicopathological parameters and survival in patients with CCRCC. • RASSF1A genotyping may be useful in predicting the prognosis of the clinical course of CCRCC, and this finding might provide a better understanding of the mechanism underlying the development and progression of CCRCC. • Functional and prospective studies with a larger number of patients are needed to confirm the results., (© 2012 BJU INTERNATIONAL.)

The author investigated protein expression and gene mutations of KIT and PDGFRA in 61 consecutive surgical cases of renal cell carcinoma (RCC). The cases of RCC consisted of 43 clear cell RCC (CCRCC), 9 chromophobe RCC (ChrRCC), or 9 papillary RCC (PaRCC). Normal distribution of KIT and PDGFRA protein was also examined in non-tumorous normal parenchyma (n=10). In normal kidneys, KIT was expressed in distal convoluted tubules and collecting ducts, and PDGFRA in distal and proximal convoluted tubules and collecting ducts. KIT expression was recognized in 9 ChrRCC (100%, 9/9), but not in 43 CCRCC (0%, 0/43) and 9 PaRCC (0%, 0/9). PDGFRA expression was recognized in 7 CCRCC (16%, 7/43) and 2 PaRCC (28%, 2/9), but not in ChrRCC (0%, 0/9). A molecular genetic analysis using PCR-direct sequencing was performed in selected 30 cases (ChrRCC=9, CCRCC=12, PaRCC=9): it revealed no mutations in KIT (exons 9, 11, 13, and 17) or PDGFRA (exons 12 and 18) genes in any cases examined. These results suggest that in normal renal parenchyma KIT is expressed in distal convoluted tubules and collecting ducts, and PDGFRA in proximal and distal convoluted tubules and collecting ducts, that KIT is expressed exclusively in ChrRCC and its incidence is 100%, that KIT-positive ChrRCC was negative for PDGFRA, that PDGFRA is expressed in a small percentage in CCRCC and PaRCC, and that mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) are absent in RCC.

Objective: To determine if the two common polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect tumour aggressiveness or prognosis of clear cell renal cell carcinoma (CCRCC) in Japanese patients., Patients and Methods: MTHFR C677T and A1298C polymorphisms have been reported to cause decreased enzyme activity, which reduces the quantity of methyl groups available for DNA methylation and leads to mis-incorporation of uracil into DNA, resulting in single-strand DNA breaks. These effects might induce the accumulation of several genetic changes, leading to the development and progression of CCRCC. Therefore, we investigated the associations between MTHFR genotypes and haplotypes and the clinicopathological characteristics and survival rates in 240 Japanese patients with histopathologically confirmed CCRCC. MTHFR C677T and A1298C were genotyped and haplotypes were analysed using appropriate software., Results: The variant genotypes of MTHFR A1298C were significantly associated with some advanced characteristics of CCRCC in all patients, and these associations were stronger among men. However, among women, the variant genotypes of MTHFR C677T were associated with some advanced characteristics of CCRCC and the C677T variant genotypes or the 677T-1298A haplotype was significantly associated with decreased overall survival (P = 0.007 and P = 0.009, respectively)., Conclusion: To our knowledge, this is the first report on the association between MTHFR polymorphisms and CCRCC aggressiveness or prognosis. These results suggest that the MTHFR genotypes and haplotype might be useful, in a gender-specific manner, as predictive factors for the clinical course of CCRCC. Furthermore, these findings will contribute to the understanding of the mechanisms underlying CCRCC progression.

Signal transducer and activator of transcription (Stat) 3 and p53 integrate upstream signals, and are positive and negative regulators of tumor cell proliferation, respectively. Stat3 and p53 also negatively regulate each other. However, their roles remain elusive in patients with renal cell carcinoma (RCC). We quantified Stat3 and p53 mRNA expression in paired tumor and non-tumor surgical samples from 47 Japanese patients with RCC by the real-time reverse transcription polymerase chain reaction (RT-PCR) technique. Absolute levels of Stat3 and p53 mRNA were lower in tumor tissues compared with non-tumor tissues (P < 0.0001). The absolute levels of Stat3 and p53 mRNA in RCC tissue were not correlated with tumor histology, stage, or metastatic behavior. Kaplan-Meier analysis showed that a high level of Stat3 or p53 mRNA expression was associated with shorter overall survival compared to low expression (P = 0.254 and P = 0.066, respectively). In addition, the tumor tissue levels of Stat3 and p53 mRNA expression were correlated with each other (r(2) = 0.697, P < 0.01). These findings suggest that Stat3 and p53 are cooperatively involved in the development of RCC, but assessment of their mRNA expression may not be useful for predicting the prognosis of patients with RCC.

Chromophobe renal cell carcinoma (RCC) is subdivided into typical and eosinophilic variants. We report such two cases with focus on imprint cytology and fluorescence in situ hybridization (FISH). The first case is a 53-year-old Japanese man and the second is a 76-year-old Japanese man. Histologically, the diagnosis of typical and eosinophilic variants of chromophobe RCC was suspected. In imprint cytology, irregularity of nuclear membrane, binucleation, perinuclear halo, and thick cell border were observed. Immunohistochemically, neoplastic cells of both tumors were positive for cytokeratin 7, E-cadherin, c-kit, and CD10. In FISH study, both tumors revealed the monosomy of chromosomes 10 and 21. Additionally, FISH study in eosinophilic variant of chromophobe RCC showed the disomy of chromosomes 7 and 17. In conclusion, we suggest that the combination study of imprint cytology and FISH of chromosomes 10 and 21 as well as routine histology may contribute to the accurate diagnosis of chromophobe RCC.

The myc target gene Mina53 was reported to be overexpressed in esophageal cancer with a poor prognosis. The purpose of the present study was to examined Mina53 expression and its relationship to clinicopathological parameters in human renal cell carcinoma (RCC). Mina53 and Ki-67 expression was examined on immunohistochemistry for 64 surgically resected RCC and non-cancerous tissue. In addition, the relationship between Mina53 expression and clinicopathological prognostic factors of RCC such as age, stage, microvenous invasion (MVI), histological subtype, Ki-67 labeling index (LI), and prognosis, was examined. Mina53 was expressed in the nuclei of tumor cells and tubular nuclei of normal renal tissue. The expression level of Mina53 was significantly higher in patients with poor prognostic factors (stage IV, MVI-positive, and sarcomatoid RCC, and high Ki-67 LI). The prognosis of high Mina53-expressing tumors was significantly poorer than that of non-Mina53-high tumors (P < 0.0001). In conclusion, Mina53 is overexpressed in RCC tissue from patients with poor prognostic factors, suggesting that Mina53 overexpression is one of the factors for poor prognosis in RCC.

Purpose: To clarify the effect of genetic polymorphisms on the response to interferon alfa (IFN-alpha) for metastatic renal cell carcinoma (MRCC), and to find a reliable molecular marker to select those patients with MRCC who would benefit from IFN-alpha immunotherapy., Patients and Methods: We carried out an association study in which 463 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in 75 Japanese patients who had received IFN-alpha for MRCC., Results: After adjusting for lung metastasis, stepwise logistic regression analysis revealed that the SNPs in signal transducer and activator 3 (STAT3) were most significantly associated with better response to IFN-alpha. Linkage disequilibrium mapping revealed that the SNP in the 5' region of STAT3, rs4796793, was the most significant predictor of IFN-alpha response (odds ratio [OR] = 2.73; 95% CI, 1.38 to 5.78). The highest OR was shown in the CC genotype at rs4796793 compared to the GG + GC genotypes (OR = 8.38, 95% CI, 1.63 to 42.96). Genotype-dependent expressions of STAT3 in B lymphocyte cell lines and the enhanced growth inhibitory effects of IFN- by STAT3 suppression in an RCC cell line supported the results of the present association study., Conclusion: The present study suggested that the STAT3 polymorphism is a useful diagnostic marker to predict the response to IFN-alpha therapy in patients with MRCC. An efficient response marker for IFN-alpha needs to be utilized to establish individual optimal treatment strategies, even when newer drug therapies are used as first line treatments for MRCC.

Aim: Biological and epidemiologic data suggest that 1 alpha, 25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) levels may influence development of renal cell carcinoma. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of 1,25(OH)(2)D(3) and additionally interacts with other cell signaling pathways that influence cancer progression. VDR gene polymorphisms may play an important role in risk of incidence for various malignant tumors. This study investigated whether VDR gene polymorphisms were associated with increased risk and prognosis of renal cell carcinoma (RCC) in a Japanese population., Methods: To analyze risk of RCC depending on VDR polymorphism, a case-control association study was performed. The VDR gene polymorphisms at three locations, BsmI, ApaI and TaqI, were genotyped in 135 RCC patients and 150 controls in a Japanese population. Logistic regression models were used to assess the genetic effects on prognosis., Results: Significant differences in the ApaI genotype were observed between RCC patients and controls (chi(2) = 6.90, P = 0.032). No statistical significant difference was found in the BsmI and TaqI polymorphisms. The frequency of the AA genotype in the ApaI polymorphism was significantly higher in the RCC patients than in the controls (odds ratio, 2.59; 95% confidence intervals, 1.21-5.55; P = 0.012). Multivariate regression analysis showed that the AA genotype was an independent prognostic factor for cause-specific survival (relative risk 3.3; P = 0.038)., Conclusion: The AA genotype at the ApaI site of the VDR gene may be a risk of incidence and poor prognosis factor for RCC in the Japanese population. Additional studies with a large sample size and investigation of the functional significance of the ApaI polymorphism in RCC cells are warranted.

The estrogen metabolite, 4-hydroxy-estrogen, has been shown to play a role in malignant transformation of male kidneys. To counteract the effects of this catechol-estrogen, the catechol-O-methyltransferase (COMT) enzyme is capable of neutralizing the genotoxic effects of this compound. A polymorphic variant of COMT has been shown to have a reduced enzyme activity, and thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for renal cell cancer (RCC). To determine this hypothesis, a study of a Japanese male population was used and the genetic distributions of COMT polymorphisms at codons 62 (C-->T), 72 (G-->T), and 158 (G-->A) were analyzed in 157 normal healthy subjects and 123 sporadic RCC (clear cell type) samples by using a sequence-specific PCR technique. These experiments show that the variant genotype (P = 0.025) and allele (P = 0.011) at codon 62 is a risk factor for RCC. The odds ratio and 95% confidence interval for cancer were 3.16 and 1.29 to 7.73, respectively, for the T/T genotype as compared with wild-type. No associations for renal cancer were found at either codons 72 or 158 in this Japanese male population. However, codons 62 and 158 were observed to be in linkage disequilibrium, and haplotype analysis shows the combined forms of T-A, T-G, and C-A to be associated with RCC as compared with C-G (P < 0.001). When evaluating the risk of COMT polymorphisms with grade of cancer, no associations were observed for any of the genotypes. This study is the first to report COMT polymorphism to be associated with RCC. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of RCC.

DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity and may influence an individual's susceptibility to carcinogenesis. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been shown to cause a reduction in repair activity. We hypothesized that SNPs of DNA repair genes may be a risk factor for renal cell carcinoma (RCC). To test this hypothesis, DNA samples from 112 cases of renal cell cancer and healthy controls (n=180) were analyzed by PCR-RFLP to determine the genotypic frequency of six different polymorphic loci on five DNA repair genes (XRCC1, XPC, ERCC1, XRCC3, and XRCC7). The chi(2) test was applied to compare the genotype frequency between patients and controls. We found that the frequency of 399Gln variant at XRCC1 Arg399Gln was significantly higher in RCC cases than in controls (OR=2.83, 95%CI=1.24-6.49, P=0.01). The frequency of T-A haplotype of XRCC1 194 Trp and XRCC1 399Gln was significantly higher in RCC than controls. No differences in genotypes were observed at the other sites. This is the first report on SNPs of DNA repair genes in renal cell carcinoma that suggests XRCC1 399Gln polymorphism may be a risk factor for RCC. Our present data suggest that the XRCC1 399Gln allele may be linked to susceptibility for RCC.

It has been shown that the matrix metalloproteinase (MMP)-1 promoter polymorphism 1G/2G is associated with an increased risk of developing various cancers including renal cell carcinoma (RCC), and is in linkage disequilibrium (LD) with the MMP-3 promoter polymorphism 5A/6A. These two genes are localized in 11q22 adjacent to each other. However, the relationship between the MMP-3 5A/6A polymorphism and susceptibility to cancer remains ambiguous. In this study, we genotyped eight polymorphisms in the region containing the MMP-1 and MMP-3 genes in 177 healthy subjects, and explored the relationships between RCC and these polymorphisms or haplotypes in 156 RCC cases and 230 age- and gender-matched controls. All the subjects studied were of Japanese descent. There were three polymorphisms that showed stronger LD with the MMP-1 1G/2G promoter variant than with the MMP-3 5A/6A promoter variant. One of these three polymorphisms was present in exon 2 of the MMP-3 gene and caused an amino acid change, Glu45Lys (G/A). When the genotype distribution of Glu45Lys was compared between RCC patients and controls, the frequency of the G/G genotype was significantly higher in the patients [age- and gender-adjusted odds ratio (OR) = 1.81, 95% confidence interval (CI) = 1.20-2.74]. A significant increase in the frequency of the 2G/2G genotype of the MMP-1 1G/2G polymorphism was also observed in the patients (age- and gender-adjusted OR = 1.86, CI = 1.23-2.82), whereas there was no significant difference for the MMP-3 5A/6A polymorphism. As expected based on these genotype-level results, the frequency of the 2G-G haplotype of MMP-1 1G/2G and MMP-3 Glu45Lys (G/A) polymorphisms was significantly higher in the patients than in the controls (crude OR = 1.95, CI = 1.31-2.91). These findings suggest that this haplotype of MMP-1 and MMP-3 variants may be associated with the risk of developing RCC.

The human androgen receptor (AR) gene contains a single nucleotide polymorphism (SNP) on codon 211 and two polymorphic short tandem repeats of CAG and GGC in the N-terminal domain that may influence transcription efficiency of AR gene. We previously reported that the lengths of the CAG and GGC repeats are inversely and linearly related to AR activity and associated with several cancers. However, little is known about this SNP on codon 211 of the AR gene in human renal cell cancer. The cause of renal cell cancer is not well understood although several factors such as chemical carcinogens and hormones have been implicated. AR has been identified in human and animal renal cell cancer. We hypothesize that the SNP on codon 211 is associated with human renal cell cancer. To test this hypothesis, the genetic distribution of the SNP on codon 211 of AR gene was investigated in renal cell cancer patients (211 cases) and healthy controls (200 cases). The allelic and genotypic distributions were determined by PCR-RFLP and direct DNA sequencing techniques. The chi2 test for these data revealed that the distribution of this SNP was not different between renal cell cancer patients as compared to normal healthy controls. The findings suggest that the SNP on codon 211 in the AR gene may not have an important role in the carcinogenesis of human renal cell cancers.

To explore the role of allelic losses at 3p25 and genetic alterations of chromosome 8, we investigated the relationships between genetic alterations in these chromosomal regions and clinicopathologic findings (such as tumor size and grade), by employing fluorescence in situ hybridization (FISH). Fifty Japanese clear-cell renal cell carcinomas (RCCs) were examined by dual-color FISH using cosmid DNA probes for 3p25.1-25.3 combined with probes for chromosome 3 centromere, 8p12, 8p21.1, 8p21.3, 8p22 and 8q24.12-24.13 (c-myc), and chromosome 8 centromere. Deletion at 3p25.1-25.3 was detected in 38 patients (76%), while 8p12 deletion, 8p21.1 deletion, 8p21.3 deletion, 8p22 deletion and c-myc gain were detected in 23 (46%), 25 (50%), 25 (50%), 25 (50%), and 20 patients (40%), respectively. There was a significant correlation between 8p21.1 deletion, 8p21.3 deletion and 8p21.1 deletion with c-myc gain and tumor grade (p = 0.04, 0.04 and 0.02, respectively). Deletions at 8p21.1 and 8p21.3 with 3p deletion were significantly related to tumor grade; the statistical significance was identical to that of sole 8p deletion with tumor grade. The deletion at 3p25.1-25.3 with c-myc gain showed a significant correlation with tumor size, indicating an association with tumor progression. Our results suggest that the allelic loss of chromosome 3p25 with c-myc gain is related to the development of clear-cell RCC., (Copyright Blackwell Munksgaard, 2003)

We investigated native Japanese subjects whether C702T, C936T and G1612A polymorphisms in the 3' untranslated region (3'-UTR) of vascular endothelial growth factor (VEGF) gene are associated with the risk of renal cell carcinoma (RCC). Genomic DNAs from 145 RCC patients and 145 healthy controls were examined by polymerase chain reaction-based restriction fragment length polymorphism. Variant allele frequencies of C702T, C936T and G1612A were 0.00, 0.20 and 0.13 in the controls, respectively. The C702T and G1612A allele frequencies were significantly different between the Japanese population and the Caucasian population reported elsewhere. For each of C936T and G1612A polymorphisms, there was no statistically significant difference in the distribution of genotype frequencies between the cases and controls. Odds ratios and 95% confidence intervals computed by logistic regression analyses were not statistically significant. Stratification for the RCC cases according to pathological cell subtype, grade or stage failed to reveal any significant heterogeneity with respect to the genotype of each VEGF polymorphism. We revealed that there are significant ethnic differences in the C702T and G1612A allele frequencies, but suggested that C702T, C936T and G1612A polymorphisms in the 3'-UTR of VEGF gene are not associated with the risk of RCC, at least in Japanese population.

Molecular epidemiologic studies have reported a relationship between 1alpha,25 dihydroxyvitamin D3 (1,25(OH)2D3) and the development and progression of malignant tumors. (1,25(OH)2D3) exerts its biological activity by binding the vitamin D receptor (VDR), while recent studies have demonstrated that VDR gene polymorphisms affect serum levels of (1,25(OH)2D3). Serum levels of (1,25(OH)2D3) are reported to be significantly lower in patients with renal cell carcinoma (RCC) compared to non-cancer control patients. The purpose of this study was to investigate the TaqI VDR polymorphism in Japanese RCC patients and non-cancer controls in order to determine if an association exists between VDR genotype and the risk of developing RCC as well as clinical risk factors. A total of 102 RCC patients and 204 controls were genotyped for a previously described TaqI restriction fragment length polymorphism (RFLP) of the VDR gene. Products were digested into T allele or the t allele according to the absence or presence of a TaqI restriction site. Individuals were classified as TT, Tt or tt. The genotype TT was statistically more frequent among RCC patients (80.4%) compared to controls (61.8%) (OR = 2.54; 95% CI, 1.44-4.46; p = 0.0006). In addition, the occurrence of the genotype TT was significantly higher in patients with rapid-growth-type group (92.1%) compared to slow-growth-type group (73.4%) (OR = 4.22; 95% CI, 1.15-15.53; p = 0.0175). These data demonstrate that VDR genotype plays an important role in determining the risk of developing more aggressive RCC in Japanese.

To better understand the molecular mechanisms that underlie the tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC), we studied the gene expression profiles of 29 ccRCC tumors obtained from patients with diverse clinical outcomes by using 21,632 cDNA microarrays. We identified gene expression alterations that were both common to most of the ccRCC studied and unique to clinical subsets. There was a significant distinction in gene expression profile between patients with a relatively nonaggressive form of the disease [100% survival after 5 years with the majority (15/17 or 88%) having no clinical evidence of metastasis] versus patients with a relatively aggressive form of the disease (average survival time 25.4 months with a 0% 5-year survival rate). Approximately 40 genes most accurately make this distinction, some of which have previously been implicated in tumorigenesis and metastasis. To test the robustness and potential clinical usefulness of this molecular distinction, we simulated its use as a prognostic tool in the clinical setting. In 96% of the ccRCC cases tested, the prediction was compatible with the clinical outcome, exceeding the accuracy of prediction by staging. These results suggest that two molecularly distinct forms of ccRCC exist and that the integration of expression profile data with clinical parameters could serve to enhance the diagnosis and prognosis of ccRCC. Moreover, the identified genes provide insight into the molecular mechanisms of aggressive ccRCC and suggest intervention strategies.

Objectives: Several clinical features, such as the spontaneous regression of some renal cell carcinoma (RCC) metastases after nephrectomy, suggest immune involvement in tumor destruction., Patients and Methods: We investigated the role of genetic variation at the HLA class II loci in RCC by analyzing the HLA-DR antigen and HLA-DRB1, DRB3, DRB4 and DRB5 alleles in 55 patients using the polymerase chain rection., Results: No statistically significant differences were observed in the frequency of the HLA-DR antigen or HLA-DRB3, DRB4, or DRB5 genes between the patients and a healthy control group. On the other hand, the HLA-DRB1*0403 and *1202 alleles were significantly more frequent in the patients than in the controls (p < 0.001 and p < 0.01, respectively)., Conclusion: RCC might be linked to these two alleles in Japanese patients., (Copyright 2000 S. Karger AG, Basel)

Incidence of the loss of heterozygosity on chromosome 3p was evaluated using 7 polymorphic probes in 35 Japanese patients with sporadic renal cell carcinoma (RCC). Overall frequency of the loss of heterozygosity on 3p was 53%, representing 16 of 30 informative cases. Examination of the relationship between histopathological phenotypes of RCC and incidence of the 3p loss revealed that the loss of heterozygosity in clear cell type tumors (75%, 12 of 16) was significantly (P less than 0.01) more frequent than that in granular cell type tumors (14%, 1 of 7). In addition, three mixed cell type tumors, consisting predominantly of granular cell components, showed no loss of chromosome 3p loci. These findings may support the notion that the loss of heterozygosity on chromosome 3p is a nonrandom event in the tumorigenesis of sporadic RCC, and suggest that this type of chromosomal rearrangement is specific to the clear cell phenotype of RCC.