Study Of Renal Cell Carcinoma Research Articles

Chromosome 11q13.3 variant modifies renal cell cancer risk in a Chinese population

A recent genome-wide association study of renal cell carcinoma (RCC) in European population has identified genetic variants in the regions of 2p21 (rs7579899), 11q13.3 (rs7105934) and 12q24.31 (rs4765623) conferred susceptibility to RCC. In our study, we assessed whether these polymorphisms are also associated with RCC risk in a Chinese population. We genotyped these polymorphisms using TaqMan method and assessed their associations with RCC risk in a case-control study of 710 patients with histologically confirmed RCC and 760 cancer-free controls. Normal renal tissues adjacent to tumors were used to evaluate the functional consequences of these polymorphisms. We found that rs7105934 was significantly associated with reduced RCC risk [adjusted odds ratio (OR) = 0.67, 95% confidence intervals (CIs) = 0.47-0.95, GA+AA versus GG], particularly among subgroups of normal-weight individuals (OR = 0.51, 95%CI = 0.29-0.88), never-smokers (OR = 0.53, 95%CI = 0.33-0.85) and non-drinkers (OR = 0.57, 95%CI = 0.370.87). Furthermore, the rs7105934 GA genotype was associated with lower levels of CCND1 mRNA compared with GG genotype, although this association was only marginally significant (P = 0.055). No significant association between rs7579899 or rs7105934 and RCC risk was observed. Our results suggest that rs7105934 on 11q13.3 may confer susceptibility to RCC in our population. Large population-based prospective and functional studies are required to validate the associations between these loci and RCC risk.

Comprehensive Analysis of 5-Aminolevulinic Acid Dehydrogenase (ALAD) Variants and Renal Cell Carcinoma Risk among Individuals Exposed to Lead

BackgroundEpidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead.MethodsThe objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.ResultsThe adjusted risk associated with the ALAD variant rs8177796CT/TT was increased (OR = 1.35, 95%CI = 1.05–1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles (GGOR = 2.68, 95%CI = 1.17–6.12, p = 0.01; GAOR = 1.79, 95%CI = 1.06–3.04 with an interaction approaching significance (pint = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results.ConclusionA common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.

Reference genes for the relative quantification of microRNAs in renal cell carcinomas and their metastases

To obtain accurate results in miRNA expression changes between different sample sets using real-time quantitative polymerase chain reaction (RT-qPCR) analyses, normalization to reference genes that are stably expressed across the sample sets is generally used. A literature search of miRNA expression studies in renal cell carcinoma (RCC) proved that non-miRNAs such as small RNAs or mRNAs have most frequently been used without preceding validation of their suitability. In this study, the most stably expressed miRNAs were ascertained from microarray-based data of miRNA expression in nonmalignant and malignant samples from clear cell RCC and from corresponding distant RCC metastases using the geNorm and NormFinder algorithms. Validation experiments with RT-qPCR were performed for the four best-ranked miRNAs (miR-28, miR-103, miR-106a, miR-151) together with the small RNU6B, RNU44, and RNU48 mostly described in literature. miR-28, miR-103, miR-106a, and RNU48 were proved as the most stably expressed genes. miR-28 is recommended as normalizer if only a single reference gene can be used, while the combinations of miR-28 and miR-103 or of miR-28, miR-103, and miR-106a, respectively, are preferred. RNU6B most frequently used as normalizer in miRNA expression studies should be abandoned in order to avoid misleading results.

Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

617 HER2 cytoplasmic staining as an independent risk factor for death in penile cancer

The involvement of peptidases in carcinogenetic processes of several tumor types has been researched in recent years. Although kidney is one of the major tissues known to express cystinyl-aminopeptidase (CAP), little is known about its role in renal neoplasia. This study analyzes fluorimetrically membrane-bound and soluble CAP activity in the three main renal cancers: clear cell (CCRCC), papillary (PRCC), and chromophobe (ChRCC) renal cell carcinomas. Overall, a marked decrease of membrane-bound CAP activity in all the three renal cell carcinomas was detected when compared with their respective surrounding non-tumor tissues. So, the tumor vs. non-tumor CAP ratios (units of peptidase per mg of protein) was as follows: 926 ± 111 vs. 3778 ± 276 for CCRCCs, 737 ± 181 vs. 4351 ± 950 for PRCCs, and 592 ± 118 vs. 4905 ± 935 for ChRCCs. In contrast, the soluble fraction of this enzyme displayed minor and non-significant changes when comparing tumor and non-tumor CAP activities in the whole series. After stratification by stage and grade, CCRCCs displayed significant differences: pT3 category had significantly higher levels of membrane-bound activity than pT1, and high grade cases (G3–4) had higher soluble CAP activity than low grade ones (G1–2). These data may open additional possibilities in the study of renal cell carcinoma with regard to the prognosis of patients.

Association of hypertension with overall outcome in patients taking sorafenib in advanced hepatocellular carcinoma (HCC).

e14536 Background: Hypertension is a commonly reported side effect following administration of vascular endothelial growth factor receptor (VEGFR) inhibitors. There have been multiple studies in renal cell carcinoma which showed elevated blood pressure correlates with better outcome in patients these drugs. In this study we assessed the predictive effect of HTN in patients taking sorafenib for advanced HCC. Methods: We looked at 41 patients from 2007 to 2009 in patients who received sorafenib for advanced HCC. Blood pressure was monitored at baseline and every 4 weeks. Elevated BP was defined as 20% increase in systolic or diastolic pressure from baseline or > 140/90 if baseline BP was within normal limits. Logrank tests were used to compare Kaplan-Meier estimates of overall survival. Results: Out of 41 patients who received sorafenib, 38 patients had complete blood pressure assessment. 15 (38%) were on HTN meds at baseline. 27 (65.9%) patients were classified as Child-Pugh (CP) A, 11 (26.8%) CP B and 3 (...

Pre‐Clinical Models of Renal Carcinoma and Their Utility in Drug Development

Significant progress has been made in the treatment of patients with advanced renal cancer. In addition to immunotherapy, there are several potentially distinct therapeutic approaches for targeting molecular pathways. The murine models detailed in this unit are useful for testing rational combination strategies. Moreover, animal models contribute immensely to the understanding of the genetic, epigenetic, and biological aspects of human disease. Compared to humans, rodent models are relatively short-lived and allow for the facile study of clinically relevant pathologies. Animal models for the study of renal cell carcinoma (RCC) are particularly useful for the development of new drugs for kidney cancer. Included in this unit are several in vivo models that are currently used to evaluate therapeutic approaches to renal cancer therapy and to investigate the pathophysiology of this condition. Included are both murine (RENCA) and renal cell carcinomas in subcutaneous and orthotopic models using tumor cell lines and human tumor tissue.

Cytogenetic Profile Predicts Prognosis of Patients With Clear Cell Renal Cell Carcinoma

The majority of cytogenetic studies in renal cell carcinoma (RCC) have been impaired by small sample size, retrospective character, and lack of a survival end point. We prospectively studied the prognostic impact of cytogenetic abnormalities on a larger cohort of patients having up to 108 months of follow-up. Tumors of 282 patients who underwent nephrectomy for clear cell RCC were cytogenetically analyzed. Results were correlated with pathological factors and disease-specific survival. The most frequently observed cytogenetic abnormalities were loss of 3p (60%), gain of 5q (33%), loss of 14q (28%), trisomy 7 (26%), loss of 8p (20%), loss of 6q (17%), loss of 9p (16%), loss of 4p (13%), and loss of chromosome Y in men (55%). Tumors with loss of 3p presented at lower TNM stages. Loss of 4p, 9p, and 14q were all associated with higher TNM stages, higher grade, and greater tumor size. A deletion of 3p was associated with better prognosis (P = .03), while loss of 4p (P < .001), loss of 9p (P < .01), and loss of 14q (P < .01) were each associated with worse prognosis. Loss of the Y chromosome led to improved progression-free survival in metastatic patients (P = .02). In multivariate analysis, loss of 9p was retained as an independent prognostic factor. This cytogenetic study serves as a proof of principal that genetic information, such as loss of chromosome 9, can be obtained from widely available technology, and can provide additional prognostic information to standard clinicopathologic variables.

Folate metabolism genes, vegetable intake and renal cancer risk in central Europe

In a multicenter case-control study of renal cell carcinoma (RCC) conducted in central and eastern Europe, we reported a strong inverse association with high vegetable intake and RCC risk. The odds ratio (OR) for high compared to the lowest tertile of vegetable intake was OR = 0.67; (95% confidence interval (CI): 0.53-0.83; p-trend < 0.001). We hypothesized that variation in key folate metabolism genes may modify this association. Common variation in 5 folate metabolism genes (CBS: Ex9+33C > T (rs234706), Ex13 +41C > T (rs1801181), Ex18 -391 G > A (rs12613); MTHFR: A222V Ex5+79C > T (rs1801133), Ex8-62A > C (rs1801131); MTR: Ex26 20A > G (rs1805087), MTRR: Ex5+136 T > C (rs161870), and TYMS:IVS2-405 C > T (rs502396), Ex8+157 C > T (rs699517), Ex8+227 A > G (rs2790)) were analyzed among 1,097 RCC cases and 1,555 controls genotyped in this study. Having at least 1 variant T allele of MTHFR A222V was associated with higher RCC risk compared to those with 2 common (CC) alleles (OR = 1.44; 95% CI: 1.17-1.77; p = 0.001). After stratification by tertile of vegetable intake, the higher risk associated with the variant genotype was only observed in the low and medium tertiles (p-trend = 0.001), but not among those in the highest tertile (p-interaction = 0.22). The association remained robust after calculation of the false discovery rate (FDR = 0.05). Of the 3 TYMS SNPs examined, only the TYMS IVS2 -405 C (rs502396) variant was associated with a significantly lower risk compared to the common genotype (OR = 0.73; 95% CI: 0.57-0.93). Vegetable intake modified the association between all 3 TYMS SNPs and RCC risk (p-interaction < 0.04 for all). In summary, these findings suggest that common variation in MTHFR and TYMS genes may be associated with RCC risk, particularly when vegetable intake is low.

Nitrate in public water supplies and the risk of renal cell carcinoma

Drinking water and dietary sources of nitrate and nitrite can react in vivo with amines and amides to form N-nitroso compounds (NOC), potent animal carcinogens. Nitrate is a widespread contaminant of drinking water supplies especially in agricultural areas. We conducted a population-based case-control study of renal cell carcinoma in 1986-1989 in Iowa, a state with elevated levels in many public water supplies. We collected a lifetime water source history, but due to limited monitoring data, most analyses focused on the subpopulation, who used Iowa public supplies with nitrate measurements (actual or imputed data) for > or = 70% of their person-years since 1960 (201 cases, 1,244 controls). We computed the average nitrate level and years using a public supply with nitrate levels >5 and >10 mg/l. Dietary nitrate and nitrite were estimated from a 55-item food frequency questionnaire. There was no association of renal cell carcinoma with the average nitrate level and years using public supplies >5 and >10 mg/l nitrate-nitrogen (10+ years >5 mg/l odds ratio (OR) = 1.03, 95% confidence interval (CI) 0.66, 1.60). However, higher nitrate exposure was associated with an increased risk among subgroups with above the median red meat intake (10+ years >5 mg/l OR = 1.91, 95% CI 1.04-3.51) or below the median vitamin C intake (10+ years >5 mg/l OR = 1.90, 95% CI 1.01, 3.56), dietary factors that increase the endogenous formation of NOC. Exclusion of long-term Des Moines residents, a large proportion of the high exposure categories, attenuated the association. These findings deserve additional study in populations with high water nitrate intake and information on dietary intakes.

Cystinyl aminopeptidase activity is decreased in renal cell carcinomas

The involvement of peptidases in carcinogenetic processes of several tumor types has been researched in recent years. Although kidney is one of the major tissues known to express cystinyl-aminopeptidase (CAP), little is known about its role in renal neoplasia. This study analyzes fluorimetrically membrane-bound and soluble CAP activity in the three main renal cancers: clear cell (CCRCC), papillary (PRCC), and chromophobe (ChRCC) renal cell carcinomas. Overall, a marked decrease of membrane-bound CAP activity in all the three renal cell carcinomas was detected when compared with their respective surrounding non-tumor tissues. So, the tumor vs. non-tumor CAP ratios (units of peptidase per mg of protein) was as follows: 926 ± 111 vs. 3778 ± 276 for CCRCCs, 737 ± 181 vs. 4351 ± 950 for PRCCs, and 592 ± 118 vs. 4905 ± 935 for ChRCCs. In contrast, the soluble fraction of this enzyme displayed minor and non-significant changes when comparing tumor and non-tumor CAP activities in the whole series. After stratification by stage and grade, CCRCCs displayed significant differences: pT3 category had significantly higher levels of membrane-bound activity than pT1, and high grade cases (G3–4) had higher soluble CAP activity than low grade ones (G1–2). These data may open additional possibilities in the study of renal cell carcinoma with regard to the prognosis of patients.

Cytogenetic alterations in renal tumors: a study of 38 Southeast Asian patients

Renal cell carcinoma (RCC) is the most common cancer of the kidney. Cytogenetic studies of renal cell carcinoma have provided valuable insight into the chromosomal abnormalities involved in the genesis and progression of the disease, and have also helped in the classification of these tumors. Our objectives were to identify nonrandom chromosome abnormalities in renal tumors in a Southeast Asian population and also to determine if they differ from those in Western populations. Structural rearrangements of 3p were specific for clear cell RCC, with the most consistent structural rearrangement being a translocation between 3p13 and 5q22. Gains of chromosomes 7 and 17 were observed in three and two cases of papillary RCC, respectively. All male patients with papillary RCC were noted to have loss of the Y chromosome. Gains of chromosomes 3 and 7, and structural aberration of chromosome 3, were observed in patients with transitional cell carcinoma of the renal pelvis (TCC). Chromosomal abnormalities in clear cell RCC, papillary RCC, and TCC did not differ between the Southeast Asian and Western populations. The aberrations seem to be common sporadic events, both geographically and racially.

Clinicopathologic study of renal cell carcinoma with rhabdoid features

To study the clinicopathologic features and biologic behavior of renal cell carcinoma (RCC) with rhabdoid features. Ten cases of RCC with rhabdoid features collected during the period from 1995 to 2005 were enrolled into the study. The clinical findings were analyzed and the hematoxylin and eosin-stained sections were reviewed. Immunohistochemistry and electron microscopy were also performed. The age of patients ranged from 33 to 69 years (mean age = 52 years). Nine of the patients were males and 1 female. Five patients showed evidence of perinephric invasion. Two patients presented with regional lymph node metastases and 1 patient showed distant metastasis to the lung. Histologically, the rhabdoid foci were characterized by loosely cohesive trabeculae, acini, lobules and clusters of rhabdoid cells in otherwise clear cell RCC (9 cases) or papillary RCC (1 case). The rhabdoid cells were round to polygonal in shape and contained globular eosinophilic inclusion bodies in the cytoplasm, eccentric nuclei, vesicular chromatin pattern and prominent nucleoli. Coagulative tumor necrosis was commonly seen. Immunohistochemical study showed that the rhabdoid cells were diffusely positive for CD10 (10/10), cytokeratin AE1/AE3 (10/10), epithelial membrane antigen (10/10) and vimentin (10/10). Focal staining for neuron-specific enolase and S-100 protein was also noted. They were negative for CK7, CK20 and myogenic markers (including myogenin, smooth muscle actin and muscle-specific actin). The mean Ki-67 labeling index of the rhabdoid component was higher than that of the non-rhabdoid component (P < 0.05). Follow-up information was available in 8 patients. While 6 patients are still alive without recurrence, 2 patients died of the disease 6 and 29 months respectively after the operation. RCC with rhabdoid elements are mainly observed in clear cell RCC and need to be distinguished from oncocytic renal tumors and malignant rhabdoid tumor of kidney. The higher proliferative activity in the rhabdoid areas may indicate more aggressive biologic behavior.

Population‐based study of renal cell carcinoma in children in Germany, 1980–2005

Childhood renal cell carcinomas (RCCs) differ histologically and biologically from their adult counterparts. The characteristics of RCC-affected children and their tumors, the influence of treatment, and outcome have so far not been studied in a nonselected, population-based cohort. A retrospective analysis was undertaken of RCC patients less than 16 years old reported to the German Childhood Cancer Registry and to the Kiel Paediatric Tumor Registry from 1980 to 2005. Forty-nine RCC in children (24 boys, 25 girls) with a median age of 10.6 years were identified. In about every third child possibly RCC-related underlying disorders (tuberous sclerosis, neuroblastoma, teratoma with chemotherapy, Saethre-Chotzen syndrome, chronic renal failure) or related diseases in their family were found. The pathologic subtypes were papillary in 16 (33%), translocation type in 11 (22%), unclassified in 8 (16%), and rarely clear-cell (n = 3) or others. Thirty-four (69%) patients had localized RCC, 8 (16%) patients regional lymph node metastases, and 4 (8%) patients distant metastases. Event-free survival and overall survival rates at 5 years were 96% for localized RCC, 69% and 75% for regional lymph node-positive, 25% and 33% for distant metastatic RCC, respectively. Two of 4 patients with distant metastases received immunotherapy combined with chemotherapy and surgery, both are alive, 1 of them disease-free for 6.9 years. Pediatric RCCs are predominantly localized diseases. Children with RCC frequently suffer underlying disorders. Survival rates in localized and regional lymph node-positive cases are favorable. Because of the rarity of RCC in childhood, an international study is necessary.

Long-term Fatty Fish Consumption and Renal Cell Carcinoma Incidence in Women

The epidemiological evidence that fatty fish consumption may be associated with the lower risk of several cancers is not consistent and no studies of renal cell carcinoma (RCC) exist. To examine the association between fatty and lean fish consumption and risk of RCC in women. The Swedish Mammography Cohort, a population-based prospective cohort study of 61,433 women aged 40 to 76 years without previous diagnosis of cancer at baseline (March 1, 1987-December 14, 1990). Participants filled in a food frequency questionnaire at baseline and in September 1997. Incident renal cell carcinoma. During a mean of 15.3 years (940,357 person-years) of follow-up between 1987 and 2004, 150 incident RCC cases were diagnosed. After adjustment for potential confounders, an inverse association of fatty fish consumption with the risk of RCC was found (P for trend = .02), but no association was found with lean fish consumption. Compared with no consumption, the multivariate rate ratio (RR) was 0.56 (95% confidence interval [CI], 0.35-0.91) for women eating fatty fish once a week or more. Compared with women consistently reporting no fish consumption, the multivariate RR was 0.26 (95% CI, 0.10-0.67) for those women reporting consistent consumption of fatty fish at baseline and 1997 (based on a subset of 36 664 women who filled in the baseline and 1997 questionnaires, with 40 incident RCC cases during the 1998-2004 follow-up period). Our study suggests that consumption of fatty fish may reduce the occurrence of RCC in women.

Prognostic Factors for Renal Cell Carcinoma: Integrating Laboratory and Molecular Factors

T he study of renal cell carcinoma (RCC), previously viewed as a dormant field due to a paucity of major advances, is no longer your mentor's renal cell carci- noma. It is now center stage in modern oncology due to major advances in molecular genetics and targeted thera- peutic approaches. It has been a preferred cancer for the introduction of innovative minimally invasive approaches, and for attempts to integrate surgery and systemic thera- pies. And yet it is still the urological cancer with the highest cancer related mortality rates, with 40% of patients eventu- ally dying of disease progression. Who is at the highest risk of recurrence or death from this cancer? Until recently this critical question could only be answered in a simplistic man- ner, based primarily upon tumor stage and obvious consti- tutional symptoms such as weight loss or a major decline in performance status. 1 The last 5 years have witnessed a major advance in our ability to prognosticate for patients with renal cell carci- noma, localized or metastatic. Sophisticated statistical anal- yses of large datasets containing clinical, pathological and, in many cases, laboratory factors have now yielded a variety of algorithms that integrate these factors, thereby substan- tially improving prognostic power. 2-4 For patients with met- astatic RCC, these algorithms allow division into groups with low, intermediate and high rates of progression, allow- ing management to be tailored appropriately. Initial obser- vation, active therapy and palliative approaches may apply to each of these groups, respectively. For patients with lo- calized RCC, the ability to segregate based upon risk of recurrence has proven useful for counseling about adjuvant protocols and intensity of surveillance. Such algorithms are now being incorporated into clinical trial design, and are commonly referenced when interpreting or comparing vari- ous conventional and historical studies. In addition to the usual litany of clinical (ie symptomatic presentation) and pathological (stage, grade, presence of histological necrosis, etc) factors, several laboratory factors have also withstood multivariate analyses to qualify as po- tential independent prognostic factors for renal cell carci- noma. These include increased serum levels of lactate dehydrogenase, anemia, increased sedimentation rates and hypercalcemia. In this issue of The Journal Bensalah et al (page 859) add to a growing literature demonstrating a similar status for thrombocystosis. In this study patients with any platelet count greater than 450,000 were approxi- mately twice as likely to die of renal cell carcinoma. This held true for patients with localized disease as well as those with metastases, and thrombocytosis proved to be indepen- dent of stage, grade and performance status on multivariate analysis. One distinct advantage of such laboratory tests is that they are routinely obtained during the evaluation of virtually all patients with this cancer and, thus, add little if

Gene Array Studies in Renal Neoplasia

Renal cell carcinoma (RCC) is comprised of several distinct histologic subtypes many of which have characteristic cytogenetic abnormalities. The molecular pathogenesis of some of these neoplasms is beginning to be elucidated. Yet renal cell carcinoma is often discovered at an advanced clinical stage and effective pharmacologic therapies for this disease remain to be discovered. For these reasons, renal cell carcinoma is ideally suited to the genome scale investigation made possible by DNA microarrays. A number of DNA array studies of renal cell carcinoma have been published. Renal cell carcinomas have also been studied by array based comparative genomic hybridization. The purpose of this review will be to summarize these studies, to compare the results of the different studies, and to suggest future areas of investigation with a particular emphasis on clinically relevant advances.

A population‐based study of renal cell carcinoma and prostate cancer in the same patients

To investigate the incidence of prostate cancer in men with renal cell carcinoma (RCC) and the incidence of RCC in men with prostate cancer. We evaluated the database of the Surveillance, Epidemiology and End Results Program of the National Cancer Institute from 1973 to 1996, to calculate the incidence of RCC in men with prostate cancer and the incidence of prostate cancer in men with RCC. The standardized incidence ratio (SIR, observed/expected) was calculated for each of the scenarios of interest, as well as for RCC and prostate cancer in men with other common malignancies. Lung/bronchus cancer, colon/rectal cancer, and non-Hodgkin lymphoma were selected for the control scenarios because they are the most common non-urological cancers among men in the USA. There was a higher incidence of RCC in men with prostate cancer (SIR 1.25, P < 0.01). RCC incidence was also higher in men with each of the other malignancies. Prostate cancer incidence was higher in men with RCC (SIR 1.42, P < 0.001), but was not significantly elevated for any of the control scenarios. The incidence of RCC is higher in men with each of the index cancers, whereas that for prostate cancer was higher only in men with RCC. A common aetiological factor is possible. However, it is also possible that detection bias explains these findings. Serial imaging might increase the detection of RCC among patients with a variety of index malignancies. Patients with RCC who are followed by a urologist might be screened more rigorously for prostate cancer than patients with other primary malignancies, leading to increased detection in these men.

Comparative study of renal cell carcinoma by CGH, multicolor-FISH and conventional cytogenic banding analysis

Using different cytogenetic techniques in combination is crucial to studying the high complexity of genetic rearrangements in tumor cells. The 8 clear cell (cc) and 5 papillary (p) renal cell carcinomas (RCC) were analyzed using multicolor fluorescence in situ hybridization (multicolor-FISH), conventional Giemsa banding (G-banding) and comparative genomic hybridization (CGH) analysis. CGH analysis was carried out with DNA from frozen tissue sections and short-term cultures of primary tumors. Using CGH analysis, both tissue sections and cell cultures of ccRCC showed the typical chromosomal changes such as the loss of 3p, 4q, 6q, 8p, 9q, 14 and a gain of 5q and 7. Most imbalances detected by CGH in cell culture could be deciphered by multicolor-FISH and G-banding analysis as unbalanced trans-locations t(3;6)(p11.1;p11.1), t(8;14)(p11.1;q11.1), t(3;5) (p14;q21-22), t(1;15)(p11;q11.1), t(3;15)(p11;q11.1)t(8;17) (p11.1;q11.1), t(8;17)(q22;p11.1). Only one balanced trans-location t(9;18)(q34;q11.1) was shown in ccRCC. CGH of papillary RCC displayed mostly gains of whole chromosomes 7, 12, 16 and 17 and a loss of chromosome Y. There was 1 papillary RCC that displayed a partial gain of chromosome 7, showing an unbalanced translocation t(7;11)(q11.1;q25). The balanced translocations t(2;9)(q11.1;q34) and t(7;15) (q22 approximately 31;q21-22) were registered in pRCC. The combined analysis of RCC by different methods allowed a more accurate characterization of the complex karyotypes of tumor tissue, and offered a comprehensive description of given tumors.

P53 Regulation and Function in Renal Cell Carcinoma

Loss of p53 function is a critical event in tumor evolution. This occurs through a range of molecular events, typically a missense p53 mutation followed by loss of heterozygosity. In many cancers, there is compelling evidence that cells that can compromise p53 function have a selective advantage. The situation in renal cell carcinoma is unclear. It has recently been suggested that p53 function is unusually compromised in renal carcinoma cells by a novel dominant, MDM2/p14ARF-independent mechanism. This is hard to reconcile with other recent studies that have identified p53 as an important prognostic indicator. Indeed, one of these latter studies found that the best predictor of poor outcome was the presence of high levels of both p53 (usually indicative of p53 mutation) and MDM2. Thus, it is important that we gain a clearer understanding of the regulation of p53 and the role of MDM2 in renal cell cancer. To address this, we have investigated the transcriptional activity of p53 in a panel of renal cell carcinoma cell lines and the contribution of MDM2 and p14ARF to p53 regulation. We have found that p53 is functional in p53 wild-type renal cell carcinoma cells and that this activity is significantly regulated by MDM2 and to a much lesser extent by p14ARF. Moreover, following induction of DNA damage with UV, the p53 response in these cells is intact. Thus, future studies of renal cell carcinoma that focus on p53 and MDM2 and their role in determining disease outcome will be required to create a better understanding of this notoriously difficult to manage disease.