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1.  Claudin-7 is Highly Expressed in Chromophobe Renal Cell Carcinoma and Renal Oncocytoma 
Journal of Korean Medical Science  2007;22(2):305-310.
Claudin-7 has recently been suggested to be a distal nephron marker. We tested the possibility that expression of claudin-7 could be used as a marker of renal tumors originating from the distal nephron. We examined the immunohistochemical expression of claudin-7 and parvalbumin in 239 renal tumors, including 179 clear cell renal cell carcinoma (RCC)s, 29 papillary RCCs, 20 chromophobe RCCs, and 11 renal oncocytomas. In addition, the methylation specific-PCR (MSP) of claudin-7 was performed. Claudin-7 and parvalbumin immunostains were positive in 3.4%, 7.8% of clear cell RCCs, 34.5%, 31.0% of papillary RCCs, 95.0%, 80.0% of chromophobe RCCs, and 72.7%, 81.8% of renal oncocytomas, respectively. The sensitivity and specificity of claudin-7 in diagnosing chromophobe RCC among subtypes of RCC were 95.0% and 92.3%. Those of parvalbumin were 80.0% and 88.9%. The expression pattern of claudin-7 was mostly diffuse in chromophobe RCC and was either focal or diffuse in oncocytoma. All of the cases examined in the MSP revealed the presence of unmethylated promoter of claudin-7 without regard to claudin-7 immunoreactivity. Hypermethylation of the promoter might not be the underlying mechanism for loss of its expression in RCC. Claudin-7 can be used as a useful diagnostic marker in diagnosing chromophobe RCC and oncocytoma.
doi:10.3346/jkms.2007.22.2.305
PMCID: PMC2693599  PMID: 17449941
Chromophobe Renal Cell Carcinoma; Oncocytoma; Claudin-7
2.  Activation of Stat3 in renal tumors 
Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target.
PMCID: PMC2776322  PMID: 19956438
Signal Transducer and activator of transcription 3 (Stat3); signal transduction; phosphorylation; renal tumors; kidney cancers
3.  Expression of parafibromin in major renal cell tumors 
Parafibromin, encoded by HRPT2 gene, is a recently identified tumor suppressor. Complete and partial loss of its expression have been observed in hyperparathyroidism-jaw tumor (HPT-JT), parathyroid carcinoma, breast carcinoma, lung carcinoma, gastric and colorectal carcinoma. However, little has been known about its expression in renal tumors. In order to study the expression of parafibromin in a series of the 4 major renal cell tumors - clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), chromophobe renal cell carcinoma (chRCC) and oncocytoma, one hundred thirty nine renal tumors including 61 ccRCCs, 37 pRCCs, 22 chRCCs and 19 oncocytomas were retrieved and used for the construction of renal tissue microarrays (TMAs). The expression of parafibromin was detected by immunohistochemical method on the constructed TMAs. Positive parafibromin stains are seen in 4 out of 61 ccRCCs (7%), 7 out of 37 pRCCs (19%), 12 out of 23 chRCCs (52%) and all 19 oncocytomas (100%). Parafibromin expression varies significantly (P<8.8×10−16) among the four major renal cell tumors and were correlated closely with tumor types. No correlation of parafibromin expression with tumor staging in ccRCCs, pRCCs and chRCCs, and Fuhrman nuclear grading in ccRCCs and pRCCs was seen. In summary, parafibromin expression was strongly correlated with tumor types, which may suggest that it plays a role in the tumorigenesis in renal cell tumors.
doi:10.4081/ejh.2012.e39
PMCID: PMC3567758  PMID: 23361235
parafibromin; renal epithelial tumors.
4.  Histological reclassification, histochemical characterization and c-kit immunoexpression in renal cell carcinoma 
Objectives:
Renal cell carcinoma is the most lethal of all urologic malignancies. Several parameters such as histological subtype, nuclear grade and TNM staging help in determining the prognosis and treatment options. A newer therapeutic modality has been suggested based on expression of c-kit antigen by the tumor cells. This study was designed to evaluate various histological parameters and correlate them with c-kit expression.
Materials and Methods:
The study was done on 40 consecutive cases of renal epithelial tumors. Histological sections were reviewed and reclassified according to WHO (2004) classification and nuclear grade assessed. Hale's colloidal iron stain was done to identify the chromophobe variant. Immunostaining with c-kit was done and its expression was studied. The results were correlated and statistical significance was assessed.
Results:
The age range was 31-81 years, with a male to female ratio of 2:1. Seventy per cent of the cases were clear cell RCC (ClRCC), 17.5% were chromophobe type, 7.5% were papillary RCCs and 5% cases were oncocytomas. Fuhrman nuclear grading revealed 60.5% cases to be of low grade and 39.5% high grade. Hale's colloidal iron staining was positive in chromophobe RCC and oncocytomas, while it was negative in ClRCC. Immunostaining with c-kit was positive only in oncocytomas.
Conclusions:
Clear cell RCC was the most common histological subtype of RCC. Clear cell RCC known to have a poor prognosis, showed a statistically significant higher nuclear grade than chromophobe and papillary RCCs which have a better prognosis. Hale's colloidal iron staining was extremely useful in distinguishing chromophobe RCC and oncocytoma from the granular cell variant of clear RCC. Our study revealed c-kit negativity in all RCC. As Imatinib could be ineffective in such tumors, its clinical activity has to be carefully assessed in such tumors through further studies.
doi:10.4103/0970-1591.42616
PMCID: PMC2684363  PMID: 19468465
C-kit; Hale's colloidal iron; renal cell carcinoma
5.  THE IMPACT OF HISTOLOGY ON CLINICOPATHOLOGIC OUTCOMES FOR PATIENTS WITH RENAL CELL CARCINOMA AND VENOUS TUMOR THROMBUS: A MATCHED COHORT ANALYSIS 
Urology  2013;82(1):136-141.
Objectives
To evaluate the impact of tumor histology on clinicopathologic outcomes for patients with renal cell carcinoma (RCC) and venous tumor thrombus (VTT).
Methods
We identified 807 patients with RCC and VTT who underwent nephrectomy at our institution between 1970–2008. All pathologic specimens were re-reviewed by a single urologic pathologist. Patients with non-clear cell RCC (non-ccRCC) (n=56) were matched 1:2 to patients with clear cell RCC (ccRCC) VTT based onsymptoms at presentation, regional lymph node involvement, distant metastases, tumor thrombus level, nuclear grade and sarcomatoid differentiation. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test.
Results
The 56 patients with non-ccRCC VTT included 26 papillary, 11 chromophobe, 5 collecting duct tumors, and 14 RCC not otherwise specified. Compared to unmatched patients with ccRCC VTT (n=751), patients with non-ccRCC VTT presented with larger tumor size (p=0.02), higher nuclear grade (p=0.04), and more frequent sarcomatoid differentiation (p<0.001) and lymph node invasion (p<0.001). However, when patients with non-ccRCC were matched to patients with cc-RCC, no significant differences were noted with regard to 5-year metastases-free survival (41% versus 34%; p=0.24) or cancer-specific survival (25% versus 27%; p=0.97).
Conclusions
Non-ccRCC VTT is associated with a high rate of adverse pathologic features. Nevertheless, when matched to patients with ccRCC, patients with non-ccRCC VTT did not have increased rates of recurrence or adverse survival. Aggressive surgical resection represents the mainstay of treatment in these cases, while continued efforts to optimize a multimodal management approach to such patients remain necessary.
doi:10.1016/j.urology.2013.02.034
PMCID: PMC3710713  PMID: 23642851
renal cell carcinoma; tumor thrombus; kidney cancer; histology
6.  Determination of Angptl4 mRNA as a Diagnostic Marker of Primary and Metastatic Clear Cell Renal-Cell Carcinoma 
PLoS ONE  2010;5(4):e10421.
Background
We have previously shown that angiopoietin-like 4 (angptl4) mRNA, a hypoxia-inducible gene, is highly expressed in clear cell renal-cell carcinoma (ccRCC), the most common subtype of RCC for which no specific marker is available. We here investigated whether angptl4 mRNA 1) could be a useful diagnostic and/or prognostic marker of ccRCC in a large and comprehensive retrospective series, 2) induction is dependent on the VHL status of tumors.
Methodology/Principal Findings
Using in situ hybridization, we report that angptl4 mRNA is expressed in 100% of both sporadic (n = 102) and inherited (n = 6) primary ccRCCs, without any statistical association with nuclear grade (p = 0.39), tumor size (p = 0.09), stage grouping (p = 0.17), progression-free survival (p = 0.94), and overall survival (p = 0.80). Angptl4 mRNA was also expressed in 26 (87%) of 30 secondary ccRCCs but neither in any other secondary RCCs (n = 7). In contrast, angptl4 mRNA was neither expressed in 94% non-ccRCC renal tumors (papillary RCCs (n = 46), chromophobe RCCs (n = 28), and oncocytomas (n = 9)), nor in non-renal clear cell carcinomas (n = 39). Angptl4 expression was also examined in tumors associated (n = 23) or not associated (n = 66) with VHL disease. 40 (98%) hemangioblastomas expressed angptl4 whereas all pheochromocytomas (n = 23) and pancreatic tumors (n = 25) were angptl4-negative, whatever their VHL status.
Conclusions/Significance
Angptl4 mRNA expression was highly associated with ccRCC (p = 1.5 10−49, Chi square test) allowing to define its expression as a diagnosis marker for primary ccRCC. Moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs. Finally, inactivation of VHL gene is neither necessary nor sufficient for angptl4 mRNA induction.
doi:10.1371/journal.pone.0010421
PMCID: PMC2861680  PMID: 20454689
7.  Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from the Netherlands cohort study 
BMC Cancer  2005;5:57.
Background
Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC). We studied the VHL mutation status in a large population-based case group.
Methods
Cases were identified within the Netherlands cohort study on diet and cancer, which includes 120,852 men and women. After 11.3 years of follow-up, 337 incident cases with histologically confirmed epithelial cancers were identified. DNA was isolated from paraffin material collected from 51 pathology laboratories and revised by one pathologist, leaving material from 235 cases. VHL mutational status was assessed by SSCP followed by direct sequencing, after testing SSCP as a screening tool in a subsample.
Results
The number of mutations was significantly higher for clear-cell RCC compared to other histological types. We observed 131 mutations in 114 out of 187 patients (61%) with clear-cell RCC. The majority of mutations were truncating mutations (47%). The mean tumor size was 72.7 mm for mutated tumors compared to 65.3 mm for wildtype tumors (p = 0.06). No statistically significant differences were observed for nuclear grade, TNM distribution or stage. In other histological types, we observed 8 mutations in 7 out of 48 patients (15%), 1 mutation in 1 of 6 oncocytoma, 3 mutations in 2 of 7 chromophobe RCC, 2 mutations in 2 of 30 papillary RCC, no mutations in 1 collecting duct carcinoma and 2 mutations in 2 of 4 unclassified RCC.
Conclusion
VHL mutations were detected in 61% of sporadic clear-cell RCC. VHL mutated and wildtype clear-cell RCC did not differ with respect to most parameters.
doi:10.1186/1471-2407-5-57
PMCID: PMC1177929  PMID: 15932632
8.  MicroRNA profile: a promising ancillary tool for accurate renal cell tumour diagnosis 
British Journal of Cancer  2013;109(10):2646-2653.
Background:
Renal cell tumours (RCTs) are clinically, morphologically and genetically heterogeneous. Accurate identification of renal cell carcinomas (RCCs) and its discrimination from normal tissue and benign tumours is mandatory. We, thus, aimed to define a panel of microRNAs that might aid in the diagnostic workup of RCTs.
Methods:
Fresh-frozen tissues from 120 RCTs (clear-cell RCC, papillary RCC, chromophobe RCC (chRCC) and oncocytomas: 30 cases each), 10 normal renal tissues and 60 cases of ex-vivo fine-needle aspiration biopsies from RCTs (15 of each subtype validation set) were collected. Expression levels of miR-21, miR-141, miR-155, miR-183 and miR-200b were assessed by quantitative reverse transcription–PCR. Receiver operator characteristic curves were constructed and the areas under the curve were calculated to assess diagnostic performance. Disease-specific survival curves and a Cox regression model comprising all significant variables were computed.
Results:
Renal cell tumours displayed significantly lower expression levels of miR-21, miR-141 and miR-200b compared with that of normal tissues, and expression levels of all miRs differed significantly between malignant and benign RCTs. Expression analysis of miR-141 or miR-200b accurately distinguished RCTs from normal renal tissues, oncocytoma from RCC and chRCC from oncocytoma. The diagnostic performance was confirmed in the validation set. Interestingly, miR-21, miR-141 and miR-155 expression levels showed prognostic significance in a univariate analysis.
Conclusion:
The miR-141 or miR-200b panel accurately distinguishes RCC from normal kidney and oncocytoma in tissue samples, discriminating from normal kidney and oncocytoma, whereas miR-21, miR-141 and miR-155 convey prognostic information. This approach is feasible in fine-needle aspiration biopsies and might provide an ancillary tool for routine diagnosis.
doi:10.1038/bjc.2013.552
PMCID: PMC3833202  PMID: 24129247
microRNAs; renal cell tumours; diagnostic tool; fine-needle biopsies
9.  Distinct Cytoplasmic Expression of KL-6 Mucin in Chromophobe Renal Cell Carcinoma: A Comparative Immunohistochemical Study with Other Renal Epithelial Cell Tumors 
Acta Histochemica et Cytochemica  2012;45(5):301-308.
The presence of cytoplasmic sialyl glycoproteins is a conspicuous feature in chromophobe renal cell carcinoma (RCC). We compared the immunohistochemical expression of sialyl glycoproteins in chromophobe RCC with that in other types of renal tumors. Formalin-fixed, paraffin-embedded tissues of surgically resected renal tumors (chromophobe RCC, 14 cases [10 cases of classic type and 4 cases of eosinophilic variant]; oncocytoma, 7 cases; and clear cell RCC, 9 cases) and kidneys from immature infants (4 cases) were immunostained with antibodies against sialyl glycoproteins (anti-KL-6 and anti-sialyl MUC1 antibodies). Cytoplasmic expression of KL-6 and sialyl MUC1 was distinctive in the chromophobe RCC and renal oncocytoma cells, and in the intercalated cells in collecting duct epithelia. Apical-surface staining of these sialyl glycoproteins was predominantly observed in clear RCC, in the epithelia of the distal tubule and collecting duct, and in the neonatal renal proximal tubule, but not in those of the adult renal proximal tubule. The above-mentioned observations provide additional evidence for similar phenotypic profiles of chromophobe RCC and renal oncocytoma, and the intercalated cells in collecting ducts and the oncofetal expression of sialyl glycoproteins in clear cell RCC. KL-6 is a potential tumor marker for renal tumors.
doi:10.1267/ahc.12020
PMCID: PMC3496866  PMID: 23209339
chromophobe renal cell carcinoma; immunohistochemistry; KL-6; MUC1; renal cell tumor
10.  Sub-typing of renal cell tumours; contribution of ancillary techniques 
Diagnostic Pathology  2009;4:21.
Background
Adult renal epithelial neoplasms are a heterogeneous group with varying prognosis and outcome requiring sub-classification.
Methods
Cases of renal cell carcinoma (RCC) in a 10 years period were analyzed with regard to the clinical features and histology. Sections were reviewed by four pathologists and the discordant cases were resolved with the help of Hale's colloidal iron stain, vimentin, CK 7, and vinculin immunostains and electron microscopy.
Results
Amongst the total of 278 cases, clear cell renal cell carcinoma was the commonest tumor with 74.8% cases, followed by papillary RCC 12.2%, chromophobe RCC 7.9%, oncocytoma 1.8%, and one case of collecting duct RCC. Eight cases were of sarcomatoid renal cell carcinoma. In 28/278 cases, diagnoses varied amongst the four pathologists and the discordance was resolved by Hale's colloidal iron stain, CK7 immunostain and electron microscopy. Vimentin and vinculin did not contribute much in differentiating subtypes of renal cell carcinomas. Relative incidence of sub-types of RCCs was compared with other series
Conclusion
To accurately subclassify renal cell carcinomas, simple ancillary techniques would possibly resolve all difficult cases. The relative incidence of sub-types of renal cell carcinoma is relatively consistent the world over. However, in India, RCCs afflict the patients two decades earlier.
doi:10.1186/1746-1596-4-21
PMCID: PMC2714064  PMID: 19558708
11.  MOLECULAR CHARACTERIZATION OF KIDNEY CANCER: ASSOCIATION OF HYALURONIC ACID FAMILY WITH HISTOLOGICAL SUBTYPES AND METASTASIS 
Cancer  2011;118(9):2394-2402.
Background
Molecular profiling of renal cell carcinomas (RCC) may improve the distinction between oncocytoma and malignant RCC subtypes and aid in early detection of metastasis. Hyaluronic acid (HA) family includes HA-synthases (HAS1, HAS2, HAS3), hyaluronidases (HYAL-1, HYAL-2, HYAL-3, HYAL-4, PH20, HYAL-P1), and HA receptors (CD44s, CD44v and RHAMM). HA family members promote tumor growth and metastasis. We evaluated the expression of HA family members in kidney specimens.
Methods
Using quantitative PCR, mRNA levels of twelve HA family members were measured in tumor specimens obtained from 86 consecutive patients undergoing nephrectomy; 80 of them also provided normal specimens. Mean and median follow-up: 15.2 ± 8.8 and 13.8 months. RCC specimens included: clear cell RCC (ccRCC): 65; papillary: 10; chromophobe: 5; oncocytoma: 6; metastasis (+): 17.
Results
Median HAS1, CD44s and RHAMM transcript levels were 3–25 elevated in ccRCC, papillary and chromophobe tumors when compared to normal tissues. HYAL-4, CD44s and RHAMM levels were 4–12-fold elevated in ccRCC and papillary tumors when compared to oncocytomas; only HYAL-4 levels distinguished between chromophobe and oncocytoma (P=0.009). CD44s and RHAMM levels were significantly higher in tumors < 4-cm (510±611; 19.6±20.8, respectively) when compared to oncocytoma (46.4±20; 3.8±2.5; P≤0.006). In univariate and multivariate analyses, CD44s (P<0.0001), RHAMM (P<0.0001), stage, tumor size, and/or renal vein involvement significantly associated with metastasis. The combined CD44s+RHAMM marker had 82% sensitivity and 86% specificity to predict metastasis.
Conclusion
CD44s and RHAMM levels distinguish between oncocytoma and RCC subtypes regardless of tumor size and are potential predictors of RCC metastasis.
doi:10.1002/cncr.26520
PMCID: PMC3232339  PMID: 21887686
Prognostic markers; HA-synthase; Hyaluronidase; HA-receptors; Renal cell carcinoma; metastasis; oncocytoma
12.  Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas 
Purpose
We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy of cancers.
Experimental Design
We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the FGFR2 isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types.
Results
We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform (“epithelial”) to IIIc isoform (“mesenchymal”) in nearly 90% of ccRCCs. This switch is kidney-specific since it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs. A re-examination of tumor histology by pathologists identified FGFR2-IIIb tumors as chromophobe RCCs and clear cell papillary RCCs.
Conclusions
FGFR2 IIIb RCCs represent mis-diagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC.
doi:10.1158/1078-0432.CCR-12-3708
PMCID: PMC3644028  PMID: 23444225
alternative splicing; renal cell carcinoma; RNA-seq; FGFR2; TCGA
13.  c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma 
Annals of Oncology  2012;24(2):343-349.
Background
Activation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines.
Methods
c-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines.
Results
Higher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08–1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197.
Conclusions
c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.
doi:10.1093/annonc/mds463
PMCID: PMC3551486  PMID: 23022995
c-Met; clear cell carcinoma; hepatocyte growth factor; renal cell carcinoma; tissue microarray
14.  Tumor signatures of PTHLH overexpression, high serum calcium, and poor prognosis were observed exclusively in clear cell but not non clear cell renal carcinomas 
Cancer Medicine  2014;3(4):845-854.
High serum calcium (Ca) due to aberrant secretion of tumor parathyroid hormone-like hormone (PTHLH) is a well-known paraneoplastic sign and is associated with poor prognosis in patients with renal cell carcinoma (RCC). However, the status of serum Ca and tumor PTHLH expression have not been verified using the 2004 World Health Organization (WHO) renal tumor classification. We retrospectively reviewed corrected serum Ca levels at initial onset (n = 683) and/or as of recurrence (n = 71) in patients with RCC. We also examined a total of 623 renal parenchymal tumor samples for PTHLH mRNA expressions by quantitative real-time PCR. High serum Ca concomitant with PTHLH overexpression in tumors was observed exclusively in clear cell RCC but not in other non clear cell subtype tumors, including papillary, chromophobe, collecting-duct, unclassified, and other rare subtype RCCs or in benign oncocytomas and angiomyolipomas. In clear cell RCC, PTHLH expression was significantly high in male patients, and was associated with a symptomatic presentation, higher grade, and higher stage cases, whereas it was not associated with VHL gene status. Univariate analyses demonstrated that high PTHLH expression was strongly associated with poor outcome both in overall survival (OS) and disease-free survival (DFS) for patients who underwent standard nephrectomy. Further multivariate Cox analyses revealed that the PTHLH expressions remained as independent prognostic parameters for OS but not for DFS. These data suggest that the previously characterized tumor signatures of high serum Ca due to high PTHLH expression and poor prognosis are clear cell RCC-specific features, whereas these characteristics are rare in non clear cell RCCs.
doi:10.1002/cam4.270
PMCID: PMC4303152  PMID: 24861371
Gene expression; prognosis; PTHLH; qRT-PCR; renal cell carcinoma; serum calcium
15.  Genetic and epigenetic alterations during renal carcinogenesis 
Renal cell carcinoma (RCC) is not a single entity, but comprises a group of tumors including clear cell RCC, papillary RCC and chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more clinicopathologically aggressive clear cell RCC may develop. Since renal carcinogenesis is associated with neither chronic inflammation nor persistent viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal tumors, precancerous conditions in the kidney have been rarely described. However, regional DNA hypermethylation on C-type CpG islands has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in precancerous conditions are basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant cancers, and even determine patient outcome. The list of tumor-related genes silenced by DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and therapy of RCCs.
PMCID: PMC3016104  PMID: 21228928
Renal cell carcinoma; copy number alteration; DNA methylation; precancerous condition; prognostication
16.  Diagnostic Utility of Caveolin-1 and MOC-31 in Distinguishing Chromophobe Renal Cell Carcinoma from Renal Oncocytoma 
Korean Journal of Urology  2011;52(2):96-103.
Purpose
Renal tumors consist of heterogeneous groups that frequently show complex and overlapping morphology, thus making it difficult to make a correct diagnosis. One of the most problematic differential diagnoses is to distinguish chromophobe renal cell carcinoma (RCC) from oncocytoma. These should be distinguished by differences in their behavior and clinical outcome. Our study was performed to identify whether caveolin-1 and MOC-31 are useful immunohistochemical markers for differentiating chromophobe RCC from oncocytoma.
Materials and Methods
We selected 23 chromophobe RCCs, 8 oncocytomas, and 25 clear cell RCCs and performed immunohistochemical staining for caveolin-1 and MOC-31.
Results
Caveolin-1 was positive in 20 (87%) of 23 chromophobe RCCs, 0 of 8 oncocytomas, and 21 (84%) of 25 clear cell RCCs. MOC-31 was positive in 22 (96%) of 23 chromophobe RCCs, 2 (25%) of 8 oncocytomas, and 14 (56%) of 25 clear cell RCCs. There was a statistically significant difference in the expression of caveolin-1 and MOC-31 between chromophobe RCC and oncocytoma (p<0.001). In addition, clear cell RCC was also significantly different from oncocytoma in the expression of caveolin-1 (p<0.001) and was significantly different from chromophobe RCC in the expression of MOC-31 (p<0.001).
Conclusions
Caveolin-1 and MOC-31 can be useful markers in the differential diagnosis of chromophobe RCC, oncocytoma, and clear cell RCC.
doi:10.4111/kju.2011.52.2.96
PMCID: PMC3045726  PMID: 21379425
Adenoma, oxyphilic; Caveolin 1; MOC-31 monoclonal antibody, human; Renal cell carcinoma
17.  Hereditary Kidney Cancer: Unique Opportunity for Disease-Based Therapy 
Cancer  2009;115(10 Suppl):2252-2261.
Kidney cancer is not a single disease; it is made up of a number of different types of cancer, each with a different histology, a different clinical course, caused by a different gene, and responding differently to therapy. The VHL gene is the gene for the hereditary cancer syndrome, von Hippel-Lindau, as well as for the common form of sporadic, non-inherited, clear cell kidney cancer. Understanding the VHL-HIF pathway has provided the foundation for the development of a number of agents targeting this pathway, such as sunitinib, sorafenib and temsirolimus. Hereditary Papillary Renal Carcinoma (HPRC) is a hereditary renal cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal, type 1 papillary renal cell carcinoma. The genetic defect underlying HPRC is MET, the cell surface receptor for hepatocyte growth factor (HGF). Mutations of MET have also been found in a subset of tumors from patients with sporadic type 1 papillary renal cell carcinoma. Clinical trials targeting the MET pathway are underway in patients with HPRC as well as patients with sporadic (non-hereditary) papillary kidney cancer. The BHD (also known as FLCN) gene is the gene for Birt-Hogg-Dubé syndrome, an autosomal dominant genodermatosis associated with a hereditary form of chromophobe, and oncocytic hybrid RCC. Preclinical studies are underway targeting the BHD gene pathway in preparation for clinical trials in Birt-Hogg-Dubé and sporadic chromophobe RCC. Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) patients are at risk for the development of cutaneous and uterine leiomyomas and a very aggressive type of RCC. HLRCC is characterized by germline mutation of the Krebs cycle enzyme, fumarate hydratase (FH). Studies of the TCA cycle and VHL-HIF pathways have provided the foundation for therapeutic approaches in patients with HLRCC-associated kidney cancer, as well as other hereditary and sporadic forms of RCC.
doi:10.1002/cncr.24230
PMCID: PMC2720093  PMID: 19402075
kidney; neoplasm; VHL; MET; BHD; fumarate hydratase
18.  Analysis and validation of tissue biomarkers for renal cell carcinoma using automated high-throughput evaluation of protein expression☆ 
Human pathology  2014;45(5):1092-1099.
Summary
The objective of this study was to compare the predictive ability of potential tissue biomarkers to known prognostic factors that predict renal cell carcinoma (RCC) recurrence using an automated system of immunohistochemical analysis. After institutional review board approval, a tissue microarray was constructed using tissue from patients who had partial or radical nephrectomy for RCC. Patients with metastatic disease were excluded. Immunohistochemical staining of the tissue microarray for Ki-67, C-reactive protein, carbonic anhydrase 9, and hypoxia-inducible factors 1α and 2α was analyzed using automated image analysis. Univariable and multivariable analyses were performed to evaluate the association of putative biomarkers and known prognostic factors. Of 216 patients who met the entrance criteria, 34 (16%) patients developed metastatic recurrence within a median follow-up interval of 60.9 (interquartile range, 13.9–87.1) months. RCC morphotypes analyzed in this study include clear cell (n = 156), papillary (n = 38), chromophobe (n = 16), and collecting duct/unclassified (n = 6). Univariate analysis identified that only increased Ki-67 was predictive of RCC recurrence among the proteins evaluated, in addition to other known clinicopathological prognostic factors. After multivariate analysis, Ki-67 was identified as an independently predictive risk factor for RCC recurrence (hazard ratio [HR], 3.73 [confidence interval {CI}, 1.60–8.68]). Other independent predictors of RCC recurrence included tumor diameter (HR, 1.20 [CI, 1.02–1.41]) and perinephric fat invasion (HR, 4.49 [CI, 1.11–18.20]). We conclude that Ki-67 positivity is independently predictive of RCC recurrence after surgery in nonmetastatic patients. Automated analysis of tissue protein expression can facilitate a more objective and expedient investigation of tissue biomarkers for RCC.
doi:10.1016/j.humpath.2014.01.008
PMCID: PMC4134351  PMID: 24746216
Multispectral imaging; Immunohistochemistry; Renal cell carcinoma; Biomarkers; Recurrence
19.  A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma 
European urology  2012;62(6):10.1016/j.eururo.2012.06.043.
Background
Sunitinib is a standard of care treatment in advanced clear-cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non-clear cell RCC (nccRCC).
Objective
To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.
Design, Setting, and Participants
This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥ 20 percent sarcomatoid histology, performance status 0–2, measurable disease, maximum 2 prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.
Intervention
Patients received sunitinib 50 mg daily on a 4-week on, 2-week off schedule.
Outcome Measurements and Statistical Analysis
Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints were safety and overall survival (OS).
Results and Limitations
Fifty-seven patients were eligible [papillary (27), chromophobe (5), unclassified (8), collecting duct or medullary carcinoma (6), sarcomatoid (7), others (4)]. Median PFS for 55 evaluable patients was 2.7 months [95% CI: 1.4, 5.4]. Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 months (95% CI: 1.4, 5.4). Median PFS for patients with chromophobe histology was 12.7 months (95% CI: 8.5, NA). Median OS for all patients was 16.8 months (95% CI: 10.7, 26.3). Treatment emergent adverse events were consistent with sunitinib’s mechanism of action. The non-randomized design and small number of patients are limitations of this study.
Conclusions
The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors on clinical trials.
doi:10.1016/j.eururo.2012.06.043
PMCID: PMC3882163  PMID: 22771265
20.  Development of Pathological Diagnostics of Human Kidney Cancer by Multiple Staining Using New Fluorescent Fluolid Dyes 
BioMed Research International  2014;2014:437871.
New fluorescent Fluolid dyes have advantages over others such as stability against heat, dryness, and excess light. Here, we performed simultaneous immunostaining of renal tumors, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, acquired cystic disease-associated RCC (ACD-RCC), and renal angiomyolipoma (AML), with primary antibodies against Kank1, cytokeratin 7 (CK7), and CD10, which were detected with secondary antibodies labeled with Fluolid-Orange, Fluolid-Green, and Alexa Fluor 647, respectively. Kank1 was stained in normal renal tubules, papillary RCC, and ACD-RCC, and weakly or negatively in all other tumors. CK7 was positive in normal renal tubules, papillary RCC, and ACD-RCC. In contrast, CD10 was expressed in renal tubules and clear cell RCC, papillary RCC, AML, and AC-RCC, and weakly in chromophobe RCC. These results may contribute to differentiating renal tumors and subtypes of RCCs. We also examined the stability of fluorescence and found that fluorescent images of Fluolid dyes were identical between a tissue section and the same section after it was stored for almost three years at room temperature. This indicates that tissue sections can be stored at room temperature for a relatively long time after they are stained with multiple fluorescent markers, which could open a door for pathological diagnostics.
doi:10.1155/2014/437871
PMCID: PMC4065777  PMID: 24995295
21.  Deregulation of PAX2 expression in renal cell tumours: mechanisms and potential use in differential diagnosis 
Expression of PAX2 (Paired-box 2) is suppressed through promoter methylation at the later stages of embryonic development, but eventually reactivated during carcinogenesis. Pax-2 is commonly expressed in the most prevalent renal cell tumour (RCT) subtypes—clear cell RCC (ccRCC), papillary RCC (pRCC) and oncocytoma—but not in chromophobe RCC (chrRCC), which frequently displays chromosome 10 loss (to which PAX2 is mapped). Herein, we assessed the epigenetic and/or genetic alterations affecting PAX2 expression in RCTs and evaluated its potential as biomarker. We tested 120 RCTs (30 of each main subtype) and four normal kidney tissues. Pax-2 expression was assessed by immunohistochemistry and PAX2 mRNA expression levels were determined by quantitative RT-PCR. PAX2 promoter methylation status was assessed by methylation-specific PCR and bisulfite sequencing. Chromosome 10 and PAX2 copy number alterations were determined by FISH. Pax-2 immunoexpression was significantly lower in chrRCC compared to other RCT subtypes. Using a 10% immunoexpression cut-off, Pax-2 immunoreactivity discriminated chrRCC from oncocytoma with 67% sensitivity and 90% specificity. PAX2 mRNA expression was significantly lower in chrRCC, compared to ccRCC, pRCC and oncocytoma, and transcript levels correlated with immunoexpression. Whereas no promoter methylation was found in RCTs or normal kidney, 69% of chrRCC displayed chromosome 10 monosomy, correlating with Pax-2 immunoexpression. We concluded that Pax-2 expression might be used as an ancillary tool to discriminate chrRCC from oncocytomas with overlapping morphological features. The biological rationale lies on the causal relation between Pax-2 expression and chromosome 10 monosomy, but not PAX2 promoter methylation, in chrRCC.
doi:10.1111/jcmm.12090
PMCID: PMC3780547  PMID: 23890189
Renal cell tumours; PAX2; differential diagnosis; chromosome 10 monosomy; promoter methylation
22.  Deregulation of PAX2 expression in renal cell tumours: mechanisms and potential use in differential diagnosis 
Expression of PAX2 (Paired-box 2) is suppressed through promoter methylation at the later stages of embryonic development, but eventually reactivated during carcinogenesis. Pax-2 is commonly expressed in the most prevalent renal cell tumour (RCT) subtypes—clear cell RCC (ccRCC), papillary RCC (pRCC) and oncocytoma—but not in chromophobe RCC (chrRCC), which frequently displays chromosome 10 loss (to which PAX2 is mapped). Herein, we assessed the epigenetic and/or genetic alterations affecting PAX2 expression in RCTs and evaluated its potential as biomarker. We tested 120 RCTs (30 of each main subtype) and four normal kidney tissues. Pax-2 expression was assessed by immunohistochemistry and PAX2 mRNA expression levels were determined by quantitative RT-PCR. PAX2 promoter methylation status was assessed by methylation-specific PCR and bisulfite sequencing. Chromosome 10 and PAX2 copy number alterations were determined by FISH. Pax-2 immunoexpression was significantly lower in chrRCC compared to other RCT subtypes. Using a 10% immunoexpression cut-off, Pax-2 immunoreactivity discriminated chrRCC from oncocytoma with 67% sensitivity and 90% specificity. PAX2 mRNA expression was significantly lower in chrRCC, compared to ccRCC, pRCC and oncocytoma, and transcript levels correlated with immunoexpression. Whereas no promoter methylation was found in RCTs or normal kidney, 69% of chrRCC displayed chromosome 10 monosomy, correlating with Pax-2 immunoexpression. We concluded that Pax-2 expression might be used as an ancillary tool to discriminate chrRCC from oncocytomas with overlapping morphological features. The biological rationale lies on the causal relation between Pax-2 expression and chromosome 10 monosomy, but not PAX2 promoter methylation, in chrRCC.
doi:10.1111/jcmm.12090
PMCID: PMC3780547  PMID: 23890189
Renal cell tumours; PAX2; differential diagnosis; chromosome 10 monosomy; promoter methylation
23.  Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer 
BMC Cancer  2010;10:503.
Background
Fibronectin 1 (FN1) is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to elucidate the role of FN1 in development of renal cell cancer (RCC) and to determine a prognostic relevance for optimal clinical management.
Methods
212 renal tissue samples (109 RCC, 86 corresponding tissues from adjacent normal renal tissue and 17 oncocytomas) were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Detection of FN1 mRNA expression was performed using quantitative real time PCR, three endogenous controls, renal proximal tubular epithelial cells (RPTEC) as biological control and the ΔΔCt method for calculation of relative quantities.
Results
Mean tissue specific FN1 mRNA expression was found to be increased approximately seven fold comparing RCC and corresponding kidney control tissues (p < 0.001; ANOVA). Furthermore, tissue specific mean FN1 expression was increased approx. 11 fold in clear cell compared to papillary RCC (p = 9×10-5; Wilcoxon rank sum test). Patients with advanced disease had higher FN1 expression when compared to organ-confined disease (p < 0.001; Wilcoxon rank sum test). Applying subgroup analysis we found a significantly higher FN1 mRNA expression between organ-confined and advanced disease in the papillary and not in the clear cell RCC group (p = 0.02 vs. p = 0.2; Wilcoxon rank sum test). There was an increased expression in RCC compared to oncocytoma (p = 0.016; ANOVA).
Conclusions
To our knowledge, this is the first study to show that FN1 mRNA expression is higher in RCC compared to normal renal tissue. FN1 mRNA expression might serve as a marker for RCC aggressiveness, indicating early systemic progression particularly for patients with papillary RCC.
doi:10.1186/1471-2407-10-503
PMCID: PMC2949811  PMID: 20860816
24.  New Insights into the Biology of Renal Cell Carcinoma 
Kidney cancer is one of the 10 most common forms of cancer in both men and women. Ninety percent or more of these cancers are believed to be of epithelial cell origin, and are referred to as renal cell carcinoma (RCC). RCCs can be further subdivided, based on their histologic appearance, into clear-cell renal carcinomas (~75%), papillary renal carcinomas (15%), chromophobe tumors (5%), and oncocytomas (5%).1,2 Studies of hereditary kidney cancer families led to the identification of genes that, when mutated in the germline, confer an increased risk of these various histologic RCC subtypes and hence a glimpse at the molecular circuits that are deregulated in these different forms of RCC.2 In practice, there is some overlap among the histologic subtypes (eg, a tumor with predominantly clear-cell features might contain areas more typical of papillary RCC). Similarly, there are some shared molecular features among these tumor types (see later discussion). This review focuses primarily on the most common form of RCC, clear-cell renal carcinoma, while making note of some recent advances in the other histologic subtypes.
doi:10.1016/j.hoc.2011.04.004
PMCID: PMC3161447  PMID: 21763962
Renal cell carcinoma; Clear-cell renal carcinoma; Hypoxia-inducible factor; HIF-responsive gene products
25.  DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma 
Epigenetics  2013;8(3):252-267.
Renal cell carcinoma (RCC) accounts for around 3% of cancers in the UK, and both incidence and mortality are increasing with the aging population. RCC can be divided into several subtypes: conventional RCC (the most common, comprising 75% of all cases), papillary RCC (15%) and chromophobe RCC (5%). Renal oncocytoma is a benign tumor and accounts for 5% of RCC. Cancer and epigenetics are closely associated, with DNA hypermethylation being widely accepted as a feature of many cancers. In this study the DNA methylation profiles of chromophobe RCC and renal oncocytomas were investigated by utilizing the Infinium HumanMethylation450 BeadChips. Cancer-specific hypermethylation was identified in 9.4% and 5.2% of loci in chromophobe RCC and renal oncocytoma samples, respectively, while the majority of the genome was hypomethylated. Thirty (hypermethylated) and 41 (hypomethylated) genes were identified as differentially methylated between chromophobe RCC and renal oncocytomas (p < 0.05). Pathway analysis identified some of the differentially hypermethylated genes to be involved in Wnt (EN2), MAPK (CACNG7) and TGFβ (AMH) signaling, Hippo pathway (NPHP4), and cell death and apoptosis (SPG20, NKX6-2, PAX3 and BAG2). In addition, we analyzed ccRCC and papillary RCC data available from The Cancer Genome Atlas portal to identify differentially methylated loci in chromophobe RCC and renal oncocytoma in relation to the other histological subtypes, providing insight into the pathology of RCC subtypes and classification of renal tumors.
doi:10.4161/epi.23817
PMCID: PMC3669118  PMID: 23428843
renal cell carcinoma; renal oncocytoma; chromophobe renal cell carcinoma; hypermethylation; hypomethylation

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