Biomarker Commons

Methylation of the APAF-1 and DAPK-1 promoter region correlates with progression of renal cell carcinoma in North Indian population.

Tumour Biol. 2012 Apr;33(2):395-402

Authors: Ahmad ST, Arjumand W, Seth A, Saini AK, Sultana S

Abstract
Aberrant promoter hypermethylation of cancer associated genes occur frequently during carcinogenesis and may serve as a cancer biomarker. The aim of this study was to investigate the occurrence and relevance of promoter methylation of the tumor suppressor DAPK-1, APAF-1 () and SPARC in relation to different pathological stages and histological grades of tumor progression that might act as possible independent prognostic factor in the susceptibility towards renal cell carcinoma (RCC) in North Indian population. Three tumor suppressor gene promoters namely APAF-1, DAPK-1 and SPARC were assessed by methylation-specific PCR (MS-PCR) in 196 primarily resected renal cell tumors paired with the corresponding normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters, pathological stage and Fuhrman nuclear grade of RCC. Significant differences in methylation frequency among the four subtypes of renal tumors were found for APAF-1 (p < 0.001), DAPK-1 (p < 0.001) and SPARC (p = 0.182), when compared with the corresponding normal tissue. Male subjects showed stronger association of methylation frequency of all the three genes with RCC than the female subjects. Additionally, higher frequency of APAF-1, DAPK-1 and SPARC promoter methylation were directly correlated with higher tumor stage (p (trend) < 0.001). Higher frequency of promoter methylation of APAF-1 and SPARC were also associated with higher nuclear grade (p < 0.001 and p = 0.036, respectively). This gene panel might contribute to a more optimal diagnostic coverage and information, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.

PMID: 21922274 [PubMed - indexed for MEDLINE]

Axitinib for the management of metastatic renal cell carcinoma.

Drugs R D. 2011;11(2):113-26

Authors: Escudier B, Gore M

Abstract
In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5 mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2-6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advanced RCC previously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable non-cumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95% CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95% CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6). In the three studies, the most common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients. An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.

PMID: 21679004 [PubMed - indexed for MEDLINE]

C-reactive protein: a clinically useful biomarker in renal cell carcinoma.

JAAPA. 2012 Jan;25(1):45-7

Authors: Johnson TV, DeLong J, Master VA

PMID: 22384756 [PubMed - indexed for MEDLINE]

Sensitivity and specificity of urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 for the diagnosis of renal cell carcinoma.

Am J Nephrol. 2011;34(5):391-8

Authors: Morrissey JJ, London AN, Lambert MC, Kharasch ED

Abstract
BACKGROUND/AIMS: Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are urinary biomarkers of diagnostic relevance in a wide variety of acute and chronic kidney diseases. Their diagnostic sensitivity and specificity for kidney cancer are largely unknown and therefore the subject of this investigation.
METHODS: A prospective cohort study was performed to evaluate urine biomarkers for clear-cell and papillary subtypes of renal cancer (67 patients undergoing nephrectomy) and 55 control patients undergoing non-kidney surgery. Urinary KIM-1 and NGAL concentrations were determined by sensitive and specific ELISAs.
RESULTS: In renal cancer patients, median NGAL excretion was 0.52 (1st to 3rd quartiles: 0.28-0.82) ng/mg urinary creatinine (U(Cr)) before nephrectomy compared to 0.15 (0.04-0.31) ng/mg U(Cr) in controls (p < 0.001), and there was a modest decrease of 30% after nephrectomy (p < 0.008). NGAL was not correlated to tumor size (r = 0.19, p = 0.27) or stage. Before nephrectomy, KIM-1 excretion was 0.68 (0.40-1.12) ng/mg U(Cr) compared to 0.03 (0.01-0.06) in controls (p < 0.001). There was a linear correlation between KIM-1 excretion before nephrectomy and tumor size (Spearman's r = 0.66, p < 0.001), tumor stage, and a 50% decrease in median KIM-1 concentration 1 month following tumor excision (p < 0.01). Biomarker concentration ranges for renal cancer patients and controls overlapped substantially for NGAL but not KIM-1.
CONCLUSION: NGAL is not a sensitive or specific urinary biomarker of kidney cancer. Although KIM-1 had diagnostic sensitivity for kidney cancer, it is well known to reflect many types of kidney injuries, thus limiting its specificity as a diagnostic biomarker for renal cancer.

PMID: 21912102 [PubMed - indexed for MEDLINE]

[Biomarker for molecular targeting therapy against renal cell carcinoma].

Gan To Kagaku Ryoho. 2012 Jan;39(1):39-42

Authors: Mizuno R, Oya M

PMID: 22454982 [PubMed - indexed for MEDLINE]

Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: clinical utility and biological implications.

BJU Int. 2012 Feb;109(4):634-8

Authors: Kruck S, Hennenlotter J, Vogel U, Schilling D, Gakis G, Hevler J, Kuehs U, Stenzl A, Schwentner C

Abstract
OBJECTIVE: •  To determine the clinical role of the exposed proliferation antigen 210 (XPA-210) of the proliferation marker thymidine kinase 1 (TK1) in a large cohort of different renal cell carcinoma (RCC) types, oncocytomas and normal renal tissues samples, as TK1 is reported to be of clinical significance in several cancer entities and is suggested as a prognostic serum biomarker for RCC.
PATIENTS AND METHODS: •  Expressions of XPA-210 were determined immunohistochemically in 40 clear cell RCCs (ccRCC), 25 papillary RCCs (papRCC), 17 chromophobe RCC (chRCC), 27 oncocytomas and 64 normal renal parenchyma paraffin-embedded specimens. •  Immunohistochemistry was performed with a monoclonal anti-XPA-210 antibody. Staining was measured by the percentage of positive cells. •  Expression was compared between subgroups and correlated with respective clinical data using one-way analysis of variance with post hoc Tukey-Kramer analyses.
RESULTS: •  XPA-210 staining in the RCC subgroup was significantly different from the oncocytomas (mean [sem] 4.1 [0.4] vs 2.2 [0.4]; P = 0.004) and from normal renal tissue (1.0 [0.1]; P < 0.001], whereas oncocytomas did not differ from normal renal parenchyma staining (P = 0.18). •  Subdivided into RCC groups, only ccRCC (mean [sem] 5.1 [0.6]; P < 0.001) and papRCC (4.4 [0.6]; P < 0.001) varied from normal renal parenchyma, whereas chRCC (1.4 [0.3]; P = 0.99) did not. •  RCC XPA-210 staining was significantly associated with higher tumour stage (T = 3, P = 0.002) and grade (G = 3, P = 0.001).
CONCLUSIONS: •  The malignant character of RCC is reflected by higher XPA-210 expression as compared with oncocytomas and normal kidney. •  The ccRCC and papRCC subgroups had higher XPA-210 levels. •  XPA-210 could be considered a potential marker for the assessment of the proliferative activity in primary RCC.

PMID: 21711439 [PubMed - indexed for MEDLINE]

The expanding role of imaging in the management of renal cell carcinoma.

Expert Rev Anticancer Ther. 2011 Dec;11(12):1871-88

Authors: Murphy G, Jhaveri K

Abstract
The management of renal cell carcinoma (RCC) is evolving owing to the increasing detection of small renal masses, greater understanding of the metabolic pathways involved, new targeted medical treatments for metastatic RCC, and evolving surgical and minimally invasive image-guided treatment techniques. Consequently, the role of imaging and radiology has expanded, with new challenges encompassing all aspects of management, including diagnosis, predicting cell type, staging, preoperative vascular mapping, image-guided treatment and biopsy, detection of recurrence and the use of imaging as a biomarker to assess response to treatment. This article is a comprehensive review of RCC, outlining the etiology of the disease, RCC histological subtypes and their imaging characteristics, imaging modality techniques for evaluation of RCC, treatment strategies and the management of small renal masses.

PMID: 22117155 [PubMed - indexed for MEDLINE]

Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.

N Engl J Med. 2012 Mar 8;366(10):883-92

Authors: Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C

Abstract
BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.
METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.
RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.
CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

PMID: 22397650 [PubMed - indexed for MEDLINE]

Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease.

Ann Oncol. 2011 Dec;22(12):2661-6

Authors: Jonasch E, McCutcheon IE, Waguespack SG, Wen S, Davis DW, Smith LA, Tannir NM, Gombos DS, Fuller GN, Matin SF

Abstract
BACKGROUND: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue.
METHODS: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC).
RESULTS: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003).
CONCLUSIONS: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.

PMID: 22105611 [PubMed - indexed for MEDLINE]

LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer.

PLoS One. 2011;6(11):e27361

Authors: Liao LM, Brennan P, van Bemmel DM, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Rothman N, Boffetta P, Chow WH, Moore LE

Abstract
PURPOSE: Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.
EXPERIMENTAL DESIGN: LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2∶1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.
RESULTS: LINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile range[IQR]: 80.84-83.47) compared to 81.67% (IQR: 80.35-83.03) among controls (p = 0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2) = 1.84(1.20-2.81), OR(Q3) = 1.72(1.11-2.65) and OR(Q4) = 2.06(1.34-3.17), with a p-trend = 0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction = 0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.
CONCLUSIONS: Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis.

PMID: 22076155 [PubMed - indexed for MEDLINE]

MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels.

PLoS One. 2011;6(9):e25787

Authors: Wulfken LM, Moritz R, Ohlmann C, Holdenrieder S, Jung V, Becker F, Herrmann E, Walgenbach-Brünagel G, von Ruecker A, Müller SC, Ellinger J

Abstract
BACKGROUND: MicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC).
METHODOLOGY/PRINCIPAL FINDINGS: We first explored microrna expression profiles in tissue and serum using taqman low density arrays in each six malignant and benign samples: Although 109 microRNAs were circulating at higher levels in cancer patients' serum, we identified only 36 microRNAs with up-regulation in RCC tissue and serum of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients: miR-7-1*, miR-93, miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum of healthy controls (n = 30) and RCC (n = 33) patients were determined using quantitative real-time PCR (TaqMan MicroRNA Assays). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of 84 RCC patients and 93 healthy controls using quantitative real-time PCR (sensitivity 77.4%, specificity 37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters.
CONCLUSIONS/SIGNIFICANCE: MicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a tumor-specific origin. We identify circulating miR-1233 as a potential biomarker for RCC patients. Larger-scaled studies are warranted to fully explore the role of circulating microRNAs in RCC.

PMID: 21984948 [PubMed - indexed for MEDLINE]

Pilot trial of bone-targeted therapy combining zoledronate with fluvastatin or atorvastatin for patients with metastatic renal cell carcinoma.

Clin Genitourin Cancer. 2011 Dec;9(2):81-8

Authors: Manoukian GE, Tannir NM, Jonasch E, Qiao W, Haygood TM, Tu SM

Abstract
BACKGROUND: The biological rationale for this study came from the observation that bisphosphonates and statins affect bone metastasis in different ways and thus combination therapy may provide synergistic benefit. This pilot trial evaluated the efficacy and safety of combining a bisphosphonate and a statin in patients with RCC metastatic to bone.
METHODS: Patients with RCC and bone metastasis received zoledronate and fluvastatin or atorvastatin. Patients were monitored clinically and by imaging for skeletal events. Concentrations of the bone resorption markers deoxypyridinoline (DPD) and N-telopeptide (NTX) and the bone formation marker bone-specific alkaline phosphatase (BSAP) were monitored for changes during treatment.
RESULTS: Eleven patients were enrolled and followed for a median of 6 months. The median time to first skeletal-related event for all patients was 9.0 months. Seven (63%) patients experienced skeletal events with a median time to first skeletal-related event of 4.0 months (range, 3-18 months); 4 patients (36%) experiences no skeletal events for a median of 12 months of follow-up (range, 2-28 months); 4 patients (36%) demonstrated treatment responses with development of sclerosis in lytic bone lesions. Differences in the median changes in biomarker levels between patients who had skeletal events and those who did not were statistically significant for DPD and NTX (P = .03 and .01, respectively) but not for BSAP (P = .4). The regimen was well tolerated, with few adverse reactions related to the study drugs.
CONCLUSION: Although the use of bone-targeting therapy combining zoledronate and fluvastatin or atorvastatin affected certain bone biomarkers and provided bone response in several patients with RCC and bone metastasis, we could not demonstrate a statistically significant improvement in time to skeletal events.

PMID: 21958521 [PubMed - indexed for MEDLINE]

Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker.

Cancer. 2012 Jan 1;118(1):82-90

Authors: de Martino M, Klatte T, Haitel A, Marberger M

Abstract
BACKGROUND: Currently, there are no established diagnostic and prognostic serum markers for renal cell carcinoma (RCC). The objective of this study was to evaluate the putative significance of serum cell-free DNA.
METHODS: Preoperative serum samples from 200 consecutive patients with sporadic, solid renal tumors were analyzed (157 patients with RCC and 43 patients with benign renal tumors). Quantitative real-time polymerase chain reaction was used to assess total cell-free DNA (ring finger protein 185 [RNF185]) and CpG island methylation of Ras association domain family member 1A (RASSF1A) von Hippel-Lindau (VHL), prostaglandin-endoperoxidase synthase 2 (PTGS2), and P16 (cyclin-dependent kinase inhibitor 2A). Associations with RCC, pathologic variables, and disease-specific survival were evaluated.
RESULTS: Total cell-free DNA levels and CpG island methylation of RASSF1A and VHL were highly diagnostic for RCC with an area under the receiver operating characteristic curve of 0.755, 0.705, and 0.694, respectively. VHL methylation was detected more frequently in patients with clear cell RCC than in those with other subtypes (P = .007). Total cell-free DNA levels were higher in patients with metastatic RCC (P < .001) and necrotic RCC (P = .003) and were associated with poorer disease-specific survival (P < .001). In multivariate analysis, the tumor stage, size, grade, and necrosis (SSIGN) score (P < .001) and categorized total cell-free DNA levels (P = .028) were retained as independent prognostic factors.
CONCLUSIONS: The current results indicated that cell-free DNA represents a novel serum-based diagnostic and prognostic biomarker for RCC. Total serum cell-free DNA levels and CpG island methylation of RASSF1A and VHL may be useful diagnostic biomarkers for RCC. VHL methylation of cell-free DNA is suggestive of clear cell RCC. Total serum cell-free DNA may be a useful prognostic biomarker that may assist in tailoring postoperative surveillance and therapy. External prospective validation of these data will be required.

PMID: 21713763 [PubMed - indexed for MEDLINE]

Urine metabolomics for kidney cancer detection and biomarker discovery.

Urol Oncol. 2011 Sep-Oct;29(5):551-7

Authors: Ganti S, Weiss RH

Abstract
Renal cell carcinoma (RCC) is one of the few human cancers whose incidence is increasing. The disease regularly progresses asymptomatically and is frequently metastatic upon presentation, thereby necessitating the development of an early method of detection. A metabolomic approach for biomarker detection using urine as a biofluid is appropriate since the tumor is located in close proximity to the urinary space. By comparing the composition of urine from individuals with RCC to control individuals, differences in metabolite composition of this biofluid can be identified, and these data can be utilized to create a clinically applicable and, possibly, bedside assay. Recent studies have shown that sample handling and processing greatly influences the variability seen in the urinary metabolome of both cancer and control patients. Once a standard method of collection is developed, identifying metabolic derangements associated with RCC will also lead to the investigation of novel targets for therapeutic intervention. The objective of this review is to discuss existing methods for sample collection, processing, data analysis, and recent findings in this emerging field.

PMID: 21930086 [PubMed - indexed for MEDLINE]

Putative biomarker genes for grading clear cell renal cell carcinoma.

Urol Int. 2011;87(2):205-17

Authors: Maruschke M, Koczan D, Reuter D, Ziems B, Nizze H, Hakenberg OW, Thiesen HJ

Abstract
OBJECTIVE: The initial objective of this renal cancer study was to identify gene sets in clear cell renal cell carcinoma (ccRCC) to support grading of ccRCC histopathology.
MATERIALS AND METHODS: Preselected ccRCC tumor tissues of grade 1 (G1, n = 14) and grade 3 (G3, n = 15) as well es 14 normal kidney tissues thereof were subjected to microarray expression analysis using Human Genome U133 Plus 2.0 Array. Event ratio scoring, hierarchical clustering and principal component analysis were used to determine gene sets that distinguish expression profiles from normal kidney tissue, G1 and G3 tumor tissues.
RESULTS: An initial set of 73 genes provided seven gene subclusters (SC01 to SC07) that distinguish RNA expression profiles from G1, G3 tumor and normal kidney tissues. A ranked list of 24 genes was determined that separated G1 from G3 tumors in high concordance with histopathological grading confirmed by immunohistochemical analysis of ceruloplasmin protein expression.
CONCLUSION: A final set of 24 genes has been determined awaiting further validation on the RNA as well as on the protein level by studying an additional cohort of ccRCC patients. A reliable separation of G1 and G3 tumor grades will be instrumental to foster and direct the administration of upcoming targeted therapeutics of ccRCC tumors in a more predictive and reliable manner.

PMID: 21757870 [PubMed - indexed for MEDLINE]

Sequential FDG-PET/CT as a biomarker of response to Sunitinib in metastatic clear cell renal cancer.

Clin Cancer Res. 2011 Sep 15;17(18):6021-8

Authors: Kayani I, Avril N, Bomanji J, Chowdhury S, Rockall A, Sahdev A, Nathan P, Wilson P, Shamash J, Sharpe K, Lim L, Dickson J, Ell P, Reynolds A, Powles T

Abstract
PURPOSE: To test the hypothesis that sequential (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant.
EXPERIMENTAL DESIGN: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. (18)F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUV(max)) at 4 and 16 weeks with overall survival (OS).
RESULTS: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUV(max) = 6.8, range: <2.5-18.4). In multivariate analysis, a high SUV(max) and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36-8.45) and 3.67 (95% CI: 1.43-9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40-1.99) or OS (HR for responders = 0.80; 95% CI: 0.34-1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43-19.02) and HR = 12.13 (95% CI: 3.72-46.45), respectively].
CONCLUSIONS: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant.

PMID: 21742806 [PubMed - indexed for MEDLINE]