Kidney Cancer

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (90)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
VHL 3p25.3 RCA1, VHL1, pVHL, HRCA1 -VHL and Kidney Cancer
460
HIF1A 14q23.2 HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA -HIF1A and Kidney Cancer
139
MET 7q31 HGFR, AUTS9, RCCP2, c-Met -C-MET and Renal Cell Carcinoma
92
FLCN 17p11.2 BHD, FLCL -FLCN and Kidney Cancer
89
PRCC 1q21.1 TPRC, RCCP1 Translocation
-t(X;1)(p11;q21) in Papillary Renal Cell Carcinoma
-PRCC and Renal Cell Carcinoma
87
MTOR 1p36.2 FRAP, FRAP1, FRAP2, RAFT1, RAPT1 -MTOR and Renal Cell Carcinoma
85
FH 1q42.1 MCL, FMRD, LRCC, HLRCC, MCUL1 -FH and Kidney Cancer
77
TSC2 16p13.3 LAM, TSC4, PPP1R160 -TSC2 and Kidney Cancer
68
PAX8 2q13 -PAX8 and Kidney Cancer
62
CA9 9p13.3 MN, CAIX -CA9 and Kidney Cancer
59
TFEB 6p21 TCFEB, BHLHE35, ALPHATFEB -TFEB and Kidney Cancer
42
TSC1 9q34 LAM, TSC -TSC1 and Kidney Cancer
41
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Kidney Cancer
40
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Kidney Cancer
40
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Kidney Cancer
40
ACHE 7q22 YT, ACEE, ARACHE, N-ACHE -ACHE and Kidney Cancer
39
PAX2 10q24 FSGS7, PAPRS -PAX2 and Kidney Cancer
37
MITF 3p14.2-p14.1 MI, WS2, CMM8, WS2A, bHLHe32 -MITF and Kidney Cancer
31
SLC2A1 1p34.2 PED, DYT9, GLUT, DYT17, DYT18, EIG12, GLUT1, HTLVR, GLUT-1, GLUT1DS -GLUT1 expression in Kidney Cancer
27
PBRM1 3p21 PB1, BAF180 -PBRM1 and Renal Cell Carcinoma
27
CD99 Xp22.32 and Yp11.3 MIC2, HBA71, MIC2X, MIC2Y, MSK5X -CD99 and Kidney Cancer
26
SDHB 1p36.1-p35 IP, SDH, CWS2, PGL4, SDH1, SDH2, SDHIP -SDHB and Kidney Cancer
26
SMARCB1 22q11.23 RDT, INI1, SNF5, Snr1, BAF47, MRD15, RTPS1, Sfh1p, hSNFS, SNF5L1, SWNTS1, PPP1R144 -SMARCB1 and Kidney Cancer
25
AMACR 5p13 RM, RACE, CBAS4, AMACRD -AMACR and Renal Cell Carcinoma
23
BAP1 3p21.1 UCHL2, hucep-6, HUCEP-13 -BAP1 and Renal Cell Carcinoma
22
SETD2 3p21.31 HYPB, SET2, HIF-1, HIP-1, KMT3A, HBP231, HSPC069, p231HBP -SETD2 and Renal Cell Carcinoma
20
CDKN1C 11p15.5 BWS, WBS, p57, BWCR, KIP2, p57Kip2 -CDKN1C and Kidney Cancer
18
POLE 12q24.3 FILS, POLE1, CRCS12 -POLE and Kidney Cancer
15
WT1-AS 11p13 WIT1, WIT-1, WT1AS, WT1-AS1 -WT1-AS and Kidney Cancer
13
ASPSCR1 17q25.3 TUG, ASPL, ASPS, RCC17, UBXD9, UBXN9, ASPCR1 -ASPSCR1 and Kidney Cancer
13
NONO Xq13.1 P54, NMT55, NRB54, P54NRB, PPP1R114 -NONO and Kidney Cancer
9
ZEB2 2q22.3 SIP1, SIP-1, ZFHX1B, HSPC082, SMADIP1 -ZEB2 and Kidney Cancer
9
KDM5C Xp11.22-p11.21 MRXJ, SMCX, MRX13, MRXSJ, XE169, MRXSCJ, JARID1C, DXS1272E -KDM5C and Kidney Cancer
9
EGLN3 14q13.1 PHD3, HIFPH3, HIFP4H3 -EGLN3 and Kidney Cancer
8
HNF1B 17q12 FJHN, HNF2, LFB3, TCF2, HPC11, LF-B3, MODY5, TCF-2, VHNF1, HNF-1B, HNF1beta, HNF-1-beta -HNF1B and Renal Cell Carcinoma
8
EPAS1 2p21-p16 HLF, MOP2, ECYT4, HIF2A, PASD2, bHLHe73 -EPAS1 and Renal Cell Carcinoma
8
MEST 7q32 PEG1 -MEST and Kidney Cancer
7
RNF139 8q24 RCA1, TRC8, HRCA1 Translocation
-t(3;8)(p14.2;q24.1) in Hereditary Renal Cell Carcinoma
-RNF139 and Kidney Cancer
7
SDHA 5p15 FP, PGL5, SDH1, SDH2, SDHF, CMD1GG -SDHA and Kidney Cancer
7
CITED1 Xq13.1 MSG1 -CITED1 and Kidney Cancer
7
KISS1 1q32 HH13, KiSS-1 -KISS1 and Renal Cell Carcinoma
6
MEG3 14q32 GTL2, FP504, prebp1, PRO0518, PRO2160, LINC00023, NCRNA00023 -MEG3 and Kidney Cancer
6
VIM 10p13 HEL113, CTRCT30 -VIM and Kidney Cancer
5
EGLN1 1q42.1 HPH2, PHD2, SM20, ECYT3, HALAH, HPH-2, HIFPH2, ZMYND6, C1orf12, HIF-PH2 -EGLN1 and Kidney Cancer
5
PPIA 7p13 CYPA, CYPH, HEL-S-69p -PPIA and Renal Cell Carcinoma
5
MINA 3q11.2 ROX, MDIG, NO52, MINA53 -MINA and Kidney Cancer
5
STIM1 11p15.5 GOK, TAM, TAM1, IMD10, STRMK, D11S4896E -STIM1 and Kidney Cancer
5
KRT7 12q13.13 K7, CK7, SCL, K2C7 -KRT7 and Kidney Cancer
5
CXCR3 Xq13 GPR9, MigR, CD182, CD183, Mig-R, CKR-L2, CMKAR3, IP10-R -CXCR3 and Kidney Cancer
5
KISS1R 19p13.3 HH8, CPPB1, GPR54, AXOR12, KISS-1R, HOT7T175 -KISS1R and Renal Cell Carcinoma
5
CA12 15q22 CAXII, HsT18816 -CA12 and Kidney Cancer
5
FABP7 6q22-q23 MRG, BLBP, FABPB, B-FABP, LTR2-FABP7 -FABP7 and Kidney Cancer
5
TGFBI 5q31 CSD, CDB1, CDG2, CSD1, CSD2, CSD3, EBMD, LCD1, BIGH3, CDGG1 -TGFBI and Kidney Cancer
4
ACTB 7p22 BRWS1, PS1TP5BP1 -ACTB and Kidney Cancer
4
CDCP1 3p21.31 CD318, TRASK, SIMA135 -CDCP1 and Kidney Cancer
4
KDM6A Xp11.2 UTX, KABUK2, bA386N14.2 -KDM6A and Kidney Cancer
4
RAP1GAP 1p36.1-p35 RAPGAP, RAP1GA1, RAP1GAP1, RAP1GAPII -RAP1GAP and Kidney Cancer
4
NNAT 20q11.2-q12 Peg5 -NNAT and Kidney Cancer
4
TNFSF15 9q32 TL1, TL1A, VEGI, VEGI192A -TNFSF1 and Kidney Cancer
4
RAB25 1q22 CATX-8, RAB11C -RAB25 and Kidney Cancer
4
SPINT2 19q13.1 PB, Kop, HAI2, DIAR3, HAI-2 -SPINT2 and Kidney Cancer
4
OSCAR 19q13.42 PIGR3, PIgR-3 -OSCAR and Kidney Cancer
4
SLIT2 4p15.2 SLIL3, Slit-2 -SLIT2 and Kidney Cancer
4
EGR2 10q21.1 AT591, CMT1D, CMT4E, KROX20 -EGR2 and Kidney Cancer
4
CAST 5q15 BS-17, PLACK -CAST and Kidney Cancer
4
LDHA 11p15.4 LDH1, LDHM, GSD11, PIG19, HEL-S-133P -LDHA and Kidney Cancer
4
CLTC 17q23.1 Hc, CHC, CHC17, CLH-17, CLTCL2 -CLTC and Kidney Cancer
4
CALCA 11p15.2 CT, KC, CGRP, CALC1, CGRP1, CGRP-I -CALCA and Kidney Cancer
3
MT1G 16q13 MT1, MT1K -MT1G and Kidney Cancer
3
RBX1 22q13.2 ROC1, RNF75, BA554C12.1 -RBX1 and Kidney Cancer
3
MIRLET7I 12q14.1 LET7I, MIRNLET7I, hsa-let-7i -MicroRNA let-7i and Kidney Cancer
3
PKHD1 6p12.2 FCYT, ARPKD, TIGM1 -PKHD1 and Renal Cell Carcinoma
3
HCK 20q11-q12 JTK9, p59Hck, p61Hck -HCK and Kidney Cancer
3
CD70 19p13 CD27L, CD27LG, TNFSF7 -CD70 and Renal Cell Carcinoma
3
GATA5 20q13.33 GATAS, bB379O24.1 -GATA5 and Renal Cell Carcinoma
3
BNIP3L 8p21 NIX, BNIP3a -BNIP3L and Kidney Cancer
3
KRT19 17q21.2 K19, CK19, K1CS -KRT19 and Kidney Cancer
3
NOX4 11q14.2-q21 KOX, KOX-1, RENOX -NOX4 and Kidney Cancer
3
SLC34A2 4p15.2 NPTIIb, NAPI-3B, NAPI-IIb -SLC34A2 and Kidney Cancer
2
VCAM1 1p32-p31 CD106, INCAM-100 -VCAM1 and Kidney Cancer
2
IL16 15q26.3 LCF, NIL16, PRIL16, prIL-16 -IL16 and Kidney Cancer
2
RARRES3 11q23 RIG1, TIG3, HRSL4, HRASLS4, PLA1/2-3 -RARRES3 and Kidney Cancer
2
IGF2-AS 11p15.5 PEG8, IGF2AS, IGF2-AS1 -IGF2-AS and Kidney Cancer
2
SLC22A18 11p15.5 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A -SLC22A18 and Kidney Cancer
2
YWHAE 17p13.3 MDS, HEL2, MDCR, KCIP-1, 14-3-3E -YWHAE and Kidney Cancer
2
MIR10B 2q31.1 MIRN10B, mir-10b, miRNA10B, hsa-mir-10b -MIR10B and Kidney Cancer
1
PDGFRL 8p22-p21.3 PDGRL, PRLTS -PDGFRL and Kidney Cancer
1
KLLN 10q23 CWS4, KILLIN -KLLN and Kidney Cancer
1
FHIT 3p14.2 FRA3B, AP3Aase Translocation
-t(3;8)(p14.2;q24.1) in Hereditary Renal Cell Carcinoma
TFE3 Xp11.22 TFEA, RCCP2, RCCX1, bHLHe33 Translocation
-t(X;1)(p11;q21) in Papillary Renal Cell Carcinoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
t(3;8)(p14.2;q24.1) in Hereditary Renal Cell CarcinomaTranslocationFHIT (3p14.2)RNF139 (8q24)
t(X;1)(p11;q21) in Papillary Renal Cell CarcinomaTranslocationTFE3 (Xp11.22)PRCC (1q21.1)

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Latest Publications

Ge YZ, Xu LW, Xu Z, et al.
Expression Profiles and Clinical Significance of MicroRNAs in Papillary Renal Cell Carcinoma: A STROBE-Compliant Observational Study.
Medicine (Baltimore). 2015; 94(16):e767 [PubMed] Related Publications
Papillary renal cell carcinoma (pRCC) is the second most prevalent subtype of kidney cancers. In the current study, we analyzed the global microRNA (miRNA) expression profiles in pRCC, with the aim to evaluate the relationship of miRNA expression with the progression and prognosis of pRCC.A total of 163 treatment-naïve primary pRCC patients were identified from the Cancer Genome Atlas dataset and included in this retrospective observational study. The miRNA expression profiles were graded by tumor-node-metastasis information, and compared between histologic subtypes. Furthermore, the training-validation approach was applied to identify miRNAs of prognostic values, with the aid of Kaplan-Meier survival, and univariate and multivariate Cox regression analyses. Finally, the online DAVID (Database for Annotation, Visualization, and Integrated Discover) program was applied for the pathway enrichment analysis with the target genes of prognosis-associated miRNAs, which were predicted by 3 computational algorithms (PicTar, TargetScan, and Miranda).In the progression-related miRNA profiles, 26 miRNAs were selected for pathologic stage, 28 for pathologic T, 16 for lymph node status, 3 for metastasis status, and 32 for histologic types, respectively. In the training stage, the expression levels of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were significantly associated with patient survival, whereas mir-200c, mir-127, mir-34a, and mir-181c were identified by multivariate Cox regression analyses as potential independent prognostic factors in pRCC. Subsequently, mir-200c, mir-127, and mir-34a were confirmed to be significantly correlated with patient survival in the validation stage. Finally, target gene prediction analysis identified a total of 113 target genes for mir-200c, 37 for mir-127, and 180 for mir-34a, which further generated 15 molecular pathways.Our results identified the specific miRNAs associated with the progression and aggressiveness of pRCC, and 3 miRNAs (mir-200c, mir-127, and mir-34a) as promising prognostic factors of pRCC.

Gupta S, Kang HC, Ganeshan DM, et al.
Diagnostic approach to hereditary renal cell carcinoma.
AJR Am J Roentgenol. 2015; 204(5):1031-41 [PubMed] Related Publications
OBJECTIVE: The purpose of this article is to discuss the histopathologic features, genetics, clinical presentation, and imaging of hereditary renal cancer syndromes.
CONCLUSION: Hereditary renal cell carcinoma syndromes can be diagnosed with a pattern-based approach focused on the predominant histologic renal cell carcinoma subtype and associated renal and extrarenal features of each syndrome.

Akhmadishina LZ, Giliazova IR, Kutlyeva LR, et al.
[DNA repair XRCC1, XPD genes polymorphism as associated with the development of bladder cancer and renal cell carcinoma].
Genetika. 2014; 50(4):481-90 [PubMed] Related Publications
We examined the correlations between the polymorphic alleles of the DNA repair genes XRCC1 (c.839G> A, rs25489; and c.1196A> G, rs25487), XPA (c.-4A> G, rs1800975), and XPD (c.2251A> C, rs13181) and the progression and severity of neoplasias in the bladder and kidney in patients of three distinct ethnic groups, Bashkir, Russians, and Tatar, residing in the Republic of Bashkorostan. The study enrolled 468 cancer patients and 351 healthy individuals. Genotyping for polymorphic alleles was carried out using the PCR-RFLP method. We identified a correlation between allele A of the c.839 G>A locus of the XRCC1 gene and the incidence of the bladder cancer (BC) and kidney cancer (KC) in the Tatar study group, using the additive genetic effects model (Odds Ratio (OR) = 5.23 and OR = 3.90). In turn, the heterozygous G/A genotype was present at a significantly higher frequency in the KC patients of Bashkir ethnic origin, compared with the control group (p = 0.0061, OR= 4.72). Additional analysis with consideration of participants' smoking status showed that the G/A genotype is significantly more frequent in smokers with BC (OR = 1.96, p = 0.05) then in healthy smokers. We also determined, using the recessive genetic model, that the genotype A/A of the c. 1196A>G locus of the XRCC1 gene was correlated with a higher risk of BC in the Russian cohort (OR = 2.29, p = 0.0082) and an increased incidence of KC in the Bashkir group (OR = 4.06, p = 0.05). A similar correlation was obtained for smokers. In contrast, the allele c.2251 A>C in the XPD gene correlated with a lower risk for BC and KC in the Tatars (p = 0.0003, OR = 0.48 and p < 0.0001, OR = 0.37) in the additive model and in the Bashkirs (p = 0.0083, OR = 0.12) and Russians (p = 0.0001, OR = 0.14) in the recessive model. Further, we uncovered that polymorphism c.839 G>A in the XRCC1 gene contributes to the progression of noninvasive and invasive BC and promotes KC at early and advanced stages of the disease. Thus, we identified similar correlations between DNA repair gene polymorphism and the incidence and progression of BC and KC. We propose that this result points to the involvement of common pathogenetic mechanisms in the initiation and progression of the urinary neoplasias.

Woo S, Kim SY, Lee MS, et al.
MDCT findings of renal cell carcinoma associated with Xp11.2 translocation and TFE3 gene fusion and papillary renal cell carcinoma.
AJR Am J Roentgenol. 2015; 204(3):542-9 [PubMed] Related Publications
OBJECTIVE. The purpose of this study was to compare the MDCT features of renal cell carcinoma (RCC) associated with Xp11.2 translocation and TFE3 gene fusion (Xp11 RCC) and papillary RCC. MATERIALS AND METHODS. The study included 19 and 39 patients with histologically proven Xp11 RCC and papillary RCC, respectively, who underwent multiphase renal MDCT before nephrectomy. CT findings were compared between Xp11 RCC and papillary RCC using the Student t test and chi-square test. Subgroup analyses of small (< 4 cm) renal masses for these features were performed. RESULTS. Patients with Xp11 RCC were younger (p < 0.001), and it was more prevalent in women (p = 0.007). Tumor size was greater in Xp11 RCC (p = 0.004) and more common in cystic change (p < 0.001). Calcification and unenhanced high-attenuating areas were more frequent in Xp11 RCC (p = 0.001 and 0.026, respectively). Xp11 RCCs were more prevalent in lymph node and distant metastasis (p < 0.001 and p = 0.031, respectively). Xp11 RCC and papillary RCC showed no significant difference in epicenter, margin, and venous and collecting duct invasion (p = 0.403-1.000). Although Xp11 RCC and papillary RCC had lower attenuation than the renal cortex on corticomedullary and early excretory phases (p < 0.001), only Xp11 RCCs were hyperattenuating to the cortex on the unenhanced phase (p < 0.001). Xp11 RCCs had significantly higher attenuation compared with papillary RCCs on all phases (p ≤ 0.02). Regarding small masses, cystic change, calcification, and lymph node metastasis were still more frequent in Xp11 RCCs (p ≤ 0.016). CONCLUSION. Greater size, more cystic change, calcification, high-attenuating areas on unenhanced imaging, and lymph node and distant metastasis were helpful for differentiating Xp11 RCC from papillary RCC.

Zheng B, Zhu H, Gu D, et al.
MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib.
Biochem Biophys Res Commun. 2015; 459(2):234-9 [PubMed] Related Publications
Chemotherapy-induced autophagy activation often contributes to cancer resistance. MiRNA-30a (miR-30a) is a potent inhibitor of autophagy by downregulating Beclin-1. In this study, we characterized the role of miR-30a in sorafenib-induced activity in renal cell carcinoma (RCC) cells. We found that expression of miR-30a was significantly downregulated in several human RCC tissues and in RCC cell lines. Accordingly, its targeted gene Beclin-1 was upregulated. Sorafenib activated autophagy in RCC cells (786-0 and A489 lines), evidenced by p62 degradation, Beclin-1/autophagy protein 5 (ATG-5) upregulation and light chain (LC)3B-I/-II conversion. Exogenously expressing miR-30a in 786-0 or A489 cells inhibited Beclin-1 expression and enhanced sorafenib-induced cytotoxicity. In contrast, knockdown of miR-30a by introducing antagomiR-30a increased Beclin-1 expression, and inhibited sorafenib-induced cytotoxicity against RCC cells. Autophagy inhibitors, including chloroquine, 3-methyaldenine or Bafliomycin A1, enhanced sorafenib activity, causing substantial cell apoptosis. Meanwhile, knockdown of Beclin-1 or ATG-5 by targeted siRNAs also increased sorafenib-induced cytotoxicity in above RCC cells. These findings indicate that dysregulation of miR-30a in RCC may interfere with the effectiveness of sorafenib-mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target for RCC.

Xu CF, Johnson T, Garcia-Donas J, et al.
IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.
Br J Cancer. 2015; 112(7):1190-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).
METHODS: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).
RESULTS: In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.
CONCLUSIONS: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.

Li Y, Jia Q, Zhang Q, Wan Y
Rab25 upregulation correlates with the proliferation, migration, and invasion of renal cell carcinoma.
Biochem Biophys Res Commun. 2015; 458(4):745-50 [PubMed] Related Publications
Renal cell carcinoma (RCC) is a common urological cancer with a poor prognosis. A recent cohort study revealed that the median survival of RCC patients was only 1.5 years and that <10% of the patients in the study survived up to 5 years. In tumor development, Rab GTPase are known to play potential roles such as regulation of cell proliferation, migration, invasion, communication, and drug resistance in multiple tumors. However, the correlation between Rabs expression and the occurrence, development, and metastasis of RCC remains unclear. In this study, we analyzed the transcriptional levels of 52 Rab GTPases in RCC patients. Our results showed that high levels of Rab25 expression were significantly correlated with RCC invasion classification (P < 0.01), lymph-node metastasis (P < 0.001), and pathological stage (P < 0.01). Conversely, in 786-O and A-498 cells, knocking down Rab25 protein expression inhibited cell proliferation, migration, and invasion. Our results also demonstrated that Rab25 is a target gene of let-7d, and further suggested that Rab25 upregulation in RCC is due to diminished expression of let-7d. These findings indicate that Rab25 might be a novel candidate molecule involved in RCC development, thus identifying a potential biological therapeutic target for RCC.

Ge YZ, Wu R, Xin H, et al.
A tumor-specific microRNA signature predicts survival in clear cell renal cell carcinoma.
J Cancer Res Clin Oncol. 2015; 141(7):1291-9 [PubMed] Related Publications
PURPOSE: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers in adults, and microRNAs (miRNAs) differentially expressed in ccRCC tumors have been identified and proposed to predict prognosis. In the present study, we comprehensively analyzed the genome-wide miRNA expression profiles in ccRCC, with the aim to generate a tumor-specific miRNA signature of prognostic values.
METHODS: The miRNA profiles in tumor and the adjacent normal tissue were analyzed, and the association of the differentially expressed miRNAs with patient survival was examined with univariate Cox regression analysis. Finally, a tumor-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate, and multivariate Cox regression analyses.
RESULTS: A total of 147 miRNAs were found differentially expressed between tumor and matched non-tumor tissues from 58 ccRCC patients. The prognostic values of these differentially expressed miRNAs were subsequently analyzed in the 411 ccRCC patients, and 22 miRNAs were found significantly correlated with patient survival. Finally, a tumor-specific miRNA signature of 22 miRNAs was generated and validated as an independent prognostic parameter.
CONCLUSIONS: A tumor-specific miRNA signature consisting of 22 miRNAs was identified and validated as an independent prognostic factor, which could serve as a novel biomarker for ccRCC prognostication and help in predicting treatment outcome.

Zhang Y, Yang D, Zhu JH, et al.
The association between NQO1 Pro187Ser polymorphism and urinary system cancer susceptibility: a meta-analysis of 22 studies.
Cancer Invest. 2015; 33(2):39-40 [PubMed] Related Publications
Numerous studies have investigated the association between NQO1 Pro187Ser polymorphism and urinary system cancer risk, but the findings are inconsistent. To derive a more precise estimation of such association, we performed a meta-analysis based on 22 publications encompassing 5,274 cases and 6,459 controls. Overall, significant association was found between NQO1 Pro187Ser polymorphism and urinary system cancer risk. Moreover, stratified analysis observed a statistically significant association for bladder cancer, prostate cancer, renal cell carcinoma, Caucasians, Asians, and hospital-based studies. In summary, this meta-analysis indicated that NQO1 Pro187Ser polymorphism conferred genetic susceptibility to urinary system cancer.

Furuya M, Hong SB, Tanaka R, et al.
Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt-Hogg-Dubé syndrome.
Cancer Sci. 2015; 106(3):315-23 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder associated with a germline mutation of the folliculin gene (FLCN). The affected families have a high risk for developing multiple renal cell carcinomas (RCC). Diagnostic markers that distinguish between FLCN-related RCC and sporadic RCC have not been investigated, and many patients with undiagnosed BHD fail to receive proper medical care. We investigated the histopathology of 27 RCCs obtained from 18 BHD patients who were diagnosed by genetic testing. Possible somatic mutations of RCC lesions were investigated by DNA sequencing. Western blotting and immunohistochemical staining were used to compare the expression levels of FLCN and glycoprotein non-metastatic B (GPNMB) between FLCN-related RCCs and sporadic renal tumors (n = 62). The expression of GPNMB was also evaluated by quantitative RT-PCR. Histopathological analysis revealed that the most frequent histological type was chromophobe RCC (n = 12), followed by hybrid oncocytic/chromophobe tumor (n = 6). Somatic mutation analysis revealed small intragenic mutations in six cases and loss of heterozygosity in two cases. Western blot and immunostaining analyses revealed that FLCN-related RCCs showed overexpression of GPNMB and underexpression of FLCN, whereas sporadic tumors showed inverted patterns. GPNMB mRNA in FLCN-related RCCs was 23-fold more abundant than in sporadic tumors. The distinctive expression patterns of GPNMB and FLCN might identify patients with RCCs who need further work-up for BHD.

Zhan HQ, Chen H, Wang CF, Zhu XZ
A case of PSF-TFE3 gene fusion in Xp11.2 renal cell carcinoma with melanotic features.
Hum Pathol. 2015; 46(3):476-81 [PubMed] Related Publications
Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) with PSF-TFE3 gene fusion is a rare neoplasm. Only 22 cases of Xp11.2 RCCs with PSF-TFE3 have been reported to date. We describe an additional case of Xp11.2 RCC with PSF-TFE3 showing melanotic features. Microscopically, the histologic features mimic clear cell renal cell carcinoma. However, the dark-brown pigments were identified and could be demonstrated as melanins. Immunohistochemically, the tumor cells were widely positive for CD10, human melanoma black 45, and TFE3 but negative for cytokeratins, vimentin, Melan-A, microphthalmia-associated transcription factor, smooth muscle actin, and S-100 protein. Genetically, we demonstrated PSF-TFE3 fusion between exon 9 of PSF and exon 5 of TFE3. The patient was free of disease with 50 months of follow-up. The prognosis of this type of tumor requires more cases because of limited number of cases and follow-up period. Xp11.2 RCC with PSF-TFE3 inevitably requires differentiation from other kidney neoplasms. Immunohistochemical and molecular genetic analyses are essential for accurate diagnosis.

Rao Q, Shen Q, Shi S, et al.
[Clinicopathologic features of clear cell papillary renal cell carcinoma].
Zhonghua Bing Li Xue Za Zhi. 2014; 43(11):728-31 [PubMed] Related Publications
OBJECTIVE: To study the clinicopathological features, differential diagnosis and prognosis of clear cell papillary renal cell carcinoma (CCPRCC).
METHODS: The histological, immunohistochemical, and molecular features were studied in 11 cases and follow-up data were also analyzed.
RESULTS: There were a total of 3 females and 8 males. The age of patients were ranged from 33 to 72 years(mean age 52.5 years). The diameters of tumors varied from 1cm to 4 cm. Histologically, papillary and cystic architecture were present at least focally in all tumors. The papillae were covered by small to medium-sized cuboidal cells with abundant clear cytoplasm and often showed extensive secondary branching, which were often folded and densely packed, resulting in a solid appearance. The nuclei were round and uniform in shape; nucleoli were not prominent (Fuhrman grade 1 or 2). Neither mitotic figures nor necrosis was present. All 11 cases exhibited moderate to strong positivity for CK7, CA9, vimentin, and HIF-1α, coupled with negative reactions for CD10, P504S, and TFE3. Ksp-cadherin was positively expressed in 8 cases.VHL gene mutations were not found in all 11 cases. Losses of chromosomes 3 (monoploid chromosome 3) was detected in 3 cases.
CONCLUSIONS: CCPRCC is uncommon and seemed to be an indolent tumor. The differential diagnosis should be included tumors, which harbor clear cell and papillary structure including clear cell renal cell carcinoma, papillary renal cell carcinoma, Xp11 translocation renal cell carcinoma, and CCPRCC. Immunohistochemical and molecular analysis may be help for its diagnosis.

Yang W, Yoshigoe K, Qin X, et al.
Identification of genes and pathways involved in kidney renal clear cell carcinoma.
BMC Bioinformatics. 2014; 15 Suppl 17:S2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is one of fatal genitourinary diseases and accounts for most malignant kidney tumours. KIRC has been shown resistance to radiotherapy and chemotherapy. Like many types of cancers, there is no curative treatment for metastatic KIRC. Using advanced sequencing technologies, The Cancer Genome Atlas (TCGA) project of NIH/NCI-NHGRI has produced large-scale sequencing data, which provide unprecedented opportunities to reveal new molecular mechanisms of cancer. We combined differentially expressed genes, pathways and network analyses to gain new insights into the underlying molecular mechanisms of the disease development.
RESULTS: Followed by the experimental design for obtaining significant genes and pathways, comprehensive analysis of 537 KIRC patients' sequencing data provided by TCGA was performed. Differentially expressed genes were obtained from the RNA-Seq data. Pathway and network analyses were performed. We identified 186 differentially expressed genes with significant p-value and large fold changes (P < 0.01, |log(FC)| > 5). The study not only confirmed a number of identified differentially expressed genes in literature reports, but also provided new findings. We performed hierarchical clustering analysis utilizing the whole genome-wide gene expressions and differentially expressed genes that were identified in this study. We revealed distinct groups of differentially expressed genes that can aid to the identification of subtypes of the cancer. The hierarchical clustering analysis based on gene expression profile and differentially expressed genes suggested four subtypes of the cancer. We found enriched distinct Gene Ontology (GO) terms associated with these groups of genes. Based on these findings, we built a support vector machine based supervised-learning classifier to predict unknown samples, and the classifier achieved high accuracy and robust classification results. In addition, we identified a number of pathways (P < 0.04) that were significantly influenced by the disease. We found that some of the identified pathways have been implicated in cancers from literatures, while others have not been reported in the cancer before. The network analysis leads to the identification of significantly disrupted pathways and associated genes involved in the disease development. Furthermore, this study can provide a viable alternative in identifying effective drug targets.
CONCLUSIONS: Our study identified a set of differentially expressed genes and pathways in kidney renal clear cell carcinoma, and represents a comprehensive computational approach to analysis large-scale next-generation sequencing data. The pathway and network analyses suggested that information from distinctly expressed genes can be utilized in the identification of aberrant upstream regulators. Identification of distinctly expressed genes and altered pathways are important in effective biomarker identification for early cancer diagnosis and treatment planning. Combining differentially expressed genes with pathway and network analyses using intelligent computational approaches provide an unprecedented opportunity to identify upstream disease causal genes and effective drug targets.

Hayes M, Peckova K, Martinek P, et al.
Molecular-genetic analysis is essential for accurate classification of renal carcinoma resembling Xp11.2 translocation carcinoma.
Virchows Arch. 2015; 466(3):313-22 [PubMed] Related Publications
Xp11.2-translocation renal carcinoma (TRCC) is suspected when a renal carcinoma occurs in young patients, patients with a prior history of exposure to chemotherapy and when the neoplasm has morphological features suggestive of that entity. We retrieved 20 renal tumours (from 17,500 archival cases) of which morphology arose suspicion for TRCC. In nine cases, TFE3 translocation was confirmed by fluorescence in situ hybridisation analysis. In 9 of the remaining 11 TRCC-like cases (7 male, 4 female, aged 22-84 years), material was available for further study. The morphological spectrum was diverse. Six tumours showed a mixture of cells with eosinophilic or clear cytoplasm in tubular, acinar and papillary architecture. One case was high grade with epithelioid, spindle cell and sarcomatoid areas. Another showed tubular, solid, and papillary areas and foci containing spindle cells reminiscent of mucinous tubular and spindle cell carcinoma. The third showed dyscohesive nests of large epithelioid and histiocytoid cells in a background of dense lymphoplasmacytic infiltrate. By immunohistochemistry, keratin AE1/AE3 was diffusely positive in three tumours, while CK7 strongly stained one tumour and another focally and weakly. CD10 and Pax8 were expressed by eight, AMACR and vimentin by seven, CA-IX by four and TFE3 and cathepsin K by two tumours. Of the two TFE3-positive tumours, one showed polysomy of chromosome 7 and the other of 17; they were VHL normal and diagnosed as unclassifiable RCC. Of the seven TFE3-negative tumours, three showed polysomy of 7/17 and VHL abnormality and were diagnosed as combined clear cell RCC/papillary RCC. One TFE3-negative tumour with normal 7/17 but LOH 3p (VHL abnormality) was diagnosed as clear cell RCC. One TFE3-negative tumour with polysomy 7/17 but normal VHL was diagnosed as papillary RCC, and two with normal chromosomes 7/17 and VHL gene were considered unclassifiable. As morphological features and IHC are heterogeneous, TRCC-like renal tumours can only be sub-classified accurately by multi-parameter molecular-genetic analysis.

Gossage L, Eisen T, Maher ER
VHL, the story of a tumour suppressor gene.
Nat Rev Cancer. 2015; 15(1):55-64 [PubMed] Related Publications
Since the Von Hippel-Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.

Melkonian SC, Wang X, Gu J, et al.
Mitochondrial DNA copy number in peripheral blood leukocytes and the risk of clear cell renal cell carcinoma.
Carcinogenesis. 2015; 36(2):249-55 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Variation of mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes has been associated with the risk of various cancers, including renal cell carcinoma (RCC). We assessed the association between mtDNAcn and clear cell RCC (ccRCC) risk in 608 cases and 629 controls frequency-matched on age and gender. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, body mass index, smoking status, history of hypertension, total energy intake and physical activity. Our results suggest an association between low mtDNAcn and ccRCC risk (OR = 1.28, 95% CI: 0.97-1.68, P = 0.09). Lower mtDNAcn was associated with increased ccRCC risk in younger individuals (age <60, OR = 1.68, 95% CI: 1.13-2.49, P = 0.01), women (OR = 1.66, 95% CI: 1.03-2.73, P = 0.04), individuals without history of hypertension (OR = 1.62, 95% CI: 1.09-2.41, P = 0.02) and individuals with low physical activity levels (OR = 1.55, 95% CI: 1.02-2.37, P = 0.05). We observed significant and marginally significant interactions between both age and history of hypertension and mtDNAcn in elevating ccRCC risk (P for interaction = 0.04 and 0.07, respectively). Additionally, low mtDNAcn was associated with ccRCC risk in younger individuals with low levels of physical activity [ORs and 95% CI for medium and low physical activity levels, respectively, 2.31 (1.18-4.52) and 2.09 (1.17-3.75), P interaction = 0.04]. To our knowledge, this is the first report to investigate the role of mtDNAcn in the ccRCC subtype and the first to suggest that this association may be modified by risk factors including age, gender, history of hypertension and physical activity.

Lin Z, Gong K, Pang B, et al.
Birt-Hogg-Dubé syndrome with clear cell renal cell carcinoma in a Chinese family.
Intern Med. 2014; 53(24):2825-8 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis that presents as a clinical triad including follicular hamartomas, renal neoplasms and lung cysts associated with an increased risk of pneumothorax. FLCN gene defects have been identified as being responsible for BHDS. We herein report the case of a 67-year-old woman with the full-blown BHDS phenotype, characterized by skin lesions, multiple lung bullae and renal neoplasms. In her family history, one of the patient's sons exhibited a similar phenotype, without renal neoplasms. Due to the relatively late age of onset of renal neoplasms among variable BHDS phenotypes, follow-up imaging is recommended for the son who has not yet developed renal neoplasms.

Gowrishankar B, Przybycin CG, Ma C, et al.
A genomic algorithm for the molecular classification of common renal cortical neoplasms: development and validation.
J Urol. 2015; 193(5):1479-85 [PubMed] Related Publications
PURPOSE: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms.
MATERIALS AND METHODS: Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization.
RESULTS: The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved.
CONCLUSIONS: In a clinical diagnostic setting the implementation of genome based molecular classification could serve as an ancillary assay to assist in the histological classification of common renal neoplasms.

Zhang HM, Yang FQ, Chen SJ, et al.
Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma.
Tumour Biol. 2015; 36(4):2947-55 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of cellular processes, such as cell growth, apoptosis, and carcinogenesis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer, pancreatic cancer, and cervical cancer. However, the role of lncRNA MALAT1 in clear cell renal cell carcinoma (ccRCC) remains unclear. Expression levels of lncRNA MALAT1 in ccRCC tissues and renal cancer cell lines were evaluated by quantitative real-time PCR (qRT-PCR), and its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA (siRNA) was used to suppress MALAT1 expression in renal cancer cells. In vitro assays were conducted to further explore its role in tumor progression. The expression level of MALAT1 was higher in ccRCC tissues and renal cancer cells compared to adjacent non-tumor tissues and normal human proximal tubule epithelial cells HK-2. The ccRCC patients with higher MALAT1 expression had an advanced clinical features and a shorter overall survival time than those with lower MALAT1 expression. And multivariate analysis showed that the status of MALAT1 expression was an independent predictor of overall survival in ccRCC. Additionally, our data indicated that knockdown expression of MALAT1 decreased renal cancer cell proliferation, migration, and invasion. Our data suggested that lncRNA MALAT1 was a novel molecule involved in ccRCC progression, which provided a potential prognostic biomarker and therapeutic target.

Sima J, Zhang B, Yu Y, et al.
Overexpression of Numb suppresses growth, migration, and invasion of human clear cell renal cell carcinoma cells.
Tumour Biol. 2015; 36(4):2885-92 [PubMed] Related Publications
The objective of the study was to investigate the impact of Numb on cell growth, cell migration, and invasion in human clear cell renal cell carcinoma (ccRCC). Endogenous expression of Numb was evaluated in the ccRCC cell lines (786-O, Caki-1, and Caki-2) and control reference human renal proximal tubular epithelial cells. Numb expression was decreased in the ccRCC cells compared with the control cells (P < 0.01). Then, 786-O and Caki-1 cells described as suitable transfection hosts were used in transfection to carry out biological function studies. The three experimental groups were as follows: Numb-ORF (transfected with Numb-ORF plasmid), blank-vector (transfected with pCMV6-entry), and cell-alone group (no DNA). Numb expression in the Numb-ORF groups was significantly higher than that in the controls (P < 0.01). Cell growth was remarkably reduced (P < 0.01), and the number of migrating or invading cells was reduced (P < 0.01) in the Numb-ORF groups compared with controls. Furthermore, the ratio of G0/G1 phase in the Numb-ORF group of 786-O cells was increased, and the S phase fraction and proliferation index was decreased (P < 0.01). Cyclin D1 and MMP-9 expression was reduced in the Numb-ORF groups compared with controls. Here, we have provided data for attenuated Numb expression in the ccRCC cells. Overexpression of Numb could induce G0/G1 phase arrest and inhibit cell proliferation, migration, and invasion. The suppressive effects might be due to downregulation of cyclin D1 or MMP-9 expression. Taken together, our data suggest that Numb may possibly function as a tumor suppressor involved in the carcinogenesis of ccRCC.

Liu YJ, Zhu Y, Yuan HX, et al.
Overexpression of HOXC11 homeobox gene in clear cell renal cell carcinoma induces cellular proliferation and is associated with poor prognosis.
Tumour Biol. 2015; 36(4):2821-9 [PubMed] Related Publications
Novel evidence has confirmed the involvement of dysregulated expression of HOX genes in cancer. HOX genes are a family of 39 transcription factors, divided in four clusters (HOXA to HOXD), that during normal development regulate cell proliferation and specific cell fate. The aim of this study was to investigate whether genes of the HOXC cluster might play a role in renal cancer. The expression of HOXC11 was detected through polymerase chain reaction and immunohistochemical staining, and we demonstrated that HOXC11 was significantly higher in renal cell carcinoma (RCC) compared to normal kidney tissue. We further demonstrated that HOXC11 overexpression in HK-2 human epithelial cell line promoted proliferation, whereas downregulation of HOXC11 endogenous levels in human RCC cells (Caki-2 cells) decreased proliferation. In RCC, expression of HOXC11 and Ki67, a marker of proliferation, correlates strongly with each other (r s  = 0.47, p < 0.003). High immunohistochemical expression of HOXC11 was correlated with T stage (p = 0.06), N stage (p = 0.07), disease stage (p = 0.08), and Ki67 expression (p = 0.07), and patients with tumors showing high number of HOXC11-positive cells had shorter overall survival (p = 0.08) and shorter progression-free survival after treatment (p = 0.08) compared with patients with tumors exhibiting low amount of HOXC11-positive cells. Our data suggest that HOXC11 may contribute to RCC carcinogenesis by increasing tumor cell proliferation and imply that HOXC11 may be an important determinant of RCC patient prognosis.

Hao JF, Ren KM, Bai JX, et al.
Identification of potential biomarkers for clear cell renal cell carcinoma based on microRNA-mRNA pathway relationships.
J Cancer Res Ther. 2014; 10 Suppl:C167-77 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) play important roles in tumor genesis. miRNA dysregulation has been widely studied and demonstrated in clear cell renal cell carcinoma (ccRCC).
MATERIALS AND METHODS: We applied a newly proposed method for selecting miRNAs that discriminate between healthy controls and cancers. We initially extracted different miRNAs and mRNAs and then selected miRNA-mRNA dysregulation pairs. The pathways that involved mRNAs were acquired according to the functional enrichment. We integrated the miRNAs, mRNAs, and pathways and constructed the miRNA-mRNA pathway relationships based on the derived significant miRNAs.
RESULTS: We acquired 566 antiregulated miRNA-mRNA pairs including 56 miRNAs and 485 mRNAs. Three significant pathways related to ccRCC, namely, arginine and proline metabolism, aldosterone-regulated sodium reabsorption, and oxidative phosphorylation, were observed. Based on the miRNA-mRNA pathway relationships, five significant miRNAs were identified as potential biomarkers: hsa-miR-425, hsa-miR-136, hsa-miR-335, hsa-miR-340, and hsa-miR-320d.
CONCLUSION: This integrative network approach revealed important miRNAs in the ccRCC that can identify specific disease biomarkers, which can be used as targets for cancer treatment.

Perrino CM, Hucthagowder V, Evenson M, et al.
Genetic alterations in renal cell carcinoma with rhabdoid differentiation.
Hum Pathol. 2015; 46(1):9-16 [PubMed] Related Publications
Renal cell carcinoma with rhabdoid differentiation (RCC-R) in adult patients is an aggressive variant of renal cancer with no known specific genetic alterations. The aim of this study was to characterize genome-wide genetic aberrations in RCC-R via utilization of high-density single-nucleotide polymorphism (SNP) arrays. We identified 20 cases of RCC-R, which displayed both clear cell renal cell carcinoma and rhabdoid histomorphologic components. DNA was extracted from formalin-fixed, paraffin-embedded tissue (from clear cell renal cell carcinoma and RCC-R areas from each case) and subjected to high-density SNP array assay. Genetic aberrations present in 10% of cases were considered significant. In areas with clear cell histomorphology, gains were most commonly observed in chromosomes 5q (66.7%, 10/15), 7 (46.7%, 7/15), and 8q (46.7%, 7/15); and losses were most commonly identified in chromosomes 14 (60%, 9/15), 8p (46.7%, 7/15), and 22 (46.7%, 7/15). In areas with rhabdoid differentiation, gains were most commonly observed in chromosome 7 (58.8%, 10/17); and losses were most commonly identified in chromosomes 9 (70.6%, 12/17), 14 (58.8%, 10/17), 4 (52.9%, 9/17), and 17p (52.9%, 9/17). Rhabdoid cells shared many chromosomal abnormalities and exhibited a greater number of copy number variations in comparison with coexisting clear cells. Loss of 11p was specific for rhabdoid differentiation, with loss found in 29.4% of rhabdoid components compared with 0% of clear cell areas. The greater number of overall genetic alterations in the rhabdoid cells and the shared genetic background between rhabdoid and clear cell areas suggest genetic evolution of the rhabdoid cells that correlates with histomorphologic progression.

Peckova K, Vanecek T, Martinek P, et al.
Aggressive and nonaggressive translocation t(6;11) renal cell carcinoma: comparative study of 6 cases and review of the literature.
Ann Diagn Pathol. 2014; 18(6):351-7 [PubMed] Related Publications
UNLABELLED: t(6;11) renal cell carcinoma (RCC) has been recognized as a rare and mostly nonaggressive tumor (NAT). The criteria for distinguishing aggressive tumors (AT) from NATs are not well established. A total of 6 cases were selected for the study. Five cases of t(6;11) RCCs behaved nonaggressively, and 1 was carcinoma with aggressive behavior. The tumors were analyzed morphologically using immunohistochemistry and by molecular-genetic methods. The specimen of aggressive t(6;11) RCC was from a 77-year-old woman who died of the disease 2.5 months after diagnosis. The specimens of nonaggressive t(6;11) RCCs were from 3 women and 2 men whose ages range between 15 and 54 years. Follow-up was available in all cases (2.5 months-8 years). The tumor size ranged from 3 to 14 cm in nonaggressive t(6;11) RCC. In the aggressive carcinoma, the tumor size was 12 cm. All tumors (6/6) were well circumscribed. Aggressive t(6;11) RCC was widely necrotic. Six (100%) of 6 all tumors displayed a solid/alveolar architecture with occasional tubules and pseudorosettes. Pseudopapillary formations lined by bizarre polymorphic cells were found focally in the aggressive t(6;11) RCC case. Mitoses, though rare, were found as well. All cases (AT and NAT) were positive for HMB-45, Melan-A, Cathepsin K, and cytokeratins. CD117 positivity was seen in 4 of 5 NATs, as well as in the primary and metastatic lesions of the AT. mTOR was positive in 2 of 5 NATs and vimentin in 4 of 5 NATs. Vimentin was negative in the primary lesion of the AT, as well as in the metastasis found in the adrenal gland. Translocation t(6;11)(Alpha-TFEB) or TFEB break was detected in 4 of 5 NATs and in the AT case. Aggressive tumor showed amplification of TFEB locus. Losses of part of chromosome 1 and chromosome 22 were found in 1 of 5 NATs and in the AT.
CONCLUSIONS: (1) Aggressive t(6;11) RCCs generally occur in the older population in comparison with their indolent counterparts. (2) In regard to the histologic findings in ATs, 3 of 5 so far published cases were morphologically not typical for t(6;11) RCC. Of the 3 cases, 2 cases lacked a small cell component and 1 closely mimicked clear cell-type RCC. (3) Necroses were only present in aggressive t(6;11) RCC. (4) Amplification of TFEB locus was also found only in the aggressive t(6;11) RCC.

Lin YL, Wang YL, Fu XL, Ma JG
Aberrant methylation of PCDH8 is a potential prognostic biomarker for patients with clear cell renal cell carcinoma.
Med Sci Monit. 2014; 20:2380-5 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: PCDH8 is a tumor suppressor that regulates cell adhesin, proliferation, and migration. It is often inactivated by aberrant promoter methylation in several human cancers, including clear cell renal cell carcinoma (CCRCC). The clinical significance of PCDH8 methylation in CCRCC remains unclear. The aim of this study was to investigate the relationship between PCDH8 methylation and clinicopathological characteristics as well as outcome of patients with CCRCC.
MATERIAL/METHODS: The methylation status of PCDH8 in 153 CCRCC tissues and 97 paired adjacent normal renal tissues were examined using methylation-specific PCR (MSP). Then the relationships between PCDH8 methylation and clinicopathological features as well as progression-free survival of CCRCC patients were evaluated.
RESULTS: PCDH8 methylation was significantly more frequent in CCRCC tissues compared with normal renal tissues. Moreover, PCDH8 methylation was significantly correlated with advanced clinical stage (P=0.0141), higher grade (P=0.0190), and lymph node metastasis (P=0.0098). In addition, multivariate analysis showed that PCDH8 methylation was independently associated with poor progression-free survival (P=0.0316).
CONCLUSIONS: PCDH8 methylation is a frequent event in CCRCC and is correlated with unfavorable clinicopathological features. Moreover, PCDH8 methylation may be a useful biomarker to predict the progression of CCRCC.

de Martino M, Taus C, Wessely IS, et al.
The T309G murine double minute 2 gene polymorphism is an independent prognostic factor for patients with renal cell carcinoma.
DNA Cell Biol. 2015; 34(2):107-12 [PubMed] Related Publications
The purpose of this study was to evaluate the association of the T309G MDM2 gene polymorphism with renal cell carcinoma (RCC) risk, pathology, and cancer-specific survival (CSS). T309G MDM2 was genotyped in 449 Caucasians, including 240 with RCC and 209 cancer-free controls. The T309G MDM2 genotype was TT in 174 (38.8%), GT in 214 (47.7%), and GG in 61 (13.6%) subjects, without any significant differences between cases and controls on both univariable (p=0.58) and multivariable logistic regression (each p>0.25). Furthermore, T309G MDM2 was not linked with T stage (p=0.75), N stage (p=0.37), M stage (p=0.94), grade (p=0.21), and subtype (p=0.55). There was, however, a statistically significant association of T309G MDM2 with CSS (p=0.022): patients with TT had significantly worse survival than GG/GT (p=0.009), while those with GT and GG had similar outcomes (p=0.92). The 5-year survival rate for patients with TT, GT, and GG was 69.5%, 84.5%, and 89.7%, respectively. On the multivariable analysis, T309G was identified as an independent prognostic factor. The T309G MDM2 polymorphism is an independent prognostic factor for patients with RCC, with the TT genotype being associated with worse prognosis. In this study, there were no significant associations with RCC risk and pathology.

Chocholatý M, Jáchymová M, Schmidt M, et al.
Polymorphisms of the receptor for advanced glycation end-products and glyoxalase I in patients with renal cancer.
Tumour Biol. 2015; 36(3):2121-6 [PubMed] Related Publications
The receptor for advanced glycation end products (RAGE) and its ligands are involved in the pathogenesis of cancer. Glyoxalase I (GLO1) is an enzyme which detoxifies advanced glycation end product (AGE) precursors. The aim of the study was to find out the relationship between four polymorphisms (single nucleotide polymorphism, SNP) of the RAGE gene (AGER) and one SNP of the GLO1 gene and clear cell renal cancer (ccRCC). All polymorphisms (rs1800625 RAGE -429T/C, rs1800624 -374T/A, rs3134940 2184A/G, rs2070600 557G/A (G82S), and GLO1 rs4746 419A/C(E111A)) were determined by PCR-RFLP in 214 patients with ccRCC. A group of 154 healthy subjects was used as control. We found significant differences in the allelic and genotype frequencies of GLO1 E111A (419A/C) SNP between patients and controls-higher frequency of the C allele in ccRCC-58.6 vs. 44.5% in controls, OR (95% CI) 1.77 (1.32-2.38), p = 0.0002 (corrected p = 0.001); OR (95% CI) CC vs. AA 2.76 (1.5-4.80), p = 0.0004 (corrected p = 0.002); and AC+CC vs. AA 2.03 (1.23-3.30), p = 0.0034 (corrected p = 0.017). High aggressiveness of the tumor (grade 4) was associated with the presence of C allele RAGE -429T/C SNP (original p = 0.001, corrected p = 0.005) and G allele RAGE 2184A/G SNP (p < 0.001 and p < 0.005), and for genotypes RAGE -429CC (original p = 0.008, corrected p = 0.04) and RAGE 2184GG SNP (original p = 0.005, corrected p = 0.025). Our results demonstrate the link of E111A GLO1 SNP to the presence of the tumor and the connection of RAGE -429T/C and 2184A/G SNPs with the aggressiveness of the tumor. Further studies are required, especially with respect to potential therapeutic implications.

Jelaković B, Castells X, Tomić K, et al.
Renal cell carcinomas of chronic kidney disease patients harbor the mutational signature of carcinogenic aristolochic acid.
Int J Cancer. 2015; 136(12):2967-72 [PubMed] Related Publications
Aristolochic acid (AA) is a potent dietary cytotoxin and carcinogen, and an established etiological agent underlying severe human nephropathies and associated upper urinary tract urothelial cancers, collectively designated aristolochic acid nephropathy (AAN). Its genome-wide mutational signature, marked by predominant A:T > T:A transversions occurring in the 5'-CpApG-3' trinucleotide context and enriched on the nontranscribed gene strand, has been identified in human upper urinary tract urothelial carcinomas from East Asian patients and in experimental systems. Here we report a whole-exome sequencing screen performed on DNA from formalin-fixed, paraffin-embedded renal cell carcinomas (RCC) arising in chronic renal disease patients from a Balkan endemic nephropathy (EN) region. In the EN regions, the disease results from the consumption of bread made from wheat contaminated by seeds of Aristolochia clematitis, an AA-containing plant. In five of eight (62.5%) tested RCC tumor specimens, we observed the characteristic global mutational signature consistent with the mutagenic effects of AA. This signature was absent in the control RCC samples obtained from patients from a nonendemic, metropolitan region. By identifying a new tumor type associated with the AA-driven genome-wide mutagenic process in the context of renal disease, our results suggest new epidemiological and public health implications for the RCC incidence worldwide, particularly for the high-risk regions with unregulated use of AA-containing traditional herbal medicines.

Frew IJ, Moch H
A clearer view of the molecular complexity of clear cell renal cell carcinoma.
Annu Rev Pathol. 2015; 10:263-89 [PubMed] Related Publications
The von Hippel-Lindau (VHL) tumor suppressor gene is mutated as an early event in almost all cases of clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer. In this review we discuss recent advances in understanding how dysregulation of the many hypoxia-inducible factor α-dependent and -independent functions of the VHL tumor suppressor protein (pVHL) can contribute to tumor initiation and progression. Recent evidence showing extensive inter- and intratumoral genetic diversity has given rise to the idea that ccRCC should actually be considered as a series of molecularly related, yet distinct, diseases defined by the pattern of combinatorial genetic alterations present within the cells of the tumor. We highlight the range of genetic and epigenetic alterations that recur in ccRCC and discuss the mechanisms through which these events appear to function cooperatively with a loss of pVHL function in tumorigenesis.

Jonasch E, Gao J, Rathmell WK
Renal cell carcinoma.
BMJ. 2014; 349:g4797 [PubMed] Related Publications
The treatment of renal cell carcinoma (RCC) has changed greatly over the past 15 years. Progress in the surgical management of the primary tumor and increased understanding of the molecular biology and genomics of the disease have led to the development of new therapeutic agents. The management of the primary tumor has changed owing to the realization that clean margins around the primary lesion are sufficient to prevent local recurrence, as well as the development of more sophisticated tools and techniques that increase the safety of partial nephrectomy. The management of advanced disease has altered even more dramatically as a result of new agents that target the tumor vasculature or that attenuate the activation of intracellular oncogenic pathways. This review summarizes data from prospective randomized phase III studies on the surgical management and systemic treatment of RCC, and provides an up to date summary of the histology, genomics, staging, and prognosis of RCC. It describes the management of the primary tumor and offers an overview of systemic agents that form the mainstay of treatment for advanced disease. The review concludes with an introduction to the exciting new class of immunomodulatory agents that are currently in clinical trials and may form the basis of a new therapeutic approach for patients with advanced RCC.

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