Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity

Shuch, Brian; Amin, Ali; Armstrong, Andrew J.; Eble, John N.; Ficarra, Vincenzo; López-Beltrán, Antonio; Martignoni, Guido; Rini, Brian I.; Kutikov, Alexander

doi:10.1016/j.eururo.2014.04.029

Cited by 461 publications

(388 citation statements)

References 103 publications

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“…However, among individuals with stage IV disease, it occurs in 15% (1,2). Although once believed to represent a distinct subtype of RCC, it is now considered a specific histologic feature (3). Whereas sarcomatoid features are found in all forms of kidney cancer, >65% of cases are found with clear cell RCC (ccRCC) (4,5).…”

Section: −17mentioning

confidence: 99%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

Bi¹

2016

JCO

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The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs,), increased frequency of nonsynonymous SSNVs in PanCancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10 −17 ); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

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Section: −17mentioning

confidence: 99%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

Bi¹

2016

JCO

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“…Among the different histological types, clear cell RCC (ccRCC) is the most common subtype and accounts for approximately 70-75% of RCC [2]. Despite the widespread use of imaging in examinations, about 17% of all RCCs have distant metastases at the time of diagnosis and about 30% of patients treated for localized RCC will relapse [3,4].…”

Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA LUCAT1 Promotes Proliferation and Invasion in Clear Cell Renal Cell Carcinoma Through AKT/GSK-3β Signaling Pathway

Zheng

Zhao

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long non-coding RNAs (lncRNAs) have emerged as new regulators and biomarkers in several cancers. However, few lncRNAs have been well characterized in clear cell renal cell carcinoma (ccRCC). Methods: We investigated the lncRNA expression profile by microarray analysis in 5 corresponding ccRCC tissues and adjacent normal tissues. Lung cancer–associated transcript 1 (LUCAT1) expression was examined in 90 paired ccRCC tissues by real-time PCR and validated by The Cancer Genome Atlas (TCGA) database. Kaplan-Meier analysis was used to examine the prognostic value of LUCAT1 and CXCL2 in ccRCC patients. Loss and gain of function were performed to explore the effect of LUCAT1 on proliferation and invasion in ccRCC cells. Western blotting was performed to evaluate the underlying mechanisms of LUCAT1 in ccRCC progression. Chemokine stimulation assay was performed to investigate possible mechanisms controlling LUCAT1 expression in ccRCC cells. Enzyme-linked immunosorbent assays were performed to determine serum CXCL2 in ccRCC patients and healthy volunteers. Receiver operating characteristic curve analysis was performed to examine the clinical diagnostic value of serum CXCL2 in ccRCC. Results: We found that LUCAT1 was significantly upregulated in both clinical ccRCC tissues (n = 90) and TCGA ccRCC tissues (n = 448) compared with normal tissues. Statistical analysis revealed that the LUCAT1 expression level positively correlated with tumor T stage (P < 0.01), M stage (P < 0.01), and TNM stage (P < 0.01). Overall survival and disease-free survival time were significantly shorter in the high-LUCAT1-expression group than in the low-LUCAT1-expression group (log-rank P < 0.01). LUCAT1 knockdown inhibited ccRCC cell proliferation and colony formation, induced cell cycle arrest at G1 phase, and inhibited cell migration and invasion. Overexpression of LUCAT1 promoted proliferation, migration, and invasion of ccRCC cells. Mechanistic investigations showed that LUCAT1 induced cell cycle G1 arrest by regulating the expression of cyclin D1, cyclin-dependent kinase 4, and phosphorylated retinoblastoma transcriptional corepressor 1. Moreover, LUCAT1 promoted proliferation and invasion in ccRCC cells partly through inducing the phosphorylation of AKT and suppressing the phosphorylation of GSK-3β. We also revealed that chemokine CXCL2, upregulated in ccRCC, induced LUCAT1 expression and might be a diagnostic and prognostic biomarker in ccRCC. Conclusions: LUCAT1 was upregulated in ccRCC tissues and renal cancer cell lines, and significantly correlated with malignant stage and poor prognosis in ccRCC. LUCAT1 promoted proliferation and invasion in ccRCC cells through the AKT/GSK-3β signaling pathway. We also revealed that LUCAT1 overexpression was induced by chemokine CXCL2. These findings indicate that the CXCL2/LUCAT1/AKT/GSK-3β axis is a potential therapeutic target and molecular biomarker for ccRCC.

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“…The majority of cases of RCC are sporadic, whereas hereditary forms comprise only 2-3% of all cases (6). The most common subtypes of RCC are clear cell RCC (70-75% of cases), papillary RCC (10-16%) and chromophobe RCC (5%), which primarily metastasize to the lung, liver, bones and brain (7). Patients with RCC are usually asymptomatic and are often coincidentally diagnosed during an imaging procedure; as a result, 25-30% of patients already have metastatic RCC (mRCC) at the time of diagnosis (8).…”

Section: Introductionmentioning

confidence: 99%

Sunitinib does not impair natural killer cell function in patients with renal cell carcinoma

et al. 2017

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Abstract. Although the available treatment options have expanded, the survival of patients with metastatic renal cell carcinoma (RCC) remains poor. As patients with RCC lack responsiveness to chemotherapy or radiation, therapeutic options predominantly include surgical interventions and immunomodulatory approaches, including the administration of tyrosine kinase inhibitors (TKIs) such as sunitinib. Natural killer (NK) cells have been reported to be key players in TKI-mediated off-target effects on the immune system. However, only limited information is available regarding the possible impact of sunitinib on the function of NK cells of individual patients. The present study reports on the immunomonitoring results of three patients with metastatic RCC who underwent sunitinib treatment. These results were compared with age-matched, healthy controls in terms of the immune status of T, B and NK cells, focusing on functional in vitro analyses of NK cells. In all three patients, NK cell number, subset distribution and function, as measured by cluster of differentiation 107a degranulation, did not exhibit any significant alterations as a result of sunitinib treatment. These results indicate that sunitinib does not negatively affect NK cell function, which supports the pursuit of therapeutic modalities that combine immunomodulation and NK cell-stimulating approaches.

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Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity

Cited by 461 publications

References 103 publications

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

Long Non-Coding RNA LUCAT1 Promotes Proliferation and Invasion in Clear Cell Renal Cell Carcinoma Through AKT/GSK-3β Signaling Pathway

Sunitinib does not impair natural killer cell function in patients with renal cell carcinoma

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