The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What's the Story Morning Glory?
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ABSTRACT:
SUBMITTER: Marchetti A
PROVIDER: S-EPMC8226484 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.
| S-EPMC8345088 | biostudies-literature
Project description:The treatment of advanced and metastatic kidney cancer has been revolutionized by the development of targeted systemic therapies. Despite the growing number of available agents approved for use against clear cell renal cell carcinoma, patients with non-clear histologies, constituting approximately 1 in 4 cases of kidney cancer, have not received the same attention. The majority of clinical trials testing novel targeted therapies have excluded non-clear subtypes, providing limited therapeutic options for patients with these diagnoses and their oncologists. This review will focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma: papillary I and II, chromophobe, and collecting duct. The unique genetic and molecular profiles of each distinct non-clear kidney cancer subtype will be described, as these differences are integral to the development and effectiveness of the novel agents used to treat them. Trials focusing on non-clear kidney cancer, or those that treated clear cell tumors along with significant numbers of non-clear subtypes, will be discussed. The role of cytoreductive nephrectomy and the use of neoadjuvant and adjuvant targeted therapy will be reviewed. Lastly, areas of future research will be highlighted.
| S-EPMC3003336 | biostudies-other
Project description:Different gut microbiota is implicated in different diseases, including cancer. However, gut microbiota differences between individuals with clear cell renal cell carcinoma (ccRCC) and healthy individuals are unclear. Here, we analyzed gut microbiota composition in 51 ccRCC patients and 40 healthy controls using 16S rRNA sequencing analysis. We observed that Blautia, Streptococcus, [Ruminococcus]_torques_group, Romboutsia, and [Eubacterium]_hallii_group were dominant and positively associated with ccRCC. We isolated and cultured Streptococcus lutetiensis to characterize specific gut microbiota that promotes ccRCC and found that it promoted in vitro ccRCC proliferation, migration, and invasion via the TGF-signaling pathway. Interactions identified between the gut microbiota and ccRCC suggest the gut microbiota could serve as a potential non-invasive tool for predicting ccRCC risk and also function as a cancer therapy target.
| S-EPMC9295744 | biostudies-literature
Project description:BackgroundRecurrent mutations in polybromo-1 (PBRM1, ~40%) and BRCA1-associated protein-1 (BAP1, ~10%) occur in clear cell renal cell carcinoma (ccRCC), but their prevalence in non-ccRCC or renal oncocytoma (RO) is unknown. We evaluated loss of PBRM1 and BAP1 staining in ccRCC, papillary RCC (pRCC), chromophobe RCC (chRCC), and RO tumors using an immunohistochemistry assay in which negative staining was associated with loss-of-function mutations.MethodsWe identified 458 patients treated surgically for ccRCC, pRCC, chRCC, and RO between 2004 and 2012. We performed immunohistochemistry assays to evaluate PBRM1 and BAP1 protein expression to classify tumors as PBRM1 or BAP1 negative. We compared loss of staining of these 2 proteins in ccRCC and non-ccRCC using the Fisher exact test.ResultsFor the total cohort of 458 patients, we successfully stained both PBRM1 and BAP1 in 408 tumor samples. Consistent with the mutation rate, loss of PBRM1 and BAP1 staining occurred in 43% (80/187) and 10% (18/187) of ccRCC cases, respectively. However, loss of PBRM1 staining occurred in only 3% (2/59), 6% (1/17), and 0% (0/34) of pRCC, chRCC, and RO tumors, respectively (P<0.0001). BAP1 loss was not observed in any of the pRCC (n = 61), chRCC (n = 17), or RO (n = 34) tumors, (P = 0.00021).ConclusionOur data suggest that biallelic inactivation of PBRM1 or BAP1 is less common in non-ccRCC when compared with ccRCC tumors. These findings suggest that loss of PBRM1 or BAP1 are key events in ccRCC, whereas other pathways may support tumorigenesis in non-ccRCC subtypes.
| S-EPMC4274200 | biostudies-literature
Project description:The category of non-clear cell renal cell carcinoma (nccRCC) includes several clinically, histologically, and molecularly diverse entities. Traditionally, they comprise type 1 and type 2 papillary, chromophobe, unclassified, and other histologies (medullary, collecting duct carcinoma, and translocation-associated). Molecular knowledge has allowed the identification of some other specific subtypes, such as fumarate hydratase–deficient renal cell carcinoma (RCC) or succinate dehydrogenase–associated RCC. In addition, it has recognized some alterations with a possible predictive role, e.g., MET proto-oncogene receptor tyrosine kinase (MET) alterations in papillary tumors. Standard therapies for the management of advanced clear cell RCC (ccRCC), i.e., vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and mammalian target of rapamycin inhibitors, have shown poorer results in nccRCC patients. Therefore, there is a need to improve the efficacy of the treatment for advanced nccRCC. Immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting programmed death 1/programmed death ligand 1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), has demonstrated a significant survival benefit in several malignant neoplasias, including ccRCC, with a proportion of patients achieving long survival. The combinations of ICI or ICI + VEGFR tyrosine kinase inhibitors (TKIs) are the standard of care in advanced ccRCC. Unfortunately, major pivotal trials did not include specific nccRCC populations. In recent years, several studies have retrospectively or prospectively evaluated ICIs alone or in combination with another ICI or with TKIs in nccRCC patients. In this article, we review data from available trials in order to elucidate clinical and molecular profiles that could benefit from immunotherapy approaches.
| S-EPMC9936973 | biostudies-literature
Project description: Not available
| S-EPMC9882438 | biostudies-literature
Project description:Background and objectivePrevious germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types.MethodsWe first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events.Key findings and limitationsClear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL.Conclusions and clinical implicationsThis analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants.Patient summaryIn this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.
| S-EPMC10940785 | biostudies-literature
Project description:A total of 3 metastatic and 3 non-metastatic ccRCC tissues were collected from patients. These tissues were flash frozen in liquid nitrogen immediately after surgery and subsequently stored at -80℃. All the resected nodules or metastatic masses were identified as renal tumor by pathologic examination. No patients received anticancer treatments before surgery in this study. We analyzed gene expression microarray data from our gene chip with 3 metastatic ccRCC tissues compared with 3 non-metastatic ccRCC tissues.
2017-08-17 | GSE88948 | GEO
Project description:Nivolumab is approved for patients with metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. The clinical activity of nivolumab in patients with non-clear cell RCC subtypes remains unknown as these patients were excluded from the original nivolumab trials.Patients from 6 centers in the United States who received at least one dose of nivolumab for non-clear cell mRCC between 12/2015 and 06/2017 were identified. A retrospective analysis including patient characteristics, objective response rate according to RECIST v1.1 and treatment-related adverse events (TRAEs) was undertaken.Forty-one patients were identified. Median age was 58 years (33-82), 71% were male, and majority had ECOG PS 0 (40%) or 1 (47%). Histology included 16 papillary, 14 unclassified, 5 chromophobe, 4 collecting duct, 1 Xp11 translocation and 1 MTSCC (mucinous tubular and spindle cell carcinoma). Among 35 patients who were evaluable for best response, 7 (20%) had PR and 10 (29%) had SD. Responses were observed in unclassified, papillary and collecting duct subtypes. In the entire cohort, median follow-up was 8.5 months and median treatment duration was 3.0 months. Median PFS was 3.5 months and median OS was not reached. Among responders, median time to best response was 5.1 months, and median duration of response was not reached as only 2 out of 7 responders had disease progression during follow-up. TRAEs of any grade were noted in 37% and most commonly included fatigue (12%), fever (10%) and rash (10%). Nivolumab treatments were postponed in 34% and discontinued in 15% of patients due to intolerance. No treatment-related deaths were observed.Nivolumab monotherapy demonstrated objective responses and was well tolerated in a heterogeneous population of patients with non-clear cell mRCC. In the absence of other data in this treatment setting, this study lends support to the use of nivolumab for patients with metastatic non-clear cell renal cell carcinoma.
| S-EPMC5789686 | biostudies-other
Project description:Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. Micro-RNAs (miRNAs) are small noncoding RNAs that play a crucial role in regulating gene expression and are involved in various biological processes, including cancer development. To better understand the biology of this tumor, we aimed to analyze the miRNA expression profile of a set of CCPRCC using microarray and quantitative reverse transcription-polymerase chain reaction. A total of 15 cases diagnosed as CCPRCC were used in this study. Among the most differentially expressed miRNA in CCPRCC, we found miR-210, miR-122, miR-34a, miR-21, miR-34b*, and miR-489 to be up-regulated, whereas miR-4284, miR-1202, miR-135a, miR-1973, and miR-204 were down-regulated compared with normal renal parenchyma. To identify consensus of differentially regulated miRNA between CCPRCC, CCRCC, and PRCC, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798). This comparison revealed that the miRNA expression profile of CCPRCC shows some overlapping characteristics between CCRCC and PRCC. Moreover, CCPRCC lacks dysregulation of important miRNAs typically associated with aggressive behavior. In summary, we describe the miRNA expression profile of a relatively infrequent type of renal cancer. Our results may help in understanding the molecular underpinning of this newly recognized entity.
| S-EPMC4332813 | biostudies-literature