Characterization of the basement membrane in kidney renal clear cell carcinoma to guide clinical therapy

Abstract

BackgroundRenal cell carcinoma (RCC) is the most common kidney cancer in adults. According to the histological features, it could be divided into several subtypes, of which the most common one is kidney renal clear cell carcinoma (KIRC), which contributed to more than 90% of cases for RCC and usually ends with a dismal outcome. Previous studies suggested that basement membrane genes (BMGs) play a pivotal role in tumor development. However, the significance and prognostic value of BMGs in KIRC still wrap in the mist.MethodsKIRC data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. A prognostic risk score (PRS) model based on BMGs was established using univariate and least absolute shrinkage and selection operator (LASSO) and the Cox regression analysis was performed for prognostic prediction. The Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, receiver operating characteristic (ROC) curves, nomogram, and calibration curves were utilized to evaluate and validate the PRS model. All KIRC cases were divided into the high-risk score (HRS) group and the low-risk score (LRS) group according to the median risk scores. In addition, single-sample gene set enrichment analysis (ssGSEA), immune analysis, tumor microenvironment (TME) analysis, principal component analysis (PCA), and half-maximal inhibitory concentration (IC50) were also applied. Expression levels of BMGs were confirmed by qRT-PCR in both human renal cancer cell lines and tissues.ResultsWe established the BMGs-based prognostic model according to the following steps. Within the TCGA cohort, patients’ prognosis of the HRS group was significantly worse than that of the LRS group, which was consistent with the analysis results of the GEO cohort. PCA patterns were significantly distinct for LRS and HRS groups and pathological features of the HRS group were more malignant compared with the LRS group. Correlation analysis of the PRS model and TME features, such as immune cell scores, stromal cell scores, and ESTIMATE values, revealed a higher immune infiltration in the HRS group compared with the LRS group. The chemotherapeutic response was also evaluated in KIRC treatment. It showed that the HRS group exhibited stronger chemoresistance to chemotherapeutics like FR-180204, GSK1904529A, KIN001-102, and YM201636. The therapeutic reactivity of the other 27 chemotherapeutic agents was summarized as well. Furthermore, the FREM2 level was measured in both human kidney tissues and associated cell lines, which suggested that lower FREM2 expression prompts a severer pathology and clinical ending.ConclusionsOur study showed that KIRC is associated with a unique BMG expression pattern. The risk scores related to the expression levels of 10 BMGs were assessed by survival status, TME, pathological features, and chemotherapeutic resistance. All results suggested that FREM2 could be a potential candidate for KIRC prognosis prediction. In this study, we established a valid model and presented new therapeutic targets for the KIRC prognosis prediction as well as the clinical treatment recommendation, and finally, facilitated precision tumor therapy for every single individual.

Unravelling the complexity of kidney renal clear cell carcinoma prognosis: integrating chromatin regulators, gene signatures and associated immune landscapes

“…The current therapeutic arsenal for kidney renal clear cell carcinoma encompasses surgical resection, radiotherapy, and chemotherapy. Unfortunately, this malignancy exhibits robust resistance to these modalities, with recurrence and metastasis persisting even after the radical resection of the primary mass [28][29][30]. The limited e cacy of these interventions necessitates the exploration of alternative avenues, leading molecularly targeted therapies to emerge as a prominent choice for advanced kidney renal clear cell carcinoma [31].…”

Assessment of the progression of kidney renal clear cell carcinoma using transcriptional profiles revealed new cancer subtypes with variable prognosis

“…Coefficient value In terms of the cellular component (CC), KIRC DEGs were significantly enriched in functional elements such as basement membrane (BM). According to a recent study, KIRC is associated with unique basement membrane gene expression patterns, and the characterization of the BM has the potential to guide clinical therapy (Xiong et al, 2022). Cellular component, collagen trimer has been similarly found in studies focused on renal cancer progression , along with molecular function enriched extracellular matrix structural constituent and platelet-derived growth factor binding van Roeyen et al, 2019).…”

“…Multiple different forms of kidney tumors make up the complex disease known as kidney cancer (Hu et al, 2019). Renal cell carcinoma (RCC) is a heterogeneous group of kidney parenchyma tumors that can be further divided into histologically defined subtypes (Znaor et al, 2015;Casuscelli et al, 2017;Xiong et al, 2022). The different subtypes have undergone multiple revisions in the past two decades, due to advancements in the morphological as well as molecular characterization of renal tumors (Kovacs et al, 1997;Lopez-Beltran et al, 2006;Srigley et al, 2013;Moch et al, 2016;Udager and Mehra, 2016).…”

Identification of a basement membrane-based risk scoring system for prognosis prediction and individualized therapy in clear cell renal cell carcinoma

“…The predictive capability of the nomogram for 3-and 5-year survival was assessed by calibration plot. Besides, decision curve analysis (DCA) was utilized to compare the net benefit of BMRS, AJCC stage and two previous BM-related gene signatures (Zhou et al, 2022a;Xiong et al, 2022) in predicting 3-and 5-year survival of ccRCC. TCGA cohort was separated into high and low risk groups according to the median of nomogram scores and was analyzed to identify their survival difference.…”