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Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

ABSTRACT: The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male (case-only odds ratio [OR] 2.68, 95% confidence interval [CI] 1.43-5.03). In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs <25 kg/m² ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs 10th percentile). In a meta-analysis of case-only results including three patient cohorts, we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors.

SUBMITTER: Purdue MP

PROVIDER: S-EPMC8628648 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

Purdue Mark P MP Rhee Jongeun J Moore Lee L Gao Xiaohua X Sun Xuezheng X Kirk Erin E Bencko Vladimir V Janout Vladimir V Mates Dana D Zaridze David D Petruzella Stacey S Hakimi Abraham Ari AA Linehan William Marston WM Chanock Stephen J SJ Brennan Paul P Furberg Helena H Troester Melissa M Rothman Nathaniel N

International journal of cancer 20210610 7

The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences acro ...[more]

PMID: 34058014

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Project description:BackgroundIntratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.ObjectiveTo evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors.Design, setting, and participantsWe identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors.Outcome measurements and statistical analysisPrimary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival.Results and limitationsIntratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3-60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10-42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32-55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy.ConclusionsApproximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor.Patient summaryPrimary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment.

Project description:Background: RNA methylation modification plays an important role in immune regulation. m7G RNA methylation is an emerging research hotspot in the RNA methylation field. However, its role in the tumor immune microenvironment of kidney renal clear cell carcinoma (KIRC) is still unclear. Methods: We analyzed the expression profiles of 29 m7G regulators in KIRC, integrated multiple datasets to identify a novel m7G regulator-mediated molecular subtype, and developed the m7G score. We evaluated the immune tumor microenvironments in m7G clusters and analyzed the correlation of the m7G score with immune cells and drug sensitivity. We tested the predictive power of the m7G score for prognosis of patients with KIRC and verified the predictive accuracy of the m7G score by using the GSE40912 and E-MTAB-1980 datasets. The genes used to develop the m7G score were verified by qRT-PCR. Finally, we experimentally analyzed the effects of WDR4 knockdown on KIRC proliferation, migration, invasion, and drug sensitivity. Results: We identified three m7G clusters. The expression of m7G regulators was higher in cluster C than in other clusters. m7G cluster C was related to immune activation, low tumor purity, good prognosis, and low m7G score. Cluster B was related to drug metabolism, high tumor purity, poor survival, and high m7G score. Cluster A was related to purine metabolism. The m7G score can well-predict the prognosis of patients with KIRC, and its prediction accuracy based on the m7G score nomogram was very high. Patients with high m7G scores were more sensitive to rapamycin, gefitinib, sunitinib, and vinblastine than other patients. Knocking down WDR4 can inhibit the proliferation, migration, and invasion of 786-0 and Caki-1 cells and increase sensitivity to sorafenib and sunitinib. Conclusion: We proposed a novel molecular subtype related to m7G modification and revealed the immune cell infiltration characteristics of different subtypes. The developed m7G score can well-predict the prognosis of patients with KIRC, and our research provides a basis for personalized treatment of patients with KIRC.

Project description:Background: Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor of the urinary system. Surgery is the preferred treatment option; however, the rate of distant metastasis is high. Mast cells in the tumor microenvironment promote or inhibit tumorigenesis depending on the cancer type; however, their role in KIRC is not well-established. Here, we used a bioinformatics approach to evaluate the roles of mast cells in KIRC. Methods: To quantify mast cell abundance based on gene sets, a single-sample gene set enrichment analysis (ssGSEA) was utilized to analyze three datasets. Weighted correlation network analysis (WGCNA) was used to identify the genes most closely related to mast cells. To identify new molecular subtypes, the nonnegative matrix factorization algorithm was used. GSEA and least absolute shrinkage and selection operator (LASSO) Cox regression were used to identify genes with high prognostic value. A multivariate Cox regression analysis was performed to establish a prognostic model based on mast cell-related genes. Promoter methylation levels of mast cell-related genes and relationships between gene expression and survival were evaluated using the UALCAN and GEPIA databases. Results: A prolonged survival in KIRC was associated with a high mast cell abundance. KIRC was divided into two molecular subtypes (cluster 1 and cluster 2) based on mast cell-related genes. Genes in Cluster 1 were enriched for various functions related to cancer development, such as the TGFβ signaling pathway, renal cell carcinoma, and mTOR signaling pathway. Based on drug sensitivity predictions, sensitivity to doxorubicin was higher for cluster 2 than for cluster 1. By a multivariate Cox analysis, we established a clinical prognostic model based on eight mast cell-related genes. Conclusion: We identified eight mast cell-related genes and constructed a clinical prognostic model. These results improve our understanding of the roles of mast cells in KIRC and may contribute to personalized medicine.

Project description:Copper toxicity involves the destruction of mitochondrial metabolic enzymes, triggering an unusual mechanism of cell death called cuproptosis, which proposes a novel approach using copper toxicity to treat cancer. However, the biological function of cuproptosis has not been fully elucidated in kidney renal clear cell carcinoma (KIRC). Using the expression profile of 13 cuproptosis regulators, we first identified two molecular subtypes related to cuproptosis defined as "hot tumor" and "cold tumor", having different levels of biological function, clinical prognosis, and immune cell infiltration. We obtained three gene clusters using the differentially expressed genes between the two cuproptosis-related subtypes, which were associated with different molecular activities and clinical characteristics. Next, we developed and validated a cuproptosis prognostic model that included two genes (FDX1 and DBT). The calculated risk score could divide patients into high- and low-risk groups. The high-risk group had a poorer prognosis, lower level of immune infiltration, higher frequency of gene alterations, and greater levels of FDX1 methylation and limited DBT methylation. The risk score was also an independent predictive factor for overall survival in KIRC. The established nomogram calculating the risk score achieved a high predictive ability for the prognosis of individual patients (area under the curve: 0.860). We then identified small molecular inhibitors as potential treatments and analyzed the sensitivity to chemotherapy of the signature genes. Tumor immune dysfunction and exclusion (TIDE) showed that the high-risk group had a higher level of TIDE, exclusion and dysfunction that was lower than the low-risk group, while the microsatellite instability of the high-risk group was significantly lower. The results of two independent immunotherapy datasets indicated that cuproptosis regulators could influence the response and efficacy of immunotherapy in KIRC. Our study provides new insights for individualized and comprehensive therapy of KIRC.

Project description:Background: Histone acetylation modification has been found to be correlated the development of renal carcinoma; however, its role in clear cell renal carcinoma (ccRCC) remains to be investigated. Thus, this study aimed to identify the molecular subtypes and establish a relevant score based on histone acetylation modification in ccRCC. Methods: Gene expression and mutation data were retrieved from The Cancer Genome Atlas database. Molecular subtypes were identified by unsupervised clustering based on histone acetylation regulators expression, and the molecular and clinical characteristics including survival, tumor microenvironment, gene set variation, immune cell infiltration, and immune checkpoints in each subtype were investigated. Next, we employed univariate Cox analysis to analyze these genes and established acetylation-related score by lasso regression analysis. Furthermore, we investigated the differences including survival, signaling pathways, mutational landscape, and tumor mutation burden (TMB) between high-risk and low-risk groups. The established score was validated by receiver operating curve and univariate and multivariate Cox regression analyses. We also established a nomogram including acetylation score, age, gender, grade, and stage and verified it by decision curve analysis and calibration plot. The E-MTAB-1980 cohort from the ArrayExpress database was employed as a reference to validate the established score. Results: Thirty-three types of histone acetylation regulators were employed in this study, and two clusters were identified. The two clusters presented significant differences in survival, tumor microenvironment, immune cell infiltration, immune checkpoints, and signaling pathways. Furthermore, an acetylation-related score, composed of six genes (BRD9, HDAC10, KAT2A, KAT5, BRDT, SIRT1, KAT6A, HDAC5), was verified to be significantly associated with prognosis and TMB. Thus, the established scores were successfully verified by the validated cohort, and the nomogram was constructed and successfully validated. Conclusion: The identification of the histone acetylation-related subtypes and score in our study may help reveal the potential relation between histone acetylation and immunity and provide novel insights for the development of individualized therapy for ccRCC.

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Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

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Differences in risk factors for molecular subtypes of clear cell renal cell carcinoma.

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