Somatic Copy Number Alterations and Associated Genes in Clear-Cell Renal-Cell Carcinoma in Brazilian Patients

Fernandes, Flávia Gonçalves; Silveira, Henrique C. S.; Júnior, João Neif Antonio; Silveira, Rosana A; Zucca, Luis Eduardo Rosa; Cárcano, Flavio Mavignier; Sanches, André Octavio Nicolau; Neder, Luciano; Scapulatempo‐Neto, Cristovam; Serrano, Sergio; Jonasch, Eric; Reis, Rui Manuel; Evangelista, Adriane Feijó

doi:10.3390/ijms22052265

Cited by 14 publications

(11 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fernandes et al reported that the most significant copy number alterations in ccRCC were loss of 3p (87.3%), 14q (35.8%) and 6q (29.3%) and increase in 5q (59.7%), 7p (29.3%) and 16q (20.6%). There were 19 related genes localized to important regions of CNA, including SETD2, BAP1, FLT4, PTEN, FGFR4, and NSD1 (70), which is consistent with our findings. Thus, DDR-related genes are involved in tumor heterogeneity through crosstalk with genomic mutations.…”

Section: Discussionsupporting

confidence: 91%

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

Jiang

Song

Xiao

et al. 2022

Front. Public Health

View full text Add to dashboard Cite

BackgroundDNA damage response and repair (DDR) related signatures play an important role in maintaining genome stability and other biological processes. It also affects the occurrence, development, and treatment of cancer. However, in renal cell carcinoma (RCC), especially clear cell renal carcinoma (ccRCC), the potential association between DDR-related signatures and tumor heterogeneity and tumor microenvironment (TME) remains unclear.MethodsUtilizing unsupervised clustering algorithm, we divided RCC into two subgroups, DCS1 and DCS2, according to the differences in DDR gene expression, and compared the characteristics of the two subgroups through multiple dimensions.ResultsCompared with DCS1, DCS2 patients have higher clinical stage/grade and worse prognosis, which may be related to active metabolic status and immunosuppression status. At the same time, the high mutation rate in DCS2 may also be an important reason for the prognosis. We also analyzed the sensitivity of the two subgroups to different therapeutic agents and established a subtypes' biomarkers-based prognostic system with good validation results to provide ideas for clinical diagnosis and treatment. Finally, we identified a pivotal role for DDX1 in the DDR gene set, which may serve as a future therapeutic target.ConclusionThis study showed that DDR has an important impact on the development and treatment of RCC. DCS2 subtypes have a poor prognosis, and more personalized treatment and follow-up programs may be needed. The assessment of DDR gene mutations in patients may be helpful for clinical decision-making. DDX1 may be one of the effective targets for RCC treatment in the future.

show abstract

Section: Discussionsupporting

confidence: 91%

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

Jiang

Song

Xiao

et al. 2022

Front. Public Health

View full text Add to dashboard Cite

show abstract

“…Fernandes et al reported that most significant copy number alterations of ccRCC were loss of 3p (87.3%), 14q (35.8%), and 6q (29.3%) and also gains of 5q (59.7%), 7p (29.3%), and 16q (20.6%). Genes mapping to CNA significant regions included SETD2, BAP1, FLT4, PTEN, FGFR4, and NSD1 (42), which was consistent with our findings. Therefore, IGF regulators were involved in tumor heterogeneity through cross-talk with genome mutations.…”

Section: Discussionsupporting

confidence: 91%

A New Thinking: Deciphering the Aberrance and Clinical Implication of IGF Axis Regulation Pattern in Clear Cell Renal Cell Carcinoma

Jiang

Wang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

RationaleThe recent research found that IGF regulator genes played a pivotal role in multiple biological processes, which may be developed for cancer treatment. However, the characteristics and implication of IGF regulators in cancers, especially in clear cell renal cell carcinoma (ccRCC), remain elusive.MethodsWe systematically analyzed the expression, prognostic valuation, genome variation, and functional implication at pan-cancer level from The Cancer Genome Atlas. According to expression levels of IGF regulator genes, ccRCC could be divided into three different subtypes via unsupervised cluster algorithm: IGF pattern cancer type1 (IPCS1), type2 (IPCS2), and type3 (IPCS3). The immune microenvironment, immunotherapy response, metabolic pattern, and tumor progression signature among the three subgroups were investigated. The clinical characteristics, genomic mutations, and potential drug sensitivity were further analyzed. IGF pattern–related risk model was constructed to predict RCC patients’ outcome. Finally, SHC1, a potential IGF axis target, was comprehensively investigated in ccRCC.ResultsWe found that IGF regulator genes were specifically upregulated in various cancer tissues, which were correlated with copy number variations and dysregulated pathways. IPCS1, IPCS2, and IPCS3 exhibited different clinical profiles and biological characteristics in ccRCC. IPCS3 subtype indicated a higher clinical stage and a worse survival. IPSC3 ccRCC displayed activated metabolic signatures to fuel the cancer progression. IPCS3 subgroup holds a higher tumor mutation burden and lower immune activities, which resulted in a low ICI therapy response and tumor immunity dysfunction state. The genome copy numbers of IPCS2/3, including arm gain and arm loss, were significantly higher than IPCS1. Besides, the drug sensitivity profiles were different among the three subgroups. The prognostic risk model based on subtype’s biomarker exerted a promising performance both in training and validation cohorts. Finally, upregulated expression of SHC1 partly induced poorer immunotherapy response and shorter survival of ccRCC patients.ConclusionTargeting IGF regulators may be functioned as a treatment approach among multi-cancers. IGF regulator–related signature could reshape the tumor immune microenvironment via activating multi-step immune programs. The inhibition of SHC1 may enhance the efficacy of immunotherapy, and SHC1 could be a suitable target for ccRCC therapy.

show abstract

“…Consistent with our study, Fernandes found that the most significant copy number alterations of ccRCC were loss of 3p (87.3%), 14q (35.8%), 6q (29.3%), 9p (28.6%) and 10q (25.0%) and gains of 5q (59.7%), 7p (29.3%) and 16q (20.6%). Genes mapping to CNA significant regions included SETD2, BAP1, FLT4, PTEN, FGFR4 and NSD1 [60]. FGFR4 regulates tumor subtype differentiation and induces metastatic disease in breast cancer [61].…”

Section: Discussionmentioning

confidence: 99%

A new thinking: deciphering the aberrance and clinical implication of copper-death signatures in clear cell renal cell carcinoma

et al. 2022

View full text Add to dashboard Cite

Rationale Recent research has indicated that cuprotosis, or copper induced cell death, is a novel type of cell death that could be utilized as a new weapon for cancer management. However, the characteristics and implications of such signatures in cancers, especially in clear cell renal cell cancer (ccRCC), remain elusive. Methods Expression, methylation, mutation, clinical information, copy number variation, functional implication, and drug sensitivity data at the pan-cancer level were collected from The Cancer Genome Atlas. An unsupervised clustering algorithm was applied to decipher ccRCC heterogeneity. Immune microenvironment construction, immune therapy response, metabolic pattern, and cancer progression signature between subgroups were also investigated. Results Cuprotosis related genes were specifically downregulated in various cancer tissues compared with normal tissues and were correlated with hypermethylation and copy number variation. Cuprotosis scores were also dysregulated in tumor tissues, and we found that such a signature could positively regulate oxidative phosphorylation and Myc and negatively regulate epithelial mesenchymal translation and myogenesis pathways. CPCS1 (cuprotosis scores high) and CPCS2 (cuprotosis scores low) in ccRCC displayed distinctive clinical profiles and biological characteristics; the CPCS2 subtype had a higher clinical stage and a worse prognosis and might positively regulate cornification and epidermal cell differentiation to fuel cancer progression. CPCS2 also displayed a higher tumor mutation burden and low tumor stemness index, while it led to a low ICI therapy response and dysfunctional tumor immunity state. The genome-copy numbers of CPCS2, including arm- gain and arm- loss, were higher than those of CPCS1. The prognostic model constructed based on subgroup biomarkers exerted satisfactory performance in both the training and validation cohorts. In addition, overexpression of the copper death activator DLAT suppressed the malignant ability, including cell migration and proliferation, of renal cell lines in vitro and in vivo. Finally, activation of cuprotosis in tumors could enhance antitumor immunity through dsDNA-cGAS-STING signaling in ccRCC. Conclusion The activation of cuprotosis might function as a promising approach among multiple cancers. The cuprotosis related signatures could reshape tumor immunity in the ccRCC microenvironment via cGAS-STING signal, thus activating tumor antigen-presenting process. Upregulation of DLAT expression in ccRCC cell lines could reactivate the copper death pattern and be treated as a suitable target for ccRCC.

show abstract

Somatic Copy Number Alterations and Associated Genes in Clear-Cell Renal-Cell Carcinoma in Brazilian Patients

Cited by 14 publications

References 53 publications

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

A New Thinking: Deciphering the Aberrance and Clinical Implication of IGF Axis Regulation Pattern in Clear Cell Renal Cell Carcinoma

A new thinking: deciphering the aberrance and clinical implication of copper-death signatures in clear cell renal cell carcinoma

Contact Info

Product

Resources

About