Genomic Instability Promotes the Progression of Clear Cell Renal Cell Carcinoma Through Influencing the Immune Microenvironment

Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression.Methods: The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores.Results: In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset.Conclusion: In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs.

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Pancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear-cell renal cell carcinoma: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-021-02768-8 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Lena Haeberle ◽

Melanie Busch ◽

Julian Kirchner ◽

Georg Fluegen ◽

Gerald Antoch ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Pancreatic Ductal Adenocarcinoma ◽

Renal Cell ◽

Clear Cell ◽

Ductal Adenocarcinoma ◽

Special Role ◽

Cell Renal Cell Carcinoma ◽

Pancreatic Metastases

Abstract Background Metastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma. Case presentation We present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body. Conclusions Renal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.

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Chromosome 9p deletions are an independent predictor of tumor progression following nephrectomy in patients with localized clear cell renal cell carcinoma

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2013.12.008 ◽

2014 ◽

Vol 32 (5) ◽

pp. 601-606 ◽

Cited By ~ 11

Author(s):

Daniel de Oliveira ◽

Marcos F. Dall’Oglio ◽

Sabrina T. Reis ◽

Marcelo Zerati ◽

Isida C. Souza ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Progression ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Independent Predictor ◽

Cell Renal Cell Carcinoma ◽

Chromosome 9P

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Exploring the Role of HIF-2α Inhibition in Advanced Clear Cell Renal Cell Carcinoma

Default Digital Object Group ◽

10.1200/adn.21.200566 ◽

2021 ◽

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma

Scientific Reports ◽

10.1038/s41598-017-10134-2 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 10

Author(s):

Fujiang Xu ◽

Kun Chang ◽

Jian Ma ◽

Yuanyuan Qu ◽

Huyang Xie ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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Development and Interpretation of a Genomic Instability Derived lncRNAs Based Risk Signature as a Predictor of Prognosis for Clear Cell Renal Cell Carcinoma Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.678253 ◽

2021 ◽

Vol 11 ◽

Author(s):

Huiying Yang ◽

Xiaoling Xiong ◽

Hua Li

Keyword(s):

Renal Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Genomic Instability ◽

Renal Cell ◽

Clear Cell ◽

Expression Profiles ◽

Enrichment Analysis ◽

Cell Renal Cell Carcinoma ◽

Prognosis Prediction

BackgroundClear cell renal cell carcinoma (ccRCC) is a kind of frequently diagnosed cancer, leading to high death rate in patients. Genomic instability (GI) is regarded as playing indispensable roles in tumorigenesis and impacting the prognosis of patients. The aberrant regulation of long non-coding RNAs (lncRNAs) is a main cause of GI. We combined the somatic mutation profiles and expression profiles to identify GI derived lncRNAs (GID-lncRNAs) in ccRCC and developed a GID-lncRNAs based risk signature for prognosis prediction and medication guidance.MethodsWe decided cases with top 25% cumulative number of somatic mutations as genomically unstable (GU) group and last 25% as genomically stable (GS) group, and identified differentially expressed lncRNAs (GID-lncRNAs) between two groups. Then we developed the risk signature with all overall survival related GID-lncRNAs with least absolute shrinkage and selection operator (LASSO) Cox regression. The functions of the GID-lncRNAs were partly interpreted by enrichment analysis. We finally validated the effectiveness of the risk signature in prognosis prediction and medication guidance.ResultsWe developed a seven-lncRNAs (LINC00460, AL139351.1, AC156455.1, AL035446.1, LINC02471, AC022509.2, and LINC01606) risk signature and divided all samples into high-risk and low-risk groups. Patients in high-risk group were in more severe clinicopathologic status (higher tumor grade, pathological stage, T stage, and more metastasis) and were deemed to have less survival time and lower survival rate. The efficacy of prognosis prediction was validated by receiver operating characteristic analysis. Enrichment analysis revealed that the lncRNAs in the risk signature mainly participate in regulation of cell cycle, DNA replication, material metabolism, and other vital biological processes in the tumorigenesis of ccRCC. Moreover, the risk signature could help assess the possibility of response to precise treatments.ConclusionOur study combined the somatic mutation profiles and the expression profiles of ccRCC for the first time and developed a GID-lncRNAs based risk signature for prognosis predicting and therapeutic scheme deciding. We validated the efficacy of the risk signature and partly interpreted the roles of the seven lncRNAs composing the risk signature in ccRCC. Our study provides novel insights into the roles of genomic instability derived lncRNAs in ccRCC.

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