MP71-10 CLINICAL FEATURES OF RECURRENT SOMATIC MUTATIONS IN CLEAR CELL RENAL CELL CARCINOMA: A LARGE COHORT

Abstract Background clear cell renal cell carcinoma (ccRCC) has been the commonest renal cell carcinoma (RCC). Although the disease classification, diagnosis and targeted therapy of RCC has been increasingly evolving attributing to the rapid development of current molecular pathology, the current situation is still challenge considering the comprehensive and progressively developing nature of malignant cancer. The study is to identify more potential responsible genes during the development of ccRCC using bioinformatic analysis, thus aiding more precise interpretation of the disease. Methods Firstly, different cDNA expression profiles from Gene Expression Omnibus (GEO) online database were used to screen the abnormal differently expressed genes (DEGs) between ccRCC and normal renal tissues. Then, based on the protein-protein interaction network (PPI) of all DEGs, the module analysis was performed to scale down the potential genes, and further survival analysis assisted our proceeding to the next step for selecting a credible key gene. Thirdly, immunohistochemistry (IHC) and quantitative real-time PCR (QPCR) were conducted to validate the expression change of the key gene in ccRCC comparing to normal tissues, meanwhile the prognostic value was verified using TCGA clinical data. Lastly, the potential biological function and signaling mechanism of gene regulation during ccRCC development was preliminary explored. Results Four cDNA expression profiles were picked from GEO database based on the number of containing sample cases, and a total of 192 DEGs, including 39 up-regulated and 153 down-regulated genes were shared in four profiles. Based on the DEGs PPI network, four function modules were identified highlighting a FGF1 gene involving PI3K-AKT signaling pathway which was shared in 3/4 modules. Further, both the IHC performed on 104 local ccRCC samples containing tissue microarray and QPCR conducted using 30 different samples confirmed that FGF1 was aberrant lost in ccRCC. And Kaplan-Meier overall survival analysis revealed that FGF1 gene loss was related to worse ccRCC patients survival. Lastly, the pathological clinical features of FGF1 gene and the probable biological functions and signaling pathways it involved were analyzed using TCGA clinical data. Conclusions Using bioinformatic analysis, we revealed that FGF1 expression was aberrant lost in ccRCC which correlated statistical significantly with patients survival, and the gene’s clinical features and potential biological functions were also explored. However, more detailed experiments and clinical trials are needed to support its potential drug-target role in clinical medical use.

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Characterization of Hypoxia-Related Molecular Subtypes in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy and Targeted Therapy via Multi-Omics Analysis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.684050 ◽

2021 ◽

Vol 8 ◽

Author(s):

Weimin Zhong ◽

Hongbin Zhong ◽

Fengling Zhang ◽

Chaoqun Huang ◽

Yao Lin ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Clear Cell ◽

Molecular Subtypes ◽

Cell Renal Cell Carcinoma ◽

Cox Regression Analysis ◽

Tumor Purity

Objective: Tumor hypoxia is a key factor in resistance to anti-cancer treatment. Herein, this study aimed to characterize hypoxia-related molecular subtypes and assess their correlations with immunotherapy and targeted therapy in clear cell renal cell carcinoma (ccRCC).Materials: We comprehensively analyzed copy number variation (CNV), somatic mutation, transcriptome expression profile and clinical information for ccRCC from TCGA and ICGC databases. Based on 98 prognosis-related hypoxia genes, samples were clustered using unsupervized non-negative matrix factorization (NMF) analysis. We characterized the differences between subtypes concerning prognosis, CNV, somatic mutations, pathways, immune cell infiltrations, stromal/immune scores, tumor purity, immune checkpoint inhibitors (ICI), response to immunotherapy and targeted therapy and CXC chemokines. Based on differentially expressed genes (DEGs) between subtypes, a prognostic signature was built by LASSO Cox regression analysis, followed by construction of a nomogram incorporating the signature and clinical features.Results: Two hypoxia-related molecular subtypes (C1 and C2) were constructed for ccRCC. Differential CNV, somatic mutations and pathways were found between subtypes. C2 exhibited poorer prognosis, higher immune/stromal scores, and lower tumor purity than C1. Furthermore, C2 had more sensitivity to immunotherapy and targeted therapy than C1. The levels of CXCL1/2/3/5/6/8 chemokines in C2 were distinctly higher than in C1. Consistently, DEGs between subtypes were significantly enriched in cytokine-cytokine receptor interaction and immune responses. This subtype-specific signature can independently predict patients’ prognosis. Following verification, the nomogram could be utilized for personalized prediction of the survival probability.Conclusion: Our findings characterized two hypoxia-related molecular subtypes for ccRCC, which can assist in identifying high-risk patients with poor clinical outcomes and patients who can benefit from immunotherapy or targeted therapy.

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Comprehensive Genomic Analysis of Metastatic Non–Clear-Cell Renal Cell Carcinoma to Identify Therapeutic Targets

JCO Precision Oncology ◽

10.1200/po.18.00372 ◽

2019 ◽

pp. 1-18 ◽

Cited By ~ 2

Author(s):

Maria I. Carlo ◽

Nabeela Khan ◽

Ahmet Zehir ◽

Sujata Patil ◽

Yasser Ged ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Clear Cell ◽

De Novo ◽

Genomic Analysis ◽

Precision Oncology ◽

Single Nucleotide Variants ◽

Cell Renal Cell Carcinoma

PURPOSENon–clear-cell renal cell carcinoma (nccRCC) encompasses approximately 20% of renal cell carcinomas and includes subtypes that vary in clinical and molecular biology. Compared with clear cell renal cell carcinoma, nccRCC demonstrates limited sensitivity to conventional vascular endothelial growth factor– and mammalian target of rapamycin–directed agents, indicating a need for better therapies. Characterizing the genomic landscape of metastatic nccRCC variants may help define novel therapeutic strategies.PATIENTS AND METHODSWe retrospectively analyzed tumor tissue from patients with metastatic nccRCC who consented to genomic analysis of their tumor and germline DNA. A hybridization capture–based assay was used to identify single nucleotide variants and small insertions and deletions across more than 340 cancer-associated genes with germline comparison. Clinical actionability of somatic mutations was assessed using OncoKB levels of evidence. Microsatellite instability (MSI) in the tumor was investigated.RESULTSOf 116 patients included in the analysis, 57 (49%) presented with de novo metastatic disease, and 59 (51%) presented with localized disease that later metastasized. Subtype classifications included unclassified (n = 41; 35%), papillary (n = 26; 22%), chromophobe (n = 17; 15%), translocation associated (n = 13; 11%), and other (n = 19; 16%). Of all tumors, 15 (13%) had putative driver somatic alterations amenable to targeted therapies, including alterations in MET, TSC1/2, and an ALK translocation. Of 45 patients who had germline testing, 11 (24%) harbored mutations, seven of which could potentially guide therapy. Of 115 available tumors for analysis, two (1.7%) had high and six (5%) had intermediate MSI status.CONCLUSIONThe mutation profiles of metastatic nccRCC vary by subtype. Comprehensive analysis of somatic mutations, germline mutations, and MSI, interpreted via an annotated precision oncology knowledge base, identified potentially targetable alterations in 22% of patients, which merits additional investigation.

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Clinicopathological and prognostic impact of somatic mutations in Chinese patients with clear cell renal cell carcinoma

Translational Andrology and Urology ◽

10.21037/tau-20-1410 ◽

2020 ◽

Vol 9 (6) ◽

pp. 2751-2763

Author(s):

Hai Bi ◽

Jipeng Yin ◽

Lang Zhou ◽

Yaqian Wu ◽

Liyuan Ge ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Clear Cell ◽

Chinese Patients ◽

Prognostic Impact ◽

Cell Renal Cell Carcinoma

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PD49-08 CORRELATING IMMUNE CELL INFILTRATION PATTERNS WITH RECURRENT SOMATIC MUTATIONS IN CLEAR CELL RENAL CELL CARCINOMA

The Journal of Urology ◽

10.1097/ju.0000000000002071.08 ◽

2021 ◽

Vol 206 (Supplement 3) ◽

Author(s):

Nicholas Chakiryan ◽

Ali Hajiran ◽

Youngchul Kim ◽

Jad Chahoud ◽

Philippe Spiess ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Immune Cell ◽

Clear Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Cell Renal Cell Carcinoma

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Assessing the frequency of somatic mutations in high-risk clear cell renal cell carcinoma to provide new perspectives.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.548 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 548-548

Author(s):

Brandon Manley ◽

Daniel Tennenbaum ◽

Jozefina Casuscelli ◽

James Hsieh

Keyword(s):

Renal Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Clear Cell ◽

Cancer Genomics ◽

Cancer Genome ◽

Mutual Exclusivity ◽

Cell Renal Cell Carcinoma

548 Background: Previous large collaborative studies have been conducted to characterize the genetic mutations found in Clear Cell Renal Cell Carcinoma (ccRCC). However, these studies have covered all stages of disease. We examine the genetic frequency of mutations in recurrently mutated genes found in ccRCC among patients with advanced localized ccRCC, defined as T3 disease and no known metastasis at presentation. Methods: Reviewing data from The Cancer Genome Atlas (TCGA), The International Cancer Genome Consortium (ICGC), The Cancer Genomics Project Tokyo, Japan and our prospectively collected intuitional database we identified 76 patients with ccRCC and T3 disease. We calculated the frequency of several previously reported recurrently mutated genes including VHL, PBRM1, SETD2, BAP1, KDM5C, TERT (including promoter), TP53, MTOR, and PTEN. .We also reviewed and reported corresponding clinical information for this cohort. Results: Table provides the frequency of somatic mutations as well as demographic information of our cohort. Mutual exclusivity was found between mutations of BAP1 and TERT in all patients studied. Additionally, KDM5Cmutations were found in 20% of our patients. Conclusions: These results describe the frequency of several recurrently mutated genes present in high-risk ccRCC. The mutual exclusivity between BAP1 and TERT, both having been associated with aggressive disease, suggests a possible interesting relationship between the two. Focusing our investigation on a more precise cohort of patients’ staged disease allows for new perspectives on the genetics present. Further investigation into how these mutation burdens differ from lower-risk disease deserves further investigation. [Table: see text]

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Comparative genomic profiling from tumor tissue and circulating tumor DNA (ctDNA) in 111 patients (Pts) with metastatic clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4565 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4565-4565 ◽

Cited By ~ 1

Author(s):

Ritesh Kotecha ◽

Erika Gedvilaite ◽

Samuel J. Murray ◽

Robert J. Motzer ◽

Dana Tsui ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Circulating Tumor Dna ◽

Large Cohort ◽

Cell Renal Cell Carcinoma ◽

Primary Tumors ◽

Primary Tissue ◽

Tumor Dna

4565 Background: Circulating tumor DNA (ctDNA) assessment is a non-invasive approach for genomic interrogation of solid tumors. As a novel tool, key benchmarks for applications in metastatic clear cell renal cell carcinoma (mccRCC) are yet to be determined. To understand the utility of ctDNA, we performed a large cohort analysis using a comparative genomics approach integrating matched primary tissue and ctDNA genomic data. Methods: Pts with prior tumor mutational profiles generated via next generation sequencing (NGS) from nephrectomy or metastatic specimens underwent single-time point plasma collection. Targeted NGS sequencing with MSK-IMPACT was performed on tumor and ctDNA with subsequent bi-directional cross genotyping using Waltz 2.0. All pts had matched germline comparison from peripheral blood; clinical data was extracted from medical record. Liberal (1-2 reads) and stringent (≥3 reads) filters were applied, with a cut-off of < 30% allele frequency to remove germline mutations. Results: 111 mccRCC pts, of whom available IMDC-risk was favorable (35%), intermediate (60%), and poor-risk (5%) were included for analysis. The median time between tissue and ctDNA collection was 23 months (R: 1-177), and 96% of patients had undergone nephrectomy prior to ctDNA collection. In primary tissue sequencing, 64/111 (58%) from nephrectomy and 42/111 (42%) from metastatic sites, 569 unique alterations were identified across the whole cohort, with a median of 4 mutations/pt (R:1-23). RCC-specific alterations included VHL (88%), PBRM1 (48%), SETD2 (34%), KDM5C (17%), TP53 (14%). Across the cohort, 176 alterations were identified in ctDNA. With cross genotyping, ctDNA alterations concordant with primary tumors were detected in 20% (22/111 pts, 28 unique alterations) using stringent criteria with a median of 1 mutation/pt (R:1-2). Using liberal criteria, concordance with primary tumors was 59% (66/111 pts, 142 unique alterations) with a median of 2 mutations/pt (R: 1-8). Conclusions: This large cohort study matching oncogenomics from tumor and ctDNA highlights complexities and challenges of applying liquid biopsy in biomarker development in mccRCC.

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