BINNING SOMATIC MUTATIONS BASED ON BIOLOGICAL KNOWLEDGE FOR PREDICTING SURVIVAL: AN APPLICATION IN RENAL CELL CARCINOMA

Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA (ctDNA) for such informative somatic mutations (liquid biopsy) is considered an important advance for precision oncology in RCC, allowing to monitor molecular disease evolution in real time. However, our knowledge about the utility of ctDNA analysis in RCC is limited, in part due to the lack of RCC-appropriate assays for ctDNA analysis. Here, by interrogating different blood compartments in xenograft models, we identified plasma cell-free (cf) DNA and extracellular vesicles (ev) DNA enriched for RCC-associated ctDNA. Additionally, we developed sensitive targeted sequencing and bioinformatics workflows capable of detecting somatic mutations in RCC-relevant genes with allele frequencies ≥ 0.5%. Applying this assay to patient-matched tumor and liquid biopsies, we captured tumor mutations in cf- and ev-DNA fractions isolated from the blood, highlighting the potentials of both fractions for ctDNA analysis. Overall, our study presents an RCC-appropriate sequencing assay and workflow for ctDNA analysis and provides a proof of principle as to the feasibility of detecting tumor-specific mutations in liquid biopsy in RCC patients.

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Somatic Mutations of TSC2 or MTOR Characterize a Morphologically Distinct Subset of Sporadic Renal Cell Carcinoma With Eosinophilic and Vacuolated Cytoplasm

The American Journal of Surgical Pathology ◽

10.1097/pas.0000000000001170 ◽

2019 ◽

Vol 43 (1) ◽

pp. 121-131 ◽

Cited By ~ 23

Author(s):

Ying-Bei Chen ◽

Leili Mirsadraei ◽

Gowtham Jayakumaran ◽

Hikmat A. Al-Ahmadie ◽

Samson W. Fine ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Sporadic Renal Cell Carcinoma ◽

Distinct Subset ◽

Vacuolated Cytoplasm

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EGFR mRNA is Upregulated, but Somatic Mutations of the Gene are Hardly Found in Renal Cell Carcinoma in Japanese Patients

Pharmaceutical Research ◽

10.1007/s11095-005-7094-2 ◽

2005 ◽

Vol 22 (10) ◽

pp. 1757-1761 ◽

Cited By ~ 14

Author(s):

Toshiyuki Sakaeda ◽

Noboru Okamura ◽

Akinobu Gotoh ◽

Toshiro Shirakawa ◽

Shuji Terao ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Somatic Mutations ◽

Japanese Patients

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

The Journal of Urology ◽

10.1016/j.juro.2016.02.1456 ◽

2016 ◽

Vol 195 (4S) ◽

Author(s):

Brandon J Manley ◽

Jozefina Casuscelli ◽

Daniel M Tennenbaum ◽

Maria F Becerra ◽

Almedina Redzematovic ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Features ◽

Renal Cell ◽

Somatic Mutations ◽

Clear Cell ◽

Large Cohort ◽

Cell Renal Cell Carcinoma

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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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