Genomic analysis uncovers prognostic and immunogenic characteristics of ferroptosis for clear 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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Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

BioMed Research International ◽

10.1155/2020/2495157 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Hui Meng ◽

Xuewen Jiang ◽

Jianfeng Cui ◽

Gang Yin ◽

Benkang Shi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Genomic Analysis ◽

Renal Clear Cell Carcinoma ◽

Genomic Feature ◽

Cell Renal Cell Carcinoma ◽

Hybridization Capture ◽

Significant Difference

Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of renal cell carcinoma. Nearly 25% of ccRCC patients were diagnosed with metastasis. Though the genomic profile of ccRCC has been widely studied, the difference between localized and metastatic ccRCC was not clarified. Primary tumor samples and matched whole blood were collected from 106 sporadic patients diagnosed with renal clear cell carcinoma at Qilu Hospital of Shandong University from January 2017 to November 2019, and 17 of them were diagnosed with metastasis. A hybridization capture-based next-generation sequencing of 618 cancer-related genes was performed to investigate the somatic and germline variants, tumor mutation burden (TMB), and microsatellite instability (MSI). Five genes with significantly different prevalence were identified in the metastatic group, especially TOP1 (17.65% vs. 0%) and SNCAIP (17.65% vs. 0%). The altered frequency of PBRM1 (0% vs. 27%) and BAP1 (24% vs. 10%) differed between the metastatic and nonmetastatic groups, which may relate to the prognosis. Of these 106 patients, 42 patients (39.62%) had at least one alteration in DNA damage repair (DDR) genes, including 58.82% of metastatic ccRCC patients and 35.96% of ccRCC patients without metastasis. Ten pathogenic or likely pathogenic (P/LP) variants were identified in 11 sporadic clear cell renal cell carcinoma patients (10.38%), including rarely reported ATM (n=1), MUTYH (n=1), NBN (n=1), RAD51D (n=1), and BRCA2 (n=1). No significant difference in the ratio of P/LP variant carriers or TMB was identified between the metastatic and nonmetastatic groups. We found a unique genomic feature of Chinese metastatic ccRCC patients with a higher prevalence of alterations in DDR, TOP1, and SNCAIP. Further investigated studies and drug development are needed in the future.

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A Proteogenomic Atlas of Clear Cell Renal Cell Carcinoma in a Chinese Population

10.21203/rs.3.rs-221123/v1 ◽

2021 ◽

Author(s):

Chen Ding ◽

Yuan-Yuan Qu ◽

Jinwen Feng ◽

Xiaohui Wu ◽

Lin Bai ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Large Scale ◽

Clear Cell ◽

Genomic Analysis ◽

Genomic Alterations ◽

Cell Renal Cell Carcinoma ◽

Genetic Features ◽

One Carbon Metabolism

Abstract Renal cell carcinoma (RCC) is among the top 10 malignant carcinomas1. Clear cell (cc)RCC, accounting for ~ 75% of RCC cases, is an aggressive histological RCC subtype. In the last decade, large-scale multiomics studies have profoundly enhanced our understanding of this disease2,3. However, despite the differences of genomic alterations between Western and Eastern ccRCC4,5, these studies mostly focused on patients in Western populations. Here we conducted a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. Genomic analysis revealed unique genetic features of Chinese ccRCC and distinct mutation patterns associated with copy number alterations. Based on proteomic profiles, ccRCC showed extensive metabolic dysregulation, especially in one-carbon metabolism. We classified ccRCC into three subtypes (GP1–3), among which the most aggressive GP1 exhibited dominant immune response, metastasis, and metabolic imbalance, linking the proteomic features, genomic alterations, and clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT) and NNMT mediated protein homocysteinylation were identified as a poor prognosis indicator and a drug target for GP1, respectively. We demonstrated that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes tumor growth in ccRCC. Treatment of N-acetyl-cysteine (NAC), an inhibitor of homocysteinylation, markedly reduced the NNMT overexpression induced radioresistance of tumor cells. This study provided valuable insights into the biological underpinnings and prognosis assessment of ccRCC, revealing a targetable metabolic vulnerability.

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MP36-09 SNP MICROARRAY GENOMIC ANALYSIS FOR CONFIRMATION OF HISTOLOGICAL SUBTYPE AND DETECTION OF CHROMOSOMAL ABERRATIONS ASSOCIATED WITH PROGNOSIS IN CLEAR CELL RENAL CELL CARCINOMA

The Journal of Urology ◽

10.1016/j.juro.2014.02.1073 ◽

2014 ◽

Vol 191 (4S) ◽

Author(s):

Austin Younger ◽

Austin DeRosa ◽

James Rosoff ◽

Heidi Hamilton ◽

Stephen Savage ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Chromosomal Aberrations ◽

Renal Cell ◽

Clear Cell ◽

Genomic Analysis ◽

Histological Subtype ◽

Cell Renal Cell Carcinoma ◽

Snp Microarray

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638: Macroscopic Tumor Necrosis is a Prognostic Indicator for Non-Metastatic Clear Cell Renal Cell Carcinoma

The Journal of Urology ◽

10.1016/s0022-5347(18)30878-4 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 214-214

Author(s):

Sung Kyu Hong ◽

Byung Kyu Han ◽

In Ho Chang ◽

June Hyun Han ◽

Ji Hyung Yu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Tumor Necrosis ◽

Clear Cell ◽

Prognostic Indicator ◽

Cell Renal Cell Carcinoma ◽

Macroscopic Tumor

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Abstract #1001: Extremely Aggressive Papillary Thyroid Cancer (PTC) with Widespread Metastases Including Spleen and Clear Cell Renal Cell Carcinoma (RCC) in one Patient: An Unknown Syndromic Entity or Manifestation of Familial PTC?

Endocrine Practice ◽

10.1016/s1530-891x(20)44123-0 ◽

2017 ◽

Vol 23 ◽

pp. 210

Author(s):

Shilpi Singh ◽

Anh-Thu Nguyen ◽

Robert Anderson

Keyword(s):

Renal Cell Carcinoma ◽

Thyroid Cancer ◽

Cell Carcinoma ◽

Papillary Thyroid Cancer ◽

Renal Cell ◽

Clear Cell ◽

Papillary Thyroid ◽

Cell Renal Cell Carcinoma

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Rare localization of renal cell carcinoma metastases in the paranasal sinuses and breast: a case report

Medical Visualization ◽

10.24835/1607-0763-2018-6-13-22 ◽

2019 ◽

Vol 22 (6) ◽

pp. 13-22

Author(s):

E. V. Kryaneva ◽

N. A. Rubtsova ◽

A. V. Levshakova ◽

A. I. Khalimon ◽

A. V. Leontyev ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Paranasal Sinuses ◽

Renal Cell ◽

Clinical Case ◽

Clear Cell ◽

Malignant Tumors ◽

Metastatic Potential ◽

Cell Renal Cell Carcinoma ◽

Metastatic Lesions

This article presents a clinical case demonsratinga high metastatic potential of clear cell renal cell carcinoma combined with atypical metastases to breast and paranasal sinuses. The prevalence of metastatic lesions to the breast and paranasal sinuses in various malignant tumors depending on their morphological forms is analyzed. The authors present an analysis of data published for the last 30 years. The optimal diagnostic algorithms to detect the progression of renal cell carcinoma and to evaluate the effectiveness of the treatment are considered.

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