The Clinical Significance of DNA Damage Repair Signatures in Clear Cell Renal Cell Carcinoma

DNA damage repair plays an important role in cancer’s initiation and progression, and in therapeutic resistance. The prognostic potential of damage repair indicators was studied in the case of clear cell renal cell carcinoma (ccRCC). Gene expression profiles of the disease were downloaded from cancer genome databases and gene ontology was applied to the DNA repair-related genes. Twenty-six differentially expressed DNA repair genes were identified, and regression analysis was used to identify those with prognostic potential and to construct a risk model. The model accurately predicted patient outcomes and distinguished among patients with different expression levels of immune evasion genes. The data indicate that DNA repair genes can be valuable for predicting the progression of clear cell renal cell carcinoma and the clinical benefits of immunotherapy.

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Genomic instability and DNA damage repair in clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4581 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4581-4581

Author(s):

Patrick Glen Pilie ◽

Lijun Zhou ◽

Pan Tong ◽

Surena F. Matin ◽

Kanishka Sircar ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Dna Damage ◽

Cell Carcinoma ◽

Genomic Instability ◽

Renal Cell ◽

Clear Cell ◽

Early Stage ◽

Cell Renal Cell Carcinoma ◽

Mutator Phenotype ◽

Damage Repair

4581 Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the von Hippel Lindau gene ( VHL), in addition to nearby genes SETD2, BAP1, and PBRM. We hypothesized that VHL loss leads to defective DDR as an early event in ccRCC carcinogenesis, giving way to a mutator phenotype. We posited that assessment of very early ccRCC tumors would inform us regarding the core mutations required to drive tumorigenesis in ccRCC, and that we could confirm these findings in appropriate model systems. Methods: We performed whole-exome (WES) DNA sequencing on 11 early-stage ccRCC tumors from 5 individuals, along with their matched normal DNA. We then analyzed ccRCC samples with and without somatic VHL mutations from the Cancer Genome Atlas (TCGA) for mutational load. Finally we assessed DDR signaling activity in renal proximal tubular cell lines (RPTEC) with VHL/SETD2 knockdown and in murine embryo fibroblasts (MEFs) from Vhl and Setd2knockout mice treated with etoposide via γH2AX expression and direct repeat-green fluorescent protein reporter assay. Results: All 11 samples revealed loss of 3p with pathogenic germline or somatic mutation in remaining VHL allele. No mutations were found in genes frequently mutated in larger ccRCC, including PBRM1, BAP1 or SETD2. WES revealed ~100 mutations/tumor, with no shared mutations across samples, even within the same individual. TCGA analysis showed similar mutational loads across ccRCC samples. MEFs with biallelic loss of Vhl and monoallelic loss of Setd2 and RPTEC with VHL and SETD2knockdown displayed increased DNA damage with impaired homologous repair and increased non-homologous end joining (NHEJ). Conclusions: Early stage ccRCC tumors with loss of VHL and chr 3p demonstrate genomic instability and a mutator phenotype similar to more advanced ccRCC. Cell line models of early ccRCC show increased DNA damage with a greater reliance on error-prone NHEJ machinery. These defects could be targeted for synthetic lethal treatment strategies.

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Construction of a Novel Multigene Panel Potently Predicting Poor Prognosis in Patients with Clear Cell Renal Cell Carcinoma

Cancers ◽

10.3390/cancers12113471 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3471

Author(s):

Xiaozeng Lin ◽

Anil Kapoor ◽

Yan Gu ◽

Mathilda Jing Chow ◽

Jingyi Peng ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Dna Helicase ◽

Poor Overall Survival ◽

Cell Renal Cell Carcinoma ◽

Damage Repair ◽

Tcga Dataset ◽

Multigene Panel

We observed associations of IQGAP1 downregulation with poor overall survival (OS) in clear cell renal cell carcinoma (ccRCC). Differentially expressed genes (DEGs, n = 611) were derived from ccRCCs with (n = 111) and without IQGAP1 (n = 397) reduction using the TCGA PanCancer Atlas ccRCC dataset. These DEGs exhibit downregulations of immune response and upregulations of DNA damage repair pathways. Through randomization of the TCGA dataset into a training and testing subpopulation, a 9-gene panel (SigIQGAP1NW) was derived; it predicts poor OS in training, testing, and the full population at a hazard ratio (HR) 2.718, p < 2 × 10−16, p = 1.08 × 10−5, and p < 2 × 10−16, respectively. SigIQGAP1NW independently associates with poor OS (HR 1.80, p = 2.85 × 10−6) after adjusting for a set of clinical features, and it discriminates ccRCC mortality at time-dependent AUC values of 70% at 13.8 months, 69%/31M, 69%/49M, and 75.3%/71M. All nine component genes of SigIQGAP1NW are novel to ccRCC. The inclusion of RECQL4 (a DNA helicase) in SigIQGAP1NW agrees with IQGAP1 DEGs enhancing DNA repair. THSD7A affects kidney function; its presence in SigIQGAP1NW is consistent with our observed THSD7A downregulation in ccRCC (n = 523) compared to non-tumor kidney tissues (n = 100). Collectively, we report a novel multigene panel that robustly predicts poor OS in ccRCC.

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Functional biomarkers of homologous repair (HR) deficiency to guide novel DNA damage response targeted therapy in clear cell renal cell carcinoma (ccRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.4576 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 4576-4576 ◽

Cited By ~ 1

Author(s):

Patrick Glen Pilie ◽

Christine B Peterson ◽

Yang Peng ◽

Lijun Zhou ◽

Timothy Anthony Yap ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Dna Damage ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Dna Damage Response ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Damage Response ◽

Functional Biomarkers

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Comprehensive Analysis of DNA Damage Repair Genes and Identification of RAD54L as an Immunological and Prognostic Biomarker in Clear Cell Renal Cell Carcinoma and Other Cancers

10.21203/rs.3.rs-683866/v1 ◽

2021 ◽

Author(s):

Song Wang ◽

Zitong Yang ◽

Jiahe Yi ◽

Zixiang Liu ◽

Jiangfeng Li ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Dna Damage ◽

Tumor Microenvironment ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Biomarker ◽

Cell Renal Cell Carcinoma ◽

Qrt Pcr ◽

Damage Repair ◽

Worse Prognosis

Abstract Background: DNA damage repair (DDR) plays a pivotal role in the tumorigenesis and progression of multiple cancers, including clear cell renal cell carcinoma (ccRCC), and immunotherapy is galvanizing research on ccRCC, while the interactions between DDR and tumor microenvironment (TME) in ccRCC still remain elusive. Methods: The expression, mutation and clinical data were downloaded from public datasets in TCGA, GTEx and human protein atlas (HPA) database. Consensus clustering analysis was used to cluster subtypes based upon the expression of DDR genes. Cox regression analysis was adopted to conduct survival analysis, and qRT-PCR method was used to verify the expression of RAD54L in ccRCC samples. GSEA was employed to explore potential enriched KEGG pathways. CIBERSORT, ssGSEA and xCell algorithms were used to evaluate the tumor microenvironment (TME).Results: Two subtypes were identified according to the expression of DDR genes in ccRCC. Subtype1 was correlated with increased proportion of higher-grade tumors, worse prognosis and lower PD-L1 expression compared to subtype2. Distinct TME was also noted between two subtypes. GSEA revealed that the TGF-β signaling pathway was significantly enriched in subtype1. RAD54L was subsequently determined as a potential immune-related DDR gene, which was positively associated with PD-L1 expression and its elevated expression predicted unfavorable prognosis in ccRCC. qRT-PCR also verified the overexpression of RAD54L in ccRCC samples. Additionally, a systematic analysis involving 33 cancer types demonstrated that RAD54L was remarkably upregulated and its overexpression tightly linked to worse prognosis in multiple cancers. Moreover, both xCell and ssGSEA algorithm showed the strong associations between RAD54L expression and immune infiltration in more than 30 cancers. Conclusions: DDR is implicated in regulating TME of ccRCC, and RAD54L is a potential immunological and prognostic biomarker in multiple types of cancer, including ccRCC.

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DNA Damage Repair (DDR) gene and VHL concurrent alterations in advanced clear cell Renal Cell Carcinoma (ccRCC) are association with good progression free survival with tyrosine kinase inhibitor therapy

European Urology ◽

10.1016/s0302-2838(21)00923-4 ◽

2021 ◽

Vol 79 ◽

pp. S742

Author(s):

W. Zhai ◽

J. Wang ◽

N. He ◽

J. Zhou ◽

J. Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Dna Damage ◽

Renal Cell ◽

Kinase Inhibitor ◽

Clear Cell ◽

Progression Free Survival ◽

Cell Renal Cell Carcinoma ◽

Free Survival ◽

Damage Repair ◽

Tyrosine Kinase Inhibitor Therapy

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Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms (NCT03207347).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e22061 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e22061-e22061

Author(s):

azka ali ◽

David L. DeRemer ◽

Ji-Hyun Lee ◽

Hiral D. Parekh ◽

Stephen Staal ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Dna Damage ◽

Cell Carcinoma ◽

Dna Damage Response ◽

Renal Cell ◽

Clear Cell ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Cell Renal Cell Carcinoma ◽

Damage Response

e22061 Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]

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DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000230 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000230 ◽

Cited By ~ 4

Author(s):

Yasser Ged ◽

Joshua L Chaim ◽

Renzo G DiNatale ◽

Andrea Knezevic ◽

Ritesh R Kotecha ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Dna Damage ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitor ◽

Clear Cell ◽

Dna Damage Repair ◽

Loss Of Function ◽

Damage Repair ◽

Gene Alterations

BackgroundLoss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.MethodsGenomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.ResultsDel DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM. Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14–1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).ConclusionDel DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.

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