DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor Outcome

Na, Joon Chae; Nagaya, Naoya; Rha, Koon Ho; Han, Woong Kyu; Kim, Isaac Yi

doi:10.1016/j.clgc.2019.05.004

Cited by 11 publications

(9 citation statements)

References 15 publications

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“…The results showed that in addition to genes such as VHL, BAP1, PBRM1, CDKN2A, SET2D, p53, mTOR, and PTEN, RCC tissues harbor mutations in several other DNA damage repair genes (Table 2). These results confirmed that RCC tissues harbor relatively high rates of mutations in DNA damage repair genes as shown by previous studies (18,19). Based on these findings, we aimed to test whether PARP inhibition would be a viable therapeutic strategy for RCC using ccRCC and pRCC cell lines.…”

Section: Rcc Tissues Harbor Mutations In Several Direct and Indirect Dna Damage Repair Genessupporting

confidence: 84%

“…Prior studies have found high rates of alterations in DNA damage repair genes in localized and metastatic RCC tissues (18,19). In the current study, we used results from literature as well as our data-mining results showing that RCC tissues harbor mutations in several DNA damage repair (HR) genes as rationale to test whether PARP inhibition is a rational therapeutic strategy against RCC.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, RCC is characterized by somatic loss of function mutations in DNA damage repair genes such as TTN, MUC4, MUC16, DST, KMT2C, KMT2D, and ARID1A (15). Notwithstanding the recognition that RCC harbors several defects in DNA damage repair (18,19), studies on the susceptibility of RCC to PARPi are scarce.…”

Section: Introductionmentioning

confidence: 99%

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The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma

et al. 2021

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Renal cell carcinoma (RCC) is the sixth most common cancer in the US. However, no significant changes in management have occurred since the tyrosine kinase era until the recent breakthrough with checkpoint inhibitors. Therefore, the need for more therapeutic options is paramount. Our objective was to determine whether PARP inhibition represents a novel therapeutic option for RCC. We used publicly available COSMIC, GDC Data Portal, and cBioPortal databases to explore mutations in DNA repair genes in RCC tissues from the TCGA cohort. We treated a human normal renal epithelial cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, veliparib, and talazoparib. Cell survival, cell proliferation, clonogenic ability, and apoptosis were assessed. RCC xenografts in SCID mice were treated with PARPi to evaluate their efficacy in vivo. Data mining revealed that ~27-32% of RCC tissues contain mutations in homologous recombination genes. Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro. Niraparib, talazoparib, and rucaparib were the most effective in reducing RCC xenograft growth in vivo. Agents such as PARPi that exploit mutations in DNA damage repair genes may be effective therapeutic options for RCC.

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Section: Rcc Tissues Harbor Mutations In Several Direct and Indirect Dna Damage Repair Genessupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma

et al. 2021

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“…These genes functioned as DNA damage checkpoints (Benjamini adjusted p -value of 0.02), intracellular signaling mediators (0.02), and cell cycle checkpoints (0.03). Alterations of these biological pathways were observed in renal carcinoma patients [ 38 , 39 ].…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Transcriptomic Analysis of Non-Tumorigenic Tissues Reveals Aging-Related Prognostic Markers and Drug Targets in Renal Cell Carcinoma

Kim

et al. 2021

Cancers

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The relationship between expression of aging-related genes in normal tissues and cancer patient survival has not been assessed. We developed a genome-wide transcriptomic analysis approach for normal tissues adjacent to the tumor to identify aging-related transcripts associated with survival outcome, and applied it to 12 cancer types. As a result, five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) in normal tissues were found to be significantly associated with a worse survival outcome in patients with renal cell carcinoma (RCC). This computational approach was investigated using nontumorigenic immune cells purified from young and aged mice. Aged immune cells showed upregulated expression of all five aging-related genes and promoted RCC invasion compared to young immune cells. Further studies revealed DUSP22 as a regulator and druggable target of metastasis. DUSP22 gene knockdown reduced RCC invasion and the small molecule inhibitor BML-260 prevented RCC dissemination in a tumor/immune cell xenograft model. Overall, these results demonstrate that deciphering the relationship between aging-related gene expression in normal tissues and cancer patient survival can provide new prognostic markers, regulators of tumorigenesis and novel targets for drug development.

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“…The DDR-associated pathway is associated with the carcinogenesis of ccRCC, and the expression of some DNA repair factors is correlated with patient prognosis (Na et al, 2019). This study was designed to determine the impact of DNA repair genes on the progression of ccRCC and patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Jun

et al. 2021

Front. Genet.

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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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DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor Outcome

Cited by 11 publications

References 15 publications

The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma

The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma

Genome-Wide Transcriptomic Analysis of Non-Tumorigenic Tissues Reveals Aging-Related Prognostic Markers and Drug Targets in Renal Cell Carcinoma

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

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