Clinical significance of novel DNA methylation biomarkers for renal clear cell carcinoma

Kubiliūtė, Raimonda; Žukauskaitė, Kristina; Žalimas, Algirdas; Ulys, Albertas; Sabaliauskaitė, Rasa; Bakavičius, Arnas; Želvys, Arūnas; Jankevičius, Feliksas; Jarmalaitė, Sonata

doi:10.1007/s00432-021-03837-7

Cited by 15 publications

(19 citation statements)

References 53 publications

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“…In our study, in urine samples from the patients with SRMs, out of five SRM-specific biomarkers, the highest diagnostic power (AUC = 0.69), with 49% sensitivity and 88% specificity, was established for PCDH8. These data are in support of our previous findings on the high diagnostic value of this biomarker in RCC [22]. Interestingly, the sensitivities of methylated TFAP2B and TAC1 for RCC SRMs were even higher than that of needle biopsy, which possibly is the result of RCC heterogeneity that is highly overlooked in single biopsy studies [27][28][29].…”

Section: Discussionsupporting

confidence: 89%

“…The present study of urinary biomarkers shows that SRMs contribute significantly to the amount of DNA detectable in urine; therefore, DNA methylation might be used as an indicator of the formation of small malignant masses in the kidney. In urine samples from the cases with SRMs, significantly higher methylation levels and/or frequencies of TFAP2B, TAC1, PCDH8, ZNF677, and FLRT2 were detected in comparison to controls in support of our previous observations of the diagnostic potential of these DNA methylation biomarkers in RCC [22]. Only the methylation changes in PCDH8 and TFAP2B were related to the amount of tumor mass or the dynamics of tumor growth, thus may potentially supplement imaging data on SRMs' growth.…”

Section: Discussionsupporting

confidence: 81%

“…Our previous genome-wide methylated DNA analysis allowed us to identify renal cancer-specific methylated DNA biomarkers with a promising potential for non-invasive renal clear cell carcinoma detection and prognosis [22]. In the present study, we analyze the same set of genes, particularly ZNF677, PCDH8, FLRT2, FBN2, TAC1, and TFAP2B, in the urine samples of patients diagnosed with SRMs and treated by AS, aiming at the evaluation of their suitability for the extremely early detection of SRMs and tumor growth prediction during the monitoring of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Urine Molecular Biomarkers for Detection and Follow-Up of Small Renal Masses

Žalimas

Kubiliūtė

Žukauskaitė

et al. 2022

IJMS

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Active surveillance (AS) is the best strategy for small renal masses (SRMs) management; however, reliable methods for early detection and disease aggressiveness prediction are urgently needed. The aim of the present study was to validate DNA methylation biomarkers for non-invasive SRM detection and prognosis. The levels of methylated genes TFAP2B, TAC1, PCDH8, ZNF677, FLRT2, and FBN2 were evaluated in 165 serial urine samples prospectively collected from 39 patients diagnosed with SRM, specifically renal cell carcinoma (RCC), before and during the AS via quantitative methylation-specific polymerase chain reaction. Voided urine samples from 92 asymptomatic volunteers were used as the control. Significantly higher methylated TFAP2B, TAC1, PCDH8, ZNF677, and FLRT2 levels and/or frequencies were detected in SRM patients’ urine samples as compared to the control. The highest diagnostic power (AUC = 0.74) was observed for the four biomarkers panel with 92% sensitivity and 52% specificity. Methylated PCDH8 level positively correlated with SRM size at diagnosis, while TFAP2B had the opposite effect and was related to SRM progression. To sum up, SRMs contribute significantly to the amount of methylated DNA detectable in urine, which might be used for very early RCC detection. Moreover, PCDH8 and TFAP2B methylation have the potential to be prognostic biomarkers for SRMs.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Urine Molecular Biomarkers for Detection and Follow-Up of Small Renal Masses

Žalimas

Kubiliūtė

Žukauskaitė

et al. 2022

IJMS

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“…Furthermore, ccRCC is a fatal disease with high intra-tumor and inter-tumor heterogeneity, making diagnosis and prediction difficult [97]. DNA methylation in urine aggravates this condition, providing a more accurate representation of tumor heterogeneity than a tissue sample [98]. Furthermore, due to the ease with which samples can be replicated, urine-based biological symptoms can be observed on a regular basis in at-risk patients, allowing for early detection of tumors or tracking the progression of cancer in real-time [99].…”

Section: Clinical Implications Of Dna Methylation As a Marker Of Rcc ...mentioning

confidence: 99%

DNA Methylation and Epigenetic Events Underlying Renal Cell Carcinomas

Tanvir¹,

Hassan²,

Albeladi³

2022

Cureus

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Renal cell carcinoma (RCC) refers to a group of tumors that develop from the epithelium of the kidney tubes, including clear cell RCC, papillary RCC, and chromophobe RCC. Most clear cell renal carcinomas have a large histologic subtype, genetic or epigenetic von Hippel-Lindau (VHL). A comprehensive analysis of the genetic modification genome suggested that chromosome 3p loss and chromosome gains 5q and 7 may be significant copy defects in the development of clear RCC. A more potent RCC may develop if chromosome 1p, 4, 9, 13q, or 14q is also lost. Renal carcinogenesis is not associated with chronic inflammation or histological changes. However, if regional hypermethylation of DNA in CpG C-type islands has already accumulated in cancer-free kidney tissue, it implies that the presence of malignant kidney lesions may also be detected by modified DNA methylation. Modification of DNA methylation in cancerous kidney tissue may advance kidney tissue to epigenetic mutations and genes, leading to more serious cancers and even determining a patient's outcome. The genetic and epigenetic profile provides accurate predictors for patients with kidney cancer. New genetic and epigenetic analysis technologies will help to speed up the identification of vital cells for kidney cancer prevention, diagnosis, and treatment.

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“…Approximately 84,400 new RCC cases were diagnosed resulting in more than 34,700 kidney cancer-related deaths within the European Union in 2017 [ 2 ]. Although there is a higher incidence of detection of small renal masses through improved diagnosis, approximately one-third of patients will develop metastatic lesions during the course of the disease [ 3 ]. Therapeutic targeting of critical biological pathways, including those involving the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR), has produced robust clinical effects and revolutionized the treatment of metastatic RCC [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia increases RCC stem cell phenotype via altering the androgen receptor (AR)-lncTCFL5-2-YBX1-SOX2 signaling axis

et al. 2022

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Background Early studies indicated that the androgen receptor (AR) could promote renal cell carcinoma (RCC) development and metastasis, but its linkage to RCC progression under hypoxia, remains unclear. Results Here we found AR expression in RCC cells decreased in response to hypoxia, which might then lead to increase the cancer stem cells (CSC) phenotype through the lncTCFL5-2-modulated YBX1/SOX2 signals. The consequences of such hypoxia-modulated AR/lncTCFL5-2/YBX1/SOX2 signals ablity to alter the CSC phenotype might render RCC cells more resistant to targeted therapy with Sunitinib. Mechanism dissection revealed that AR might alter the lncTCFL5-2/YBX1/SOX2 signaling through transcriptional suppression of the lncTCFL5-2 expression via the AR-response-elements (AREs) on the lncTCFL5-2 promoter. The lncTCFL5-2 interacts with YBX1 to increase its stability, which in turn increases SOX2 expression at a transcriptional level via the YBX1-response-elements (YBX1Es) on the SOX2 promoter. The in vivo mouse model with orthotopic xenografts of RCC cells also validates the in vitro data, and a human RCC sample survey demonstrated the clinical significance of the AR/lncTCFL5-2/YBX1/SOX2 signaling axis for the RCC prognosis, likely as a result of regulating CSC phenotypes. Conclusions Together, these findings suggest that hypoxia may increase the RCC CSC phenotype via altering the AR/lncTCFL5-2/YBX1/SOX2 signaling axis and a potential therapy to target this newly identified signal perhaps may help improve the targeted therapy with Sunitinib to better suppress RCC progression.

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Clinical significance of novel DNA methylation biomarkers for renal clear cell carcinoma

Cited by 15 publications

References 53 publications

Urine Molecular Biomarkers for Detection and Follow-Up of Small Renal Masses

Urine Molecular Biomarkers for Detection and Follow-Up of Small Renal Masses

DNA Methylation and Epigenetic Events Underlying Renal Cell Carcinomas

Hypoxia increases RCC stem cell phenotype via altering the androgen receptor (AR)-lncTCFL5-2-YBX1-SOX2 signaling axis

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