EACR25-0822

Promoter methylation regulates CDHR5 and UPB1 expression in clear cell Renal Cell Carcinoma with sarcomatoid differentiation

F. Fernandes-Pontes1,2,3, V. Constâncio4,2,5, J. Lobo6,2,7, M. Alzamora6,2, R. Silva-Santos6,2, R. Henrique6,2,7, V. Miranda-Gonçalves4,2, C. Jerónimo4,2,7
1Portuguese Oncology Institute of Porto (IPO Porto), Cancer Biology and Epigenetics Group (IPO Porto Research Center of IPO Porto), Porto, Portugal
2Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), Porto, Portugal
3ICBAS – School of Medicine and Biomedical Sciences, Master Program in Oncology, Porto, Portugal
4Portuguese Oncology Institute of Porto (IPO Porto), Cancer Biology and Epigenetics Group (IPO Porto Research Center), Porto, Portugal
5ICBAS – School of Medicine and Biomedical Sciences, Doctoral Program in Biomedical Sciences, Porto,
6Portuguese Oncology Institute of Porto (IPO Porto), Cancer Biology and Epigenetics Group (IPO Porto Research Center) and Department of Pathology, Porto, Portugal
7ICBAS – School of Medicine and Biomedical Sciences, Department of Pathology and Molecular Immunology, Porto, Portugal
Introduction:

Renal Cell Carcinoma (RCC), particularly clear cell RCC (ccRCC), is one of the most lethal among urological cancers, with 25% of cases diagnosed at metastatic stage and 20% of these exhibiting sarcomatoid features, which drive tumor aggressiveness and poor prognosis. Although it is known that altered DNA methylation occurs during ccRCC progression, its contribution to the emergence of sarcomatoid differentiation remains elusive. This study aims to find new DNA methylation biomarkers that accurately identify sarcomatoid features arising in ccRCC.

Material and method:

In silico analyses were conducted to assess differentially methylated genes in sarcomatoid ccRCC (sccRCC) using The Cancer Genome Atlas (TCGA), focusing on specific genes linked to normal cellular function, cell stemness, and metabolism. Promoter methylation and expression were validated for the candidate genes in a tissue sample set (54 ccRCC and 34 sccRCC) using Mann-Whitney U test to compare gene methylation and transcript levels between ccRCC and sarcomatoid ccRCC groups and by plotting Receiver Operator Characteristics (ROC) with the respective biomarker performance estimates. Ethics approval was conceded by the Ethics Committee of IPO Porto (CES. 158/023).

Result and discussion:

CDHR5 and UPB1 promoter methylation levels were significantly higher in sarcomatoid ccRCC than in ccRCC without sarcomatoid features, while respective transcript levels were significantly diminished in both independent cohorts (TCGA and IPO Porto). When combining CDHR5me and UPB1me levels in a panel, sccRCC was discriminated from ccRCC with 78.7% specificity and 63% sensitivity. Furthermore, increased CDHR5me levels significantly associated with metastatic dissemination at diagnosis in sccRCC patients.

Conclusion:

Promoter methylation of CDHR5 and UPB1 is recognized as a possible hallmark to identify sarcomatoid change in ccRCC and may serve as a biomarker to this end. Validation in liquid biopsies could enhance the clinical utility of these findings.