DNA Methylation Biomarkers Predict Progression-Free and Overall Survival of Metastatic Renal Cell Cancer (mRCC) Treated with Antiangiogenic Therapies

Abstract

VEGF-targeted therapy increases both the progression-free (PFS) and overall survival (OS) of patients with metastasized renal cell cancer (mRCC). Identification of molecular phenotypes of RCC could improve risk-stratification and the prediction of the clinical disease course. We investigated whether gene-specific DNA hypermethylation can predict PFS and OS among patients undergoing anti-VEGF-based therapy. Primary tumor tissues from 18 patients receiving targeted therapy were examined retrospectively using quantitative methylation-specific PCR analysis of CST6, LAD1, hsa-miR-124-3, and hsa-miR-9-1 CpG islands. PFS and OS were analyzed for first-line and sequential antiangiogenic therapies using the log rank statistics. Sensitivity and specificity were determined for predicting first-line therapy failure. Hypermethylation of CST6 and LAD1 was associated with both a shortened PFS (log rank p = 0.009 and p = 0.004) and OS (p = 0.011 and p = 0.043). The median PFS observed for the high and low methylation groups of CST6 and LAD1 was 2.0 vs.11.4 months. LAD1 methylation had a specificity of 1.0 (95% CI 0.65–1.0) and a sensitivity of 0.73 (95% CI 0.43–0.90) for the prediction of first-line therapy. CST6 and LAD1 methylation are candidate epigenetic biomarkers showing unprecedented association with PFS and OS as well as specificity for the prediction of the response to therapy. DNA methylation markers should be considered for the prospective evaluation of larger patient cohorts in future studies.

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Peters et al [70] examined epigenetic biomarkers, namely the methylation status in primary tumor tissues in a cohort of 18 patients treated with either sunitinib (n = 12), sorafenib (n = 4), axitinib (n = 1), or bevacizumab (n = 1), as a first-line treatment. A decreased PFS and OS were observed for the hyper methylated status of CST6 and LAD1.…”

Prognostic DNA Methylation Markers for Renal Cell Carcinoma: A Systematic Review

“…This is especially important in order to discriminate between the prognostic and predictive value of the investigated markers, as markers with predictive value have a different outcome related to a specific therapy. Moreover, it could be that methylation markers have combined prognostic and predictive value, as was demonstrated for methylation of NEFH [31,39] and LAD1 [31,40]. Additionally, most studies included in this review were retrospective and conducted in a small number of patients, with 21 out of 49 studies (43%) including <100 patients.…”

“…Promoter CpG island methylation of GATA5 [29,[33][34] was associated with poorer prognosis in three studies, although different end points were used. Promoter methylation of LAD1 [31,39] and NEFH [31,40] not only predicted patient survival, but also response to treatment with antiangiogenic agents. Conflicting results regarding the prognostic value of promoter methylation of SFRP1 [27][28][29], PCDH8 [29,32,38], GREM1 [27,[29][30] and RASSF1A [26,[35][36][37] were found.…”

“…For several other genes statistically significant associations between methylation and patient survival were found, but were only reported in a single study [27,31,39,, and for some other genes null associations were reported [26][27]32,[34][35]39,42,[67][68][69][70] (Figure 3 & Supplementary Table 4).…”

“…In 2014, Peters et al [39] reported that methylation of LAD1 was associated with both shortened PFS and OS (HR: 6.4, 95% CI: 1.6-26.0 and HR: 2.9, 95% CI: 1.0-8.6, respectively) in RCC patients treated with antiangiogenic agents such as sunitinib, sorafenib, axitinib and bevacizumab. Recently, our group also demonstrated the prognostic value of methylation of LAD1 for patients with ccRCC [31].…”