Abstract
BackgroundDespite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis.ResultsTo address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as ‘low risk’ by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0–3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score.ConclusionsThis study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0–3).
Highlights
Cancers of the kidney and renal pelvis affect > 65,000 patients annually and rank 8th in causes of cancer-related death in the United States
Using a 10% change in methylation (|Δβ|≥ 0.1) and p < 0.01 between short term survivors (STS) and long term survivors (LTS) groups in cohort 1 we identified 5929 differentially methylated CpGs (DMCpG) with 4570 sites hypermethylated in STS and 1359 sites hypomethylated in STS, relative to LTS (Fig. 1b)
The majority (n = 5231) of DMCpGs overlap with one or more of three histone marks characteristic of gene regulatory regions based on Encyclopedia of DNA Elements (ENCODE) data from normal adult kidney, including H3K4me3 ± H3K27ac, H3K4me1 only, and H3K4me1 + H3K27ac
Summary
Cancers of the kidney and renal pelvis affect > 65,000 patients annually and rank 8th in causes of cancer-related death in the United States. They are on the low end of the frequency spectrum for all types of genetic variation, including many of the classical cancer-associated driver pathways (e.g. RAS, BRAF, TP53, and RB) [4, 9] These observations, along with the frequent mutation of epigenetic regulators [dominated by SETD2 (2–16%), PBRM1 (1–43%), KDM5C (18%), and BAP1 (1–17%)] [4], emphasize the importance of epigenetic deregulation to the initiation and progression of ccRCC. Despite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) relapse and die of recurrent disease, indicat‐ ing additional molecular parameters are needed for improved prognosis
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