Abstract
We have recently reported tumor suppressive role of DAB2IP in RCC development. In this study, We identified one CpG methylation biomarker (DAB2IP CpG1) located UTSS of DAB2IP that was associated with poor overall survival in a cohort of 318 ccRCC patients from the Cancer Genome Atlas (TCGA). We further validated the prognostic accuracy of DAB2IP CpG methylation by pyrosequencing quantitative methylation assay in 224 ccRCC patients from multiple Chinese centers (MCHC set), and 239 patients from University of Texas Southwestern Medical Center at Dallas (UTSW set) by using FFPE samples. DAB2IP CpG1 can predict the overall survival of patients in TCGA, MCHC, and UTSW sets independent of patient age, Fuhrman grade and TNM stage (all p<0.05). DAB2IP CpG1 successfully categorized patients into high-risk and low-risk groups with significant differences of clinical outcome in respective clinical subsets, regardless of age, sex, grade, stage, or race (HR: 1.63-7.83; all p<0.05). The detection of DAB2IP CpG1 methylation was minimally affected by ITH in ccRCC. DAB2IP mRNA expression was regulated by DNA methylation in vitro. DAB2IP CpG1 methylation is a practical and repeatable biomarker for ccRCC, which can provide prognostic value that complements the current staging system.
Highlights
More than 270,000 people are expected to be diagnosed with kidney cancer every year worldwide [1]
We investigated the relationship between the three upstream of the transcription start site (UTSS) CpG methylation sites and patient prognosis of Clear cell RCC (ccRCC) in the the Cancer Genome Atlas (TCGA) set
We reported that DAB2IP CpG1 methylation in DAB2IP UTSS, the area important for transcriptional regulation, is associated with poorer survival in ccRCC patients
Summary
More than 270,000 people are expected to be diagnosed with kidney cancer every year worldwide [1]. Clear cell RCC (ccRCC) is the most common subtype of kidney cancer, accounting for approximately 80–90% of cases [2]. Extensive effort has been devoted to identifying molecular biomarkers for ccRCC, there are few validated markers that aid disease prognosis, and none are used routinely in clinical practice [3,4,5]. DAB2IP gene hypermethylation is correlated with the development of many cancer types. Loss of DAB2IP in prostate cancer cells acquires their radio- or chemo-therapy resistance [8,9,10,11,12]. We reported that loss of DAB2IP enhances the malignant transformation of RCC and ccRCC resistance to targeted therapeutics [13]
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