1. GBX2 Methylation Is a Novel Prognostic Biomarker and Improves Prediction of Biochemical Recurrence Among Patients with Prostate Cancer Negative for Intraductal Carcinoma and Cribriform Architecture
- Author
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Theodorus van der Kwast, Carmelle Cuizon, Andrea J. Savio, Neil Fleshner, Alex Zlotta, Ekaterina Olkhov-Mitsel, Fang Zhao, Shivani Kamdar, Renu Jeyapala, Richard S.C. Liu, and Bharati Bapat
- Subjects
Male ,Oncology ,Biochemical recurrence ,medicine.medical_specialty ,Urology ,030232 urology & nephrology ,Dioxygenases ,Epigenesis, Genetic ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Recurrence ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Internal medicine ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,Radiology, Nuclear Medicine and imaging ,Epigenetics ,Homeodomain Proteins ,Prostatectomy ,business.industry ,breakpoint cluster region ,Prostatic Neoplasms ,Methylation ,DNA Methylation ,Middle Aged ,Prostate-Specific Antigen ,Prognosis ,medicine.disease ,Survival Analysis ,DNA-Binding Proteins ,Carcinoma, Intraductal, Noninfiltrating ,030220 oncology & carcinogenesis ,DNA methylation ,Biomarker (medicine) ,Kallikreins ,Surgery ,Neoplasm Grading ,business - Abstract
Tumor intraductal carcinoma/cribriform architecture (IDC/C) is associated with an unfavorable prognosis and biochemical recurrence (BCR) in prostate cancer (PCa). Up to 70% of PCa patients are IDC/C-negative, but it is estimated that 20% of these cases still experience BCR. Thus, biomarkers for better detection of aggressive disease in IDC/C-negative patients are required.To investigate tumor-specific methylation of the transcription factor GBX2 as a novel prognosticator and predictor of BCR in PCa patients stratified by histopathologic features including IDC/C.Using genome-wide methylome profiling, we identified higher GBX2 methylation in grade group (GG) 4 tumors compared to GG1 (discovery cohort). The prognostic nature of GBX2 methylation was validated in silico using The Cancer Genome Atlas data (n=478) and a quantitative methylation assay for radical prostatectomy samples (n=254). Regulation of GBX2 methylation was investigated in prostate cells using methyl-CpG-binding domain sequencing and methylation analysis in functional knockouts of TET2, a key epigenetic player in prostate carcinogenesis.The association of GBX2 methylation with Gleason score (GS), pathologic stage (pT), IDC/C, and BCR was analyzed using Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression analyses were used to predict BCR.GBX2 methylation was associated with GS (p0.05), pT (p0.01), and BCR (p0.05). GBX2 methylation (p=0.004), GS (p0.001), pT (p=0.012), and prostate-specific antigen (p=0.005) were independent predictors of BCR. Among IDC/C-negative patients, GBX2 methylation improved prediction of BCR (p=0.002). Loss of TET2 in prostate cells resulted in greater GBX2 methylation.We identified GBX2 methylation as a novel prognostic factor in PCa and an independent predictor of BCR. We demonstrated the additive value of GBX2 methylation in predicting BCR among IDC/C-negative patients and elucidated a novel TET2-mediated upstream epigenetic regulatory mechanism of GBX2.We identified GBX2 methylation as a promising prognostic biomarker that could improve the identification of prostate cancer patients at higher risk of biochemical recurrence.
- Published
- 2019