Neil Fleshner

MD, MPH, FRCSC

Phone

(416) 946-4501 ext. 2899

Assistant(s)

Biography

Dr. Neil Fleshner is Chair and Professor at the Division of Urology, University of Toronto. Dr. Fleshner is certified in both urology and epidemiology. He earned his MPH degree from the School of Public Health at Columbia University and completed his oncology training at Memorial Sloan Kettering Cancer Center.

Dr. Fleshner is an avid music lover and father of three.

Areas of Specialty and Research Interests

Aside from surgical practice, Dr. Fleshner conducts research on urologic cancer prevention with an emphasis on prostate cancer. He has authored over 400 scientific papers. Dr. Fleshner's current research projects include 2 randomized trials of nutritional intervention in prostate cancer as well as laboratory work assessing oxidative biomarkers and cell cycle regulation in prostate cancer cells exposed to micronutrients.

Affiliated Hospital(s)

Mount Sinai Hospital, Princess Margaret Cancer Centre (UHN), Toronto General Hospital (UHN)
 
 

Latest Publications

Exploring targets of TET2-mediated methylation reprogramming as potential discriminators of prostate cancer progression.

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Exploring targets of TET2-mediated methylation reprogramming as potential discriminators of prostate cancer progression.

Clin Epigenetics. 2019 03 27;11(1):54

Authors: Kamdar S, Isserlin R, Van der Kwast T, Zlotta AR, Bader GD, Fleshner NE, Bapat B

Abstract
BACKGROUND: Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, the identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology.
RESULTS: Using a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes-ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX-exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n = 423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n = 50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n = 19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site.
CONCLUSIONS: Our study identifies seven genes governed by TET2 loss in PCa which exhibit an association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.

PMID: 30917865 [PubMed - indexed for MEDLINE]