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Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosisassociated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasimesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK coexpression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

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Prostate cancer (PCa) is the most prevailing cancer in the male population and the second-leading cause of cancer-related death in the Western world. Although genomic alterations during PCa development have been recently characterized [1], substantial evidence shows that genome-wide epigenetic insults complement or even precede genetic alterations [2]. Promoter CpG island methylation frequently correlates with gene silencing of functional genes. Therefore we hypothesized that scanning for early-silenced genes by profiling hypermethylation sites of promoter CpG islands would facilitate identification of novel methylation biomarkers with potential functions during prostate carcinogenesis. DNA from 9 primary pT2a tumors and matched normal tissue was subjected to enrichment of methylated sequences using Methyl CpG Immunoprecipitation (MCIp) [3], followed by array co-hybridization using Agilent CpG island arrays. Candidate genes were selected according to 1) hypermethylation in gene promoter regions in tumor tissue and 2) reduced expression in PCa in comparison to normal prostate tissue based on published gene expression datasets. DNA methylation was quantified by mass spectrometry-based EpiTYPER technology [4]. We identified 245 promoter CpG islands corresponding to 207 genes that were hypermethylated in at least 6/9 early stage PCa. Gene ontology enrichment analyses indicated enrichment of homeobox genes, and of gene functions such as regulation of transcription, cellular biosynthesis and morphogenesis, and neuron development. Quantitative methylation analysis of 9 selected candidate genes confirmed significant hypermethylation in the range of 20 -50% in 6/9 tumors of the initial discovery set in comparison with normal prostate tissue. Further validation in 37 sample triplets of matched normal tissue - prostate intraepithelial neoplasia (PIN) - tumor tissue indicated significant hypermethylation of SPG20 (spastic paraplegia 20, p=0.023, Wilcoxon signed-rank test), SPATA6 (spermatogenesis associated 6, p=0.017), and DUOXA1 (dual oxidase maturation factor 1 alpha, p=0.017) already at the PIN stage. Moreover, methylation analysis of 60 prostate tumor samples with increasing malignancy revealed a significant correlation between DNA hypermethylation patterns and biochemical recurrence of prostate cancer (p=0.008, log-rank test). From this genome-wide study we identified relevant biomarkers for early-detection and prognosis of early stage prostate cancer. The identified genes might represent interesting candidates to further investigate their function in the molecular pathogenesis and development of prostate cancer. Citation Format: Po-Hsien J. Huang, Wolfgang Göring, Thomas Hielscher, Dieter Weichenhan, Wolfgang A. Schulz, Christoph Plass, Clarissa Gerhäuser. Genome-wide DNA methylation profiling identifies novel diagnostic and prognostic biomarkers in early stage prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2. doi:10.1158/1538-7445.AM2013-2