Molecular Comparison of Ulcerative Colitis Different in Age and - PowerPoint PPT Presentation

Molecular Comparison of Ulcerative Colitis Different in Age and Extent of Disease by Colon Biopsy mRNA Expression Profiling Richard Strauss, MD Disclosure: Janssen Research and Development

Adult vs. Pediatric UC – Data Compatibility Adult UC Pediatric UC Data Sim poni UC T1 7 GSE1 0 6 1 6 * Data type Colon biopsy Colon biopsy Platform (all in situ Affymetrix HT HG Affymetrix HG U133 oligonucleotide) U133+ PM array Plus 2 Total # of probes 54,715 54,675 Analysis In-house In-house Analysis cutoff | FC| > 2x, adjust | FC| > 2x, adjust p< 0.05 p< 0.05 Sample size 87 UC, 21 normal 10 UC, 11 normal Disease profile 2253 probe sets 2129 probe sets *Data extracted from Nature Genetics 2008

Top Ranked Canonical Pathways in Adult and Pediatric UC P-values based on Fisher’s exact test 0.0 25.5 -log(p-value)< 1.3 considered significant enrichment (p-value < 0.05)

Common Upstream Expression Molecules Observed in Adult and Pediatric UC -7.64 0 12.84 Activation z-score inhibited activated

Extensive vs. Local Disease: Adult Patients Dataset: C0154T17 ADULT ULCERATIVE COLITIS STUDY, BASELINE SAMPLES Avg Limited 14 Correlation=0.9915 12 PValue=0.0000e+000 10 Avg Limited 8 6 4 2 0 ExtentDisease 0 2 4 6 8 10 12 14 Avg Extensive • Disease profile in extensive UC is high correlated with that in local disease • Unsupervised clustering of the disease profile shows no segregation of extensive (n= 27) vs. limited (n= 60) UC in adult patients.

Extensive vs. Local Disease: Pediatric Subjects Dataset: CNTO148UC01001 PEDIATRIC ULCERATIVE COLITIS STUDY, BASELINE SAMPLES avg.EXTENSIVE 14 Correlation=0.9750 12 PValue=0.0000e+000 10 avg.LIMITED UC 8 6 4 2 Disease Extension 0 2 4 0 6 8 10 12 14 • Disease profile in extensive UC is high correlated with that in local disease • Unsupervised clustering of the disease profile shows no segregation of extensive (n= 13) vs. limited (n= 7) UC in adult patients.

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Figure 2A Top Canonical Pathw ays in Pediatric and Adult UC B Cell Development^ Leukocyte Hepatic Fibrosis / 30 Extravasation Hepatic Stellate Cell Signaling^ Activation* ^ 25 Granulocyte Adhesion 20 TREM1 Signaling^ and Diapedesis* ^ 15 Role of Macrophages, 10 Agranulocyte Fibroblasts and Adhesion and Endothelial Cells in 5 Diapedesis* ^ RA^ 0 Diff. Reg. of Cytokine Production in Atherosclerosis Intestinal Epithelial Signaling* ^ Cells by IL-17A/ F* Altered T Cell and B Inhibition of Matrix Cell Signaling in Metalloproteases* RA* ^ LPS/ I L-1 Mediated Dendritic Cell Inhibition of RXR Maturation* ^ Function* Pediatric UC (GSE10616) Role of IL-17A in Adult UC (C0524T17) Psoriasis* Significant Enrichment Cutoff