expression of SMAD4 characterized patient derived xenografts (PDX), and identify profiles that may predict response to radiation. Materials/Methods:With IACUC approval, 20 PDAC PDXs characterized for KRAS, p53 and SMAD4 were implanted into bilateral flanks of mice and irradiated. Left flank tumors received 5 Gy/day for 2 days using the right flank as a control (n Z 5 per group). Tumor dimensions were obtained twice weekly (volumeZ (LxW2)/2); tumor growth inhibition (TGI) was calculated (treated tumor volume/control tumor volume). Gene expression data (Affymetrix GeneChip) was preprocessed with quantile normalization and log2 transformation. Methylation microarrays (Illumina 450k) were processed with quantile normalization, beta-value scale, and M-value. Key pathways of differentially expressed genes were investigated with KEGG pathway enrichment analysis. Results: Comparison of SMAD4 mutant (n Z 10) and intact (n Z 10) tumors revealed 621 and 602 differentially expressed genes following gene expression and methylation array analysis, respectively. Prominent KEGG pathways included endocytosis, melanogenesis, tight junction, ascorbate and aldarate metabolism, steroid hormone biosynthesis, and androgen and estrogen metabolism. Three genes with the strongest inverse correlation between levels of methylation and mRNA expression included ACOX2 (r Z -.56, p Z .01), CTAGE5 (r Z -.7, p Z .0004), and LY75 (r Z .61, p Z .004). Gene expression and methylation analysis as a function of relative TGI revealed 301 and 447 differentially expressed genes, respectively, and these were enriched in the pathways in cancer, melanoma, and aldosterone-regulated sodium reabsorption pathways. Irradiated tumors revealed a varying range of TGI (-58% to +72%). Using univariate linear regression to correlate TGI with gene expression and methylation revealed 5 target genes (C6orf125, CFD, DNAI1, GLI3, and TRIM24) with strong inverse correlation (r Z .53-.61, p<.02). Conclusions: Correlation of gene expression with methylation profiles of SMAD4-characterized PDAC revealed gene signatures suggestive of metabolic and hormonal dysregulation, which may contribute to the aggressive nature of SMAD4-mutant tumors. Further investigation is underway to identify potential molecular drug targets, and a signature to predict response to RT and patterns of failure. Author Disclosure: R. Tuli: None. Z. Liu: None. R. Nv: None. A.J. Surmak: None. C. Iacobuzio-Donahue: None. M. Hidalgo: None. J.M. Herman: None. S.H. Lin: None.