 In the lab through translational research studies, we hope to identify re-expression or a reduction in promoter methylation of genes involved in tumor suppressor pathways known to be important in colorectal cancer CRC or involved in EGFR signaling pathway. Candidate genes we will evaluate will include genes described in prior studies as associated with the CpG island methylator phenotype CIMP as well as genes previously reported to be hypermethylated in association with colorectal neoplasia. These will include APC, SFRP family members, CDH-1 e-cadherin and p16 Belshaw et al., 2008; Lind et al., 2004; Suehiro et al., 2008. Other genes more specific to EGFR or KRAS signaling that will be assessed include: RASSF1A , a tumor suppressor gene know to be hypermethylated in several human cancers including CRC, is occasionally associated with KRAS wild type and when silenced by methylation allows for RAS activation Kang et al., 2006; Oliveira et al., 2005; SOX17, a member of the transcription factor superfamily know to be hypermethylated in CRC and lead to disrupted Wnt signaling Zhang et al., 2008; SOCS-1 a negative regulator of STAT3 an activating ligand for EGFR that has been shown to be silenced by hypermethylation and allow for constitutive signaling via EGFR Lee et al., 2006; and PTEN, a tumor suppressor that antagonizes the PI3K- AKTPKB signaling pathway by dephosphorylating phosphoinositides Noro et al., 2007. Further candidate genes may be discovered or added based on preliminary data and ongoing research. Methylation analysis and gene expression pattern changes will be done using methylation specific PCR and bisulfite sequencing of genes known to be involved in EGFR signaling pathways and colorectal neoplasia as described above. We have prior data from our own work as well as others to suggest the use of a hypomethylating agent can resensitize colon cancer cells to therapeutic agents Karpf et al., 1999; Morita et al., 2006. The translational component of this research will be supported by institutional translational grant awarded to the PI, Kimberly Jones, as of July 1st, 2008. This information may help identify other important targets and allow for the design of better combination therapies. We plan to do these assays on weekly blood and buccal samples while patients are on therapy, on epithelial cells swabbed from panitumumab associated skin rash, and on archived or biopsied tumor specimens when available from KRAS testing required and optional end-of treatment biopsy. 