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225PEXTENSIVE METHYLATION OF EPIDERMAL GROWTH FACTOR-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 1 (EFEMP1) PROMOTER COULD PREDICT MALIGNANT FORMATION IN INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS (IPMN).

ABSTRACT Introduction: Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are pancreatic cystic tumors. Genetic and epigenetic alterations are believed to be accumulated during tumor progression. Whereas the specific genetic mutations and DNA methylation for each type of lesion have been somewhat known, the fundamental understanding for the dynamics of methylation expansion across specific CpG dinucleotides in a gene promoter during carcinogenesis remains unclear. We sought to evaluate whether the expansion of methylation in the EFEMP1 promoter could serve as a predictive biomarker for malignant IPMNs. Methods: KRAS mutations and the methylation status of two discrete regions within the EFEMP1 promoter in 65 IPMN tissues, including 30 IPMNs with low- and intermediate-grade dysplasia, 12 IPMNs with high-grade dysplasia and 23 invasive IPMN, were determined using genomic sequencing and High Sensitive Assay for bisulfate modification DNA (Hi-SA) - a modified COBRA by which fluorescence labeled DNA fragments are detected using a genetic analyzer (Nagasaka T et al., JNCI 2009), respectively. Thereafter, correlation between mutant KRAS, methylation status and various clinic-pathological features were examined. Results: KRAS mutations were detected in 42.9% of low- and intermediate-grade IPMNs, 33.3% of high-grade IPMNs and 71.4% of invasive IPMNs. All mutations were confined to codon 12 of the KRAS gene, and these mutations did not correlate with a specific histological grade or type of lesions, or any of the other clinic-pathological features. On the other hand, while the methylation of the region 1 or region 2 within the EFEMP1 promoter was observed in more than 80% of non-invasive IPMNs and invasive IPMNs, simultaneous methylation of both regions occurred in 0% of noninvasive vs. 34.7% of invasive IPMNs (p = 0.00148). These results suggest that KRAS mutations and extensive methylation within the EFEMP1 promoter were one of the early and late events in cancer progression, respectively. Conclusions: The extensive methylation in EFEMP1 promoter could be a potential predictive marker for identification of invasive IPMNs, and provides an attractive rationale for developing this molecular signature as a substrate for the development of non-invasive screening for invasive IPMNs. Disclosure: All authors have declared no conflicts of interest.