TERC and c-MYC COPY number gain in intraductal papillary mucinous neoplasms (IPMNs): promising biomarkers of progression to malignancy

Introduction: Intraductal papillary mucinous neoplasm (IPMN) is the most common cystic precancerous lesion of pancreatic cancer (PDA). IPMNs can progress from low to high-grade dysplasia, to invasive PDAC, but exact data regarding cancer risks are limited. PDAC is the fourth leading cause of cancer death . The overall 5-year survival is 6%, but survival of patients with early stage PDAC is significantly better. AIM: We used an approach coupling high resolution cytogenetic analysis (Affymetrix Oncoscan FFPE Array) with a clinically-oriented bioinformatic interpretation of data to understand what are the most relevant pathways altered in precursor lesions. Materials and methods: High resolution cytogenetic analysis was performed in 20 formalin fixed paraffin embedded samples of IPMNs by Oncoscan FFPE assay. Genomic data were analyzed for copy number gains and losses, loss of heterozygosity and for a panel of recurrent somatic mutations. Results were validated by qPCR and FISH analysis. Results: Twenty samples, including 14 mixed-type IPMNs (70%), 4 branch-duct IPMNs (20%) and 2 main-duct IPMNs (10%), were collected. We identified micro-invasive carcinoma (< 1 mm) and invasive carcinoma in 25% and in 10% of IPMNs respectively. By our high resolution cytogenetic analysis we observed that 8 IPMNs (40%) presented a nearly normal karyotype (< 4 copy number alterations), while 12 IPMNs (60%) showed a complex karyotype (> 10 alterations). In the latter subgroup were detected specific copy number gains of TERC and c-MYC oncogenes. Interestingly we noticed that TERC and c-MYC overexpression, present in 92% and 45% of complex karyotype samples respectively, were only observed in high-grade IPMNs, suggesting a possible role in a progression to malignancy. Oncoscan data were confirmed by Real Time and FISH analysis. Conclusions: Those results suggest a role of TERC and c-MYC overexpression as a possible biomarkers in the early identification of patients with complex karyotype IPMNs in order to better stratification of cystic lesions that could require surgery