Mucinous Cystic Neoplasms of the Pancreas and Liver share a similar DNA methylation profile with mucinous ovarian tumors

Mucinous cystic neoplasms (MCN) remain a major riddle in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and 6 hepatic MCNs (MCN-L). Unsupervised analysis of DNA methylation profiles of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN-P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing 5 tumor types and normal bile duct tissue from 136 unique samples, MCN-L demonstrated a specific methylation profile when compared to all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors—featuring 5 tumor types, normal fallopian tube, and normal ovarian tissue from 90 unique samples—we found that both MCN-P and MCN-L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors. Notably, low-grade MCNs exhibited greater DNA methylation similarities to mucinous borderline ovarian tumors, while high-grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and 4 normal tissue types, n = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in anetwork analysis of differentially methylated probes indicated that MCN-P and MCN-L share significant methylomic traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN-P and MCN-L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. Analysis of MCN-P and MCN-L FFPE samples through immunohistochemistry, targeted DNA sequencing, and genome-wide DNA methylation profiling. DNA methylation analysis was performed using Illumina Infinium MethylationEPIC v1 BeadChip array.