Mucinous cystic neoplasms (MCNs) of the pancreas (MCN-P) and liver (MCN-L) exhibit epigenetic similarity based on DNA methylation profiles to mucinous ovarian tumors, including borderline and carcinomatous subtypes, according to a recent study.
MCNs of the MCN-P and MCN-L are rare lesions characterized by mucinous epithelium and ovarian-like stroma. These tumors predominantly occur in women and have a documented risk of progression to invasive carcinoma. Researchers, led by Zoe Leoni of the Institute of Pathology, Charité – Universitätsmedizin Berlin, performed immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a rare cohort of 21 mucinous cystic neoplasms — 15 MCN-P and six MCN-L — to examine their molecular characteristics and relationships to other neoplasms.
Unsupervised DNA methylation analysis of 224 pancreatic samples across 11 tumor types and normal tissue showed that MCN-P formed a separate group, distinct from other pancreatic lesions. Similarly, in a cohort of 136 hepatic samples, MCN-L exhibited a DNA methylation pattern that was distinct from intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and other bile duct neoplasms. Within the ovarian tumor cohort of 90 samples, both MCN-P and MCN-L grouped with mucinous borderline ovarian tumors (mBOTs) and primary mucinous ovarian carcinomas (PMOCs). Low-grade MCNs demonstrated greater similarity to mBOTs, while high-grade and invasive MCNs were more closely associated with PMOCs.
Published in The Journal of Pathology, analysis across all 430 samples representing pancreatic, hepatic, and ovarian tumors showed that MCN-P and MCN-L clustered with mucinous ovarian tumors and normal ovarian tissue. A network-based analysis of differentially methylated CpGs indicated zero differences between MCN-P and MCN-L and identified mBOTs as the most closely related neoplasm. Additional relationships were observed between MCN-P and certain pancreatic ductal lesions, such as gastric-type intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasias.
Pathway analysis of differentially methylated CpGs revealed activation of germ cell–related pathways and reduced expression of immune and digestive-related pathways. Cell-type deconvolution suggested enrichment of stromal and endothelial cells and reduced acinar and ductal cell content in MCNs when compared with normal tissues. These findings support the developmental hypothesis that MCNs may originate from primordial germ cells or gonadal remnants, consistent with previously proposed theories regarding the role of stromal signaling in their pathogenesis.
Together, these findings support the classification of MCN-P and MCN-L as distinct tumor types within pancreatic and hepatic neoplasia – indicating that their DNA methylation profiles are similar to those of mucinous ovarian tumors.
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