Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low grade (LG) to high grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multi-region sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy number alterations (CNAs) and transcriptomics changes, that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histological dysplasia obtained from 24 patients (total of 74 independent histological lesions), followed by whole exome and whole transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification, in particular, being associated with HG progression and with cases that harbored cooccurring PDAC. Furthermore, the combined assessment of single nucleotide variants (SNVs) and CNAs identified both linear and branched evolutionary trajectories, underscoring the heterogeneity in the progression of LG lesions to HG and PDAC. At the transcriptome level, upregulation of MYC-regulated targets and downregulation of transcripts associated with the MHC class I antigen presentation machinery was a common feature of progression to HG. Taken together, this work emphasizes the role of 1q copy number amplification as a putative biomarker of high-risk IPMNs, underscores the importance of immune evasion even in non-invasive precursor lesions, and supports a previously underappreciated role of CNA-driven branching evolution as an avenue for IPMN progression. Our study provides important molecular context for risk stratification and cancer interception opportunities in IPMNs. SignificanceIntegrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.