Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project.
Alexander SemaanVincent BernardJustin W WongYuki MakinoDaniel B SwartzlanderKimal I RajapaksheJaewon J LeeAdam OfficerC Max SchmidtHoward H WuCourtney L ScaifeKajsa E AffolterDaniela NachmansonMatthew A FirpoMichele T Yip-SchneiderAndrew M LowyOlivier HarismendySubrata SenAnirban MaitraYasminka A JakubekPaola A GuerreroPublished in: Cancer research communications (2023)
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 transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histological dysplasia obtained from 23 patients, followed by whole exome and whole transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification being associated with HG progression and with cases that harbored co-occurring 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 as well as pathways related to glycosylation were a common feature of progression to HG. Additionally, the established PDAC transcriptional subtypes (basal-like and classical) were readily apparent within IPMNs. 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 reinforces that evolutionary pathways in IPMNs are heterogenous, comprised of both SNV and CNA-driven events.
Keyphrases
- copy number
- low grade
- high grade
- genome wide
- mitochondrial dna
- single cell
- dna methylation
- gene expression
- fluorescent probe
- transcription factor
- magnetic resonance imaging
- rna seq
- lymph node
- machine learning
- clinical trial
- prognostic factors
- ejection fraction
- signaling pathway
- oxidative stress
- depressive symptoms
- randomized controlled trial
- mass spectrometry
- living cells
- magnetic resonance
- diffusion weighted imaging
- high resolution
- squamous cell
- clear cell
- young adults