Abstract B114: Mutational "lineage traces" of an acinar cell-of-origin in human pancreatic ductal adenocarcinoma

Abstract

Abstract A clinical challenge of pancreatic ductal adenocarcinoma (PDAC) is that most cases are detected late, after intractable metastasis is well underway. This also poses a challenge to our basic understanding of PDAC development, as the early steps of neoplasia are separated by a gulf of years or decades from accessible biospecimens and cell lines. Although mouse genetic models of PDAC have helped to fill in this gap, key questions remain incompletely answered. For example, what is the cell of origin of human PDAC – and does the answer to this question actually matter at a clinical level? In mouse, PDAC can be induced from both acinar and duct cells, with the former apparently more susceptible to transformation while the latter appears harder to transform, but capable of generating more aggressive tumors. Meanwhile, human PDAC has been divided into two major subtypes based on genomic data, classical and basal-like, the latter of which appears to be more aggressive. Is there a relationship between cell-of-origin, tumor subtype and clinical outcomes? This question requires the ability to directly infer cell-of-origin in human tumors, an approach to which we report here. Studies in human non-pancreatic cancers have identified somatic “passenger” (non-selected) mutations in several highly-expressed genes of the normal organ – for example, mutations in the ALB (albumin) gene in hepatocellular carcinoma, or SFTP genes (surfactant proteins) in lung adenocarcinoma. These might indicate a mutational process occurring in normal cells, prior to transformation, and constituting a “lineage mark” for the cell of origin – however, as these genes are also highly-transcribed in the cancer cells themselves, their mutations may arise after tumorigenesis is underway. This problem does not apply to acinar genes and PDAC: we and others have established that an initiating event in Kras-induced transformation of acinar cells is complete downregulation of acinar-specific gene products. Therefore, if a mechanism of transcription-induced mutation applies in the pancreas, we would expect it to leave a trace in acinar-derived PDAC. We have completed a large-scale analysis (n>2,000) of human whole genome sequencing data, across several carcinoma types including pancreas and liver, focused on unbiased detection of tissue-specific mutations similar to those previously found in the ALB and SFTP genes. Remarkably, we find robust enrichment of mutations in acinar-specific genes in PDAC, affecting approximately 25% of tumors. This constitutes the first in vivo genetic evidence for an acinar cell-of-origin in human pancreatic cancer, and opens the door to comparative genomic, transcriptomic and outcomes analyses of acinar-derived tumors. These are underway, and the results will be described in our presentation. Citation Format: Charles Murtaugh. Mutational "lineage traces" of an acinar cell-of-origin in human pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B114.