Abstract 7369: Passenger mutations link cellular origins and transcriptional identity in human lung adenocarcinoma

Abstract Lineage plasticity hinders identification of cellular origin of cancers, as malignant cells cease to resemble benign cells from which they presumably evolved. Lung adenocarcinoma (LUAD), the most common primary lung cancer in United States is thought to arise from alveolar type II (AT2) cells. However recent mouse models have shown that LUADs may also arise from other cell types such as basal and club. Although such mouse models are considered to be gold standard for identifying cell of origin for cancers, they are generally limited to a specific genetic context and lack all cell types that are present in human lung. Thus, to better understand the cellular origins of LUAD, we utilized a publicly available lung scRNA-seq atlas from Human Cell Atlas, spanning over 584,000 cells from 107 individuals to investigate cell type specific passenger mutational footprints of transcriptional coupled repair process (a sub-pathway of nucleotide excision repair that preferentially corrects mutations in highly expressed genes) across 295 lung cancer WGS profiles. As most mutations in self-renewing tissues are thought to occur prior to the onset of tumorigenesis, genes that are most highly transcribed in the cell of origin would have fewer somatic single nucleotide variants (SNV). To test this hypothesis, our study correlated somatic mutational density with gene expression profiles of cell types to identify Alveolar Type 0 (AT0, newly identified cell type) cells to be most strongly associated with LUAD mutation density, suggesting that the ancestor of LUAD cells in tumor spent most of their non-cancerous time in AT0 state. Interestingly studies have shown that following DNA damage in AT2 cells, transition to AT1 occurs to repair the damage. However, if the damage is detrimental, the transition of AT2 to AT1 is stalled and the cells remain in AT0 (i.e., a transitionary) state. We propose that such stalling for a long period of time can give rise to LUAD. Further our study identified a subset of LUAD patients with non-AT2 (i.e., proximal) origin. In particular, we observed significantly higher KRAS mutations in distal origin LUAD patients compared to those in proximal origin LUADs. Finally, a subset of LUAD patients with distal cell of origin adopted a more proximal transcriptional identity. Extending our analysis to lung squamous cell carcinoma (LUSC) patients, we observed basal resting cells to be the Cell of Origin (COO) for LUSC. Our study provides a novel approach for identifying cell of origin for cancers and points to a complex interplay between origin and identify in lung adenocarcinoma evolution. Citation Format: Sukanya Panja, Padmaja Mantri, Juan Andrade Martinez, Marcin Imielinski. Passenger mutations link cellular origins and transcriptional identity in human lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7369.