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Abstract
DNA hypomethylation represents the most prevalent epigenetic alteration in human cancer, yet its cellular origins remain incompletely understood. In lung adenocarcinoma (LUAD), DNA hypomethylation is associated with upregulation of distinct gene groups, including: cancer-germline (CG) genes normally restricted to testicular germ cells, and stratified epithelium (SE) genes typically expressed in multilayered epithelia. Among the latter, FAM83A has emerged as a pro-tumoral gene implicated in cancer progression and therapy resistance. Here, we asked whether FAM83A activation in LUAD represents an epigenetic abnormality or if it reflects redirection of malignant cells towards an existing epithelial program. By analyzing single-cell RNA sequencing data from normal lung we found that, while FAM83A is undetectable in whole lung tissue homogenates, it is expressed in subsets of airway epithelial cells corresponding to basal/suprabasal and goblet cell populations. In contrast, CG gene MAGEA1 is silent in all lung cell types. Consistently, RT-qPCR detected FAM83A, but not MAGEA1, in primary and immortalized human lung basal cells. Bisulfite sequencing showed that the promoter of FAM83A, but not MAGEA1, is unmethylated in these cells. Analyses of transcriptomic datasets from LUAD cell lines and tissues demonstrated that FAM83A expression is correlated with markers of suprabasal and goblet lineages in malignant cells. They further revealed co-expression of FAM83A with NAPSA, a marker of alveolar AT2 cells, from which LUAD originates. Together, these findings indicate that, whereas MAGEA1 activation in LUAD results from an aberrant process of DNA demethylation, FAM83A upregulation in LUAD reflects redirection of alveolar cells towards an airway differentiation program.
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Wangermez, C., Carlier, F., Lecocq, M., Pilette, C., & De Smet, C. (2026). Hypomethylation of FAM83A in lung adenocarcinoma mirrors an epigenetic signature of airway cell differentiation states. Discover Oncology, 17(1), 1154. https://doi.org/10.1007/s12672-026-05380-8 (Original work published 2026)