Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are associated with increased duodenal cancer incidence. The molecular pathogenesis underlying FAP- and MAP-associated duodenal disease is poorly defined, such that targeted therapies to treat the disease are lacking. In their study on page 515, Meuser and colleagues evaluated FAP- and MAP-associated duodenal tumor genomic and transcriptomic characteristics using whole exome and whole transcriptome sequencing, respectively. The authors discovered recurring somatic mutations in the gene encoding phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA), which is required for glycophosphatidylinositol (GPI) anchor synthesis, in the duodenal tumor samples. Correspondingly, using a fluorescent marker that specifically binds mammalian GPI anchors and flow cytometry, the authors found that duodenal organoids derived from patient tumors harboring PIGA mutations exhibited diminished GPI anchor abundance. The cover image depicts ontology analysis of genes differentially expressed among PIGA mutant and non-PIGA mutant duodenal tumors, which included genes encoding established GPI-anchored proteins.