STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma

A genetic hallmark of pancreatic ductal adenocarcinoma (PDA) is the presence of somatic KRAS mutations in over 90 to 95% of tumors, the most prevalent being KRASG12D[1,2]. A fundamental question remains the identification of somatic aberrations arising in the complex genomic landscape of PDA that drive the progression of KRAS mutant neoplastic cells in humans in vivo. Furthermore, of significant interest are those selected aberrations that create therapeutic vulnerabilities that can be exploited to advance improved and more personalized care of patients. The STAG2 gene encodes a subunit of the cohesion complex, which plays an essential role in the proper division and segregation of chromosomes, a process that is essential for the maintenance of genome stability and cell survival [3,4]. Mutations targeting this class of genes have been studied in model systems, but have been detected in a relatively small number of somatic tumors arising in patients in vivo[5-7]. Recently, somatic aberrations and loss of STAG2 expression have been reported in a subset of tumors and cell lines, including melanomas, sarcomas, and glioblastomas [3]. Notably, truncating mutations in STAG2 have been shown to be one of the most common genetic lesions in bladder carcinoma [8]. Functional analysis has shown that loss of STAG2 leads to chromosome missegregation and aneuploidy in human cell lines and may promote a mutator phenotype [3,4]. The development of a KRASG12D-driven genetically engineered mouse (GEM) model of PDA has provided a powerful resource for the study of the events that accelerate tumorigenesis and drive tumor progression in the pancreas [9]. Strikingly, STAG2 was one of the most frequent and significant insertion targets reported in a transposon-mediated screen of the KRASG12D GEM model of PDA. However, mutations in STAG2 and clinically relevant variations in its protein expression levels have not been reported to date in human PDA samples [3,8]. Thus, the clinical significance of STAG2 expression and its role as a tumor suppressor gene in human PDA remains to be elucidated.