Impact of Somatic STAT2 Mutations on the Antitumor Type I Interferon Response in Colon Cancer
Jorge Canar1 and Ana Gamero, PhD1
1Lewis Katz School of Medicine at Temple University, Department of Medical Genetics and Molecular Biochemistry
Colorectal cancer (CRC) is the third deadliest cancer in the US, with an alarming increase in incidence rates in young adults, especially among African Americans and non-Hispanic Whites. There is an urgent need to better understand the biology of this disease to identify new targets and develop novel therapeutic interventions. Signal transducer and activator of transcription 2 (STAT2) is a positive effector of antitumor type I interferon (IFN-I) signaling. In previous studies, we reported that, paradoxically, STAT2 is tumorigenic in CRC. Our studies now show STAT2 protein is elevated and activated in human colorectal tumors. We analyzed TCGA-CRC datasets and found high STAT2 mRNA levels associated with poor prognosis. We also identified five somatic STAT2 missense mutations of interest that based on their location, could potentially alter IFN-I responses in CRC. Of particular interest was R148>W because it was identified as a lethal homozygous germline mutation in children born with a condition known as type I interferonopathy. To interrogate their functionality, we generated STAT2 deficient colon cancer cell lines and reintroduced different STAT2 mutations individually. Western blot analysis showed STAT2 mutants are expressed to comparable levels as wild-type STAT2. To determine their transcriptional activity in response to IFN-I, we measured luciferase reporter transcriptional activity. Interestingly, STAT2 R148W displayed reduced activity to wild type STAT2, in stark contrast to the expected phenotype of aberrant IFN-I signaling. Similar responses were seen with STAT2 R310C. These novel findings reveal somatic STAT2 mutations in CRC can impair IFN-I signaling and potentially their antitumor effects.
