Non-autophagic function of ATG16L1 in human colorectal cancer

A greater understanding of the impact of host genetics in the clinicopathology of CRC may lead to improved criteria for treatment and identification of genes involved in antitumor host responses. ATG16L1 is an autophagy-related gene with autophagy-independent functions in host immunity. A common non-synonymous polymorphism in ATG16L1 (T300A) previously associated with Crohn's disease (CD) and present in approximately 50% of alleles of European ancestry has recently been linked to improved clinical outcomes in thyroid cancer. Considering the function of ATG16L1 in host immune responses, and particularly in the gastrointestinal tract, we hypothesized that the T300A variant influences clinical outcomes in CRC patients. To test this we studied patients treated for CRC at the University of Chicago Medical Center and identified an association between prolonged overall survival, fewer metastatic cancers, and the ATG16L1 Ala/Ala genotype. These observations were correlated with increased type I interferon activity in stage I adenocarcinomas from ATG16L1 Ala/Ala patients, suggesting that differences in production of antitumor cytokines may underlie this association. When introduced into human CRC cells by homologous recombination, the T300A variant did not affect bulk (non-selective) autophagy but increased basal production of type I interferon (IFN) and increased sensitivity to the dsRNA mimic poly(I:C) through a mitochondrial antiviral signaling (MAVS)-dependent pathway. These cell-autonomous functions of ATG16L1 were associated with reduced proliferation, decreased glycolysis, and hyperpolarized elongated mitochondria. Thus, ATG16L1 T300A is a relevant host genetic variant that impacts CRC outcomes and cancer cell pathophysiology. These results may have applications for the use of oncolytic viruses and p(I:C) as immunoadjuvants to cancer therapy.