The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon

Abstract

ObjectiveATG16L1 is an autophagy gene known to control host immune responses to viruses and bacteria. Recently, a non-synonymous single-nucleotide polymorphism in ATG16L1 (Thr300Ala), previously identified as a risk factor in Crohn's disease (CD), was associated with more favourable clinical outcomes in thyroid cancer. Mechanisms underlying this observation have not been proposed, nor is it clear whether an association between Thr300Ala and clinical outcomes will be observed in other cancers. We hypothesised that Thr300Ala influences clinical outcome in human colorectal cancer (CRC) and controls innate antiviral pathways in colon cancer cells.DesignWe genotyped 460 patients with CRC and assessed for an association between ATG16L1 Thr300Ala and overall survival and clinical stage. Human CRC cell lines were targeted by homologous recombination to examine the functional consequence of loss of ATG16L1, or introduction of the Thr300Ala variant.ResultsWe found an association between longer overall survival, reduced metastasis and the ATG16L1 Ala/Ala genotype. Tumour sections from ATG16L1 Ala/Ala patients expressed elevated type I interferons (IFN-I)-inducible, MxA, suggesting that differences in cytokine production may influence disease progression. When introduced into human CRC cells by homologous recombination, the Thr300Ala variant did not affect bulk autophagy, but increased basal production of type I IFN. Introduction of Thr300Ala resulted in increased sensitivity to the dsRNA mimic poly(I:C) through a mitochondrial antiviral signalling (MAVS)-dependent pathway.ConclusionsThe CD-risk allele, Thr300Ala, in ATG16L1 is associated with improved overall survival in human CRC, generating a rationale to genotype ATG16L1 Thr300Ala in patients with CRC. We found that Thr300A alters production of MAVS-dependent type I IFN in CRC cells, providing a mechanism that may influence clinical outcomes.

Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

“…This is consistent with the elevated risk of IBD patients to develop colorectal cancer (Ekbom et al, 1990). Human patient data also suggest that bulk autophagy is not perturbed in colorectal cancer cells carrying the ATG16L1 T300A variant, while the level of type I interferon is highly elevated and improves survival (Grimm et al, 2016). These findings support a proposal that the differentiation and proper functioning of Atg16 mutant EE/Paneth cells does not depend on bulk autophagy.…”

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

“…28 In a recent study, ATG16L1 (T300A) was found to be associated with reduced metastasis in colorectal cancer patients. 36 Collectively, these observations indicate that our finding of an association between SNPs and BM in patients with NSCLC may be biologically plausible.…”

Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth

“…Interestingly, during the preparation of the manuscript, it was reported that the T300A variant of ATG16L1 was associated with strong type I IFN responses and improved survival in patients with CRC (ref. 41). In addition, we found that the morphology of Paneth cells and goblet cells was abnormal in the tumour-free mucosa of Apc +/− Atg7 −/− mice, resulting from the attachment of some bacteria to the epithelium.…”