title: The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon.
abstract: OBJECTIVE
  ATG16L1 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  The 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.
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Wesley A
authors: WA
authors: Grimm
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Jeannette S
authors: JS
authors: Messer
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Stephen F
authors: SF
authors: Murphy
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Thomas
authors: T
authors: Nero
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: James P
authors: JP
authors: Lodolce
authors: Departments of Pathology, University of Chicago, Chicago, Illinois, USA.
authors: Christopher R
authors: CR
authors: Weber
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Mark F
authors: MF
authors: Logsdon
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Sarah
authors: S
authors: Bartulis
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Brooke E
authors: BE
authors: Sylvester
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Amanda
authors: A
authors: Springer
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Urszula
authors: U
authors: Dougherty
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Timothy B
authors: TB
authors: Niewold
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Sonia S
authors: SS
authors: Kupfer
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Nathan
authors: N
authors: Ellis
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Dezheng
authors: D
authors: Huo
authors: Departments of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors: Marc
authors: M
authors: Bissonnette
authors: Departments of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA.
authors: David L
authors: DL
authors: Boone
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071183:Autophagy-Related Proteins; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D007370:Interferon Type I
keywords: CROHN'S DISEASE; GENETICS; IBD - GENETICS; INFLAMMATION
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