Crohn's disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer

EBioMedicine

Chad E. Storer¹  William A. LaFramboise²  Ta-Chiang Liu³  Uma Chandran³  Douglas J. Hartman⁴  Liron Pantanowitz⁴  Changqing Ma⁴  Talin Haritunians⁴  Richard D. Head⁵  Patricia Petrosko⁶  Madison Frank⁶ 

[1] Corresponding authors.;Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States;Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, United States;Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, A-610, Pittsburgh, PA 15213, United States;F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States;UPMC Hillman Cancer Center, Cancer Genomics Facility, Pittsburgh, PA 15232, United States;

关键词: Autophagy;    Apoptosis;    Genotyping;    Transcriptomics;    Stratification;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: A non-synonymous single nucleotide polymorphism of the ATG16L1 gene, T300A, is a major Crohn's disease (CD) susceptibility allele, and is known to be associated with increased apoptosis induction in the small intestinal crypt base in CD subjects and mouse models. We hypothesized that ATG16L1 T300A genotype also correlates with increased tumor apoptosis and therefore could lead to superior clinical outcome in cancer subjects. Methods: T300A genotyping by Taqman assay was performed for gastric carcinoma subjects who underwent resection from two academic medical centers. Transcriptomic analysis was performed by RNA-seq on formalin-fixed paraffin-embedded cancerous tissue. Tumor apoptosis and autophagy were determined by cleaved caspase-3 and p62 immunohistochemistry, respectively. The subjects' genotypes were correlated with demographics, various histopathologic features, transcriptome, and clinical outcome. Findings: Of the 220 genotyped subjects, 163 (74%) subjects carried the T300A allele(s), including 55 (25%) homozygous and 108 (49%) heterozygous subjects. The T300A/T300A subjects had superior overall survival than the other groups. Their tumors were associated with increased CD-like lymphoid aggregates and increased tumor apoptosis without concurrent increase in tumor mitosis or defective autophagy. Transcriptomic analysis showed upregulation of WNT/β-catenin signaling and downregulation of PPAR, EGFR, and inflammatory chemokine pathways in tumors of T300A/T300A subjects. Interpretation: Gastric carcinoma of subjects with the T300A/T300A genotype is associated with repressed EGFR and PPAR pathways, increased tumor apoptosis, and improved overall survival. Genotyping gastric cancer subjects may provide additional insight for clinical stratification.

【 授权许可】

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