The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

Abstract

Background and aims: Protein and organelle turnover by autophagy is a key component to maintain cellular homeostasis. Loss of the autophagy protein ATG16L1 is associated with reduced bacterial killing and aberrant interleukin-1β production, perpetuating inflammation and carcinogenesis. Here we hypothesized that the functional p.T300A gene variant in ATG16L1 is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis. Methods:A case-control study was performed using a prospective derivation cohort (107 patients with HCC and 101 controls) and an independent validation cohort (124 patients with HCC and 108 controls) of patients with cirrhosis of any aetiology. ATG16L1 p.T300A (rs2241880) and PNPLA3 p.I148M (rs738409) variants were determined by real-time PCR.Results: The G allele of the ATG16L1 p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, P = .022) and in the validation cohort (0.59 vs. 0.50, P = .045). In combined analysis, the odds ratios (OR) were 1.76 (95% CI: 1.07-2.88) for G allele positivity and 2.43 (95% CI: 1.37-4.31) for p.T300A G allele homozygosity. This association was independent from the presence of a PNPLA3 variant, which was also associated with HCC (OR 2.10; 95% CI: 1.20-3.66), and it remained significant after adjustment for male sex, age and aetiology in multivariate analysis. Conclusion:The common germ-line ATG16L1 gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by ATG16L1 and PNPLA3 may be used for risk-based surveillance in cirrhosis. K E Y W O R D S ATG16L1, autophagy, cirrhosis, genetic polymorphisms, hepatocellular carcinoma | 2361 REUKEN Et al.

A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients

“… 151 The role of ATG16L1 loss-of-function alleles has also been reported for other cancers than HNSCC. Indeed, rs2241880 has been described as a risk factor both for developing hepatocellular carcinoma in the context of cirrhosis, 152 breast cancer, 153 and gastric cancer. 154 Moreover, the ATG16L1 AG genotype was found to be associated with an earlier age at diagnosis of melanoma.…”

Association of ATG16L1 and ATG5 gene polymorphisms with susceptibility to hepatitis B virus infection and progression to HCC in central China

“…In addition, ATG16L1 proteins were upregulated in HBV‐related HCC compared to adjacent nontumor tissues 29 . Furthermore, ATG16L1 and ATG5 gene polymorphisms are linked to susceptibility to multiple diseases 30–32 . To date, the influence of ATG16L1 and ATG5 polymorphisms on HBV infection has not been reported in central China.…”

“…29 Furthermore, ATG16L1 and ATG5 gene polymorphisms are linked to susceptibility to multiple diseases. [30][31][32] To date, the influence of ATG16L1 and ATG5 polymorphisms on HBV infection has not been reported in central China. Hence, to further investigate the role of autophagy in HBV infection, we conducted this study to confirm the influence of ATG (ATG16L1 and ATG5) gene polymorphisms on susceptibility to HBV infection and the progression of HBV-related HCC.…”

NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP

“…The function of beclin-1 is inhibited by B-cell CLL/lymphoma 2, and thus, it has been demonstrated that beclin-1 acts as a tumor suppressor [ 22 , 23 ]. ATG proteins, such as ATG3, ATG12, and ATG16L1, are also demonstrated to have anti-oncogenic properties [ 24 , 25 , 26 , 27 ]. The impairment of autophagy causes the accumulation of P62, leading to the development of HCC [ 28 ].…”