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Colonic diverticulosis is a very common condition. Many patients develop diverticulitis or other complications of diverticular disease. Recent genome-wide association studies (GWAS) consistently identified three major genetic susceptibility factors for both conditions, but did not discriminate diverticulititis and diverticulosis in particular due the limitations of registry-based approaches. Here, we aimed to confirm the role of the identified variants for diverticulosis and diverticulitis, respectively, within a well-phenotyped cohort of patients who underwent colonoscopy. Risk variants rs4662344 in Rho GTPase-activating protein 15 (ARHGAP15), rs7609897 in collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) and rs67153654 in family with sequence similarity 155 A (FAM155A) were genotyped in 1,332 patients. Diverticulosis was assessed by colonoscopy, and diverticulitis by imaging, clinical symptoms and inflammatory markers. Risk of diverticulosis and diverticulitis was analyzed in regression models adjusted for cofactors. Overall, the variant in FAM155A was associated with diverticulitis, but not diverticulosis, when controlling for age, BMI, alcohol consumption, and smoking status (OR adjusted 0.49 [95% CI 0.27-0.89], p = 0.002). Our results contribute to the assessment specific genetic variants identified in GWAS in the predisposition to the development of diverticulitis in patients with diverticulosis.

Background and Aims: Liver steatosis is one of the side effects of chemotherapy. The PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 p.G17E variants represent genetic determinants for progressive liver diseases. Here, we investigate their association with chemotherapy-associated steatosis., Patients and Methods: Prospectively, we recruited 87 patients undergoing systemic chemotherapy for gastrointestinal cancers. Hepatic fat (controlled attenuation parameter, CAP) and liver stiffness (LSM) were measured non-invasively before the initiation of chemotherapy (T0) and after at least two (T1) and four cycles (T2). Genetic variants were genotyped using allelic discrimination assays., Results: In the final dataset (n = 60) patients demonstrated the following CAP values: T0 - 215.0 ± 55.7 dB/m, T1 - 223.3 ± 53.6 dB/m, T2 - 223.4 ± 56.7 dB/m, consistent with mild steatosis. Initial CAP correlated with BMI (P < 0.01) and serum triglyceride concentrations (P = 0.03). Whereas at T0 none of the variants was associated with CAP or LSM, carriers of the prosteatotic PNPLA3 p.148M allele showed significantly (P = 0.008) higher steatosis at T1 as compared to patients carrying the homozygous wild-type genotype [II]., Conclusions: Our preliminary results show that patients carrying the PNPLA3 p.I148 M risk allele might be prone to hepatic fat accumulation during chemotherapy. Further studies are be needed to validate the clinical value of these findings., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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., (© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.)

Objectives: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC., Methods: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression., Results: The development of HCC was independently associated with PNPLA3 rs738409 (OR adjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10 -12 ) and TM6SF2 rs58542926 (OR adjusted 1.66 [1.30-2.13], p = 5.13 × 10 -05 ), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (OR adjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined., Conclusions: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.

Objective: Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes with microsatellite instability (MSI) as its molecular hallmark. Hepatocellular carcinoma (HCC) has not been considered part of the tumor spectrum. The aim was to provide a detailed molecular characterization of an HCC associated with Lynch Syndrome (Muir-Torre variant)., Materials and Methods: HCC samples were analyzed for MSI, MMR protein expression and coding microsatellite instability (cMSI). Since cMSI also affected SEC63 coding for an endoplasmic reticulum membrane protein with implications for intracellular protein translocation, its impact on hepatocyte growth control was assessed in an established short-term model. Recombinant inbred mouse lines (BXD) showing different basal SEC63 expression levels were treated with the chemocarcinogen diethylnitrosamine (DEN) intraperitoneally. Proliferation and apoptosis of hepatocytes were determined after 48 h using Ki67 and TUNEL assays., Results: The HCC was high-grade microsatellite unstable with loss of MSH2 expression. cMSI was detected in four genes (ASTE1, SEC63, TAF1B, TGFBR2). However, only TGFBR2 is known to be involved in hepatocarcinogenesis. When investigating the impact of SEC63 expression on hepatocyte growth control in the murine model, low hepatic expression correlated significantly (p < 0.05) with a decrease in apoptosis and increased proliferative activity., Conclusions: For the first time, an HCC with characteristic molecular features of association with Lynch syndrome is described. The pro-carcinogenic growth behavior of hepatocytes with low SEC63 expression in the murine model indicates a potential role for SEC63 in hepatocarcinogenesis in general, but this needs further functional validation.