Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis.

Felix Stickel,Thomas Berg,Jonas Rosendahl,Daniel Gotthardt,Pierre Deltenre,Steffen Zopf,Arndt Vogel,Felix Braun,Silke Marhenke,Martha M Kirstein,Stephan Buch,Karl Heinz Weiss,Clemens Schafmayer,Marsha Y Morgan,Florian Eyer,Andrew Mcquillin,Ulrich Spengler,Markus Casper,Hans Dieter Nischalke,Janett Fischer,Henning Wege,Frank Lammert,Mona Elamly,Thorsten Buch,Astrid Marot,Johann Von Felden

doi:10.1038/s41395-018-0041-8

Abstract

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. 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. The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2 rs58542926 (ORadjusted 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 (ORadjusted 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. 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.

Highlights

The incidence of hepatocellular carcinoma (HCC) is increasing and it is the fifth most frequent cancer and third most frequent cause of cancer-related mortality world-wide [1,2,3]
The odds ratio (OR) for homozygous carriers of the risk allele patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 G was 3.26 compared to the risk in heterozygous carriers of 1.70
Of particular importance is the definition of the risk factors predisposing an individual with an a priori cancer risk, i.e. cirrhosis, to the development of life-threatening malignancy if defining the risk factors would allow development of a strategy for more individualized screening and targeted prevention

Summary

Introduction

The incidence of hepatocellular carcinoma (HCC) is increasing and it is the fifth most frequent cancer and third most frequent cause of cancer-related mortality world-wide [1,2,3]. In Western countries, the presence of cirrhosis is a major risk factor for the development of HCC which only rarely evolves in non-cirrhotic livers [1,4,5]. Between 5 to 15% of patients with alcohol-related cirrhosis are potentially at risk for developing HCC with a 5-year cumulative risk of around 8% [1]. Identifying diseasemodulating factors which render some individuals more susceptible to its development than others is clearly of major importance as it would allow more specific targeting of surveillance programmes. Mounting evidence suggest that host genetic factors may significantly modify the risk for developing HCC. Identifying these factors in patients with alcoholrelated cirrhosis is clearly of major importance

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