Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

Objective Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10−9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10−5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10−44). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

[1]  C. Datz,et al.  The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis , 2021, Hepatology communications.

[2]  M. Ziol,et al.  Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. , 2021, The Lancet. Oncology.

[3]  D. Thabut,et al.  Burden of liver disease progression in hospitalized patients with type 2 diabetes mellitus. , 2021, Journal of hepatology.

[4]  H. Tseng,et al.  Diagnostic Criteria and LI‐RADS for Hepatocellular Carcinoma , 2021, Clinical liver disease.

[5]  J. Griffin,et al.  Liver‐Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer , 2021, Hepatology.

[6]  J. Zucman‐Rossi,et al.  Hepatocellular carcinoma , 1998, Nature Reviews Disease Primers.

[7]  M. Ziol,et al.  Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target. , 2020, Journal of hepatology.

[8]  M. Kanai,et al.  Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases , 2020, Nature Genetics.

[9]  Meng Xu,et al.  Single nucleotide polymorphisms in telomere length-related genes are associated with hepatocellular carcinoma risk in the Chinese Han population , 2020, Therapeutic advances in medical oncology.

[10]  J. Zucman‐Rossi,et al.  Genetics of Hepatocellular Carcinoma: Approaches to Explore Molecular Diversity , 2020, Hepatology.

[11]  J. Nault,et al.  The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. , 2020, Journal of hepatology.

[12]  Christopher D. Brown,et al.  The GTEx Consortium atlas of genetic regulatory effects across human tissues , 2019, Science.

[13]  C. Datz,et al.  Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers , 2020, Hepatology.

[14]  H. Carter,et al.  Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response , 2019, bioRxiv.

[15]  C. Datz,et al.  The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu , 2019, Journal of Molecular Medicine.

[16]  M. Ziol,et al.  Molecular and histological correlations in liver cancer. , 2019, Journal of hepatology.

[17]  M. Ziol,et al.  A 17‐Beta‐Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease , 2019, Hepatology.

[18]  J. Zucman‐Rossi,et al.  The role of telomeres and telomerase in cirrhosis and liver cancer , 2019, Nature Reviews Gastroenterology & Hepatology.

[19]  P. Nahon,et al.  Hepatocellular carcinoma in the setting of alcohol-related liver disease. , 2019, Journal of hepatology.

[20]  U. Huber-Schönauer,et al.  Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms , 2019, Gut.

[21]  Sina A. Gharib,et al.  Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis , 2018, bioRxiv.

[22]  P. Donnelly,et al.  The UK Biobank resource with deep phenotyping and genomic data , 2018, Nature.

[23]  P. Schirmacher,et al.  EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. , 2018, Journal of hepatology.

[24]  F. Lammert,et al.  Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol‐related cirrhosis , 2018, The American Journal of Gastroenterology.

[25]  L. Carlsson,et al.  Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver , 2017, Journal of internal medicine.

[26]  Erdogan Taskesen,et al.  Functional mapping and annotation of genetic associations with FUMA , 2017, Nature Communications.

[27]  P. Nahon,et al.  Constitutional and functional genetics of human alcohol‐related hepatocellular carcinoma , 2017, Liver international : official journal of the International Association for the Study of the Liver.

[28]  Alan D. Lopez,et al.  The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level , 2017, JAMA oncology.

[29]  K. Sylvester,et al.  Role of the Wnt/β-Catenin Pathway in the Pathogenesis of Alcoholic Liver Disease. , 2017, Current molecular pharmacology.

[30]  Gonçalo R. Abecasis,et al.  GAS Power Calculator: web-based power calculator for genetic association studies , 2017, bioRxiv.

[31]  H. Reeves,et al.  Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease , 2017, Cancer medicine.

[32]  Alexander M. Fraser,et al.  Cohort Profile: The Hepatitis C Virus (HCV) Research UK Clinical Database and Biobank , 2016, International journal of epidemiology.

[33]  Ying'ai Zhang,et al.  Associations of TERT polymorphisms with hepatocellular carcinoma risk in a Han Chinese population. , 2017, International journal of clinical and experimental pathology.

[34]  Jochen Hampe,et al.  The genetics of alcohol dependence and alcohol-related liver disease. , 2017, Journal of hepatology.

[35]  Alan M. Kwong,et al.  Next-generation genotype imputation service and methods , 2016, Nature Genetics.

[36]  Jiyue Zhu,et al.  Human Specific Regulation of the Telomerase Reverse Transcriptase Gene , 2016, Genes.

[37]  K. Huse,et al.  A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis , 2015, Nature Genetics.

[38]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[39]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[40]  J. Dufour,et al.  Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. , 2014, Journal of hepatology.

[41]  Anne Tybjærg-Hansen,et al.  Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease , 2014, Nature Genetics.

[42]  Wei Lu,et al.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer , 2013, Nature Genetics.

[43]  Peter Kraft,et al.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression , 2013, Human molecular genetics.

[44]  L. Rodrigo,et al.  Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. , 2013, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[45]  Qiang Ding,et al.  Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma , 2012, Nature Genetics.

[46]  Andreas Hierholzer,et al.  Wnt/β-Catenin Signaling Regulates Telomerase in Stem Cells and Cancer Cells , 2012, Science.

[47]  Manuel Mattheisen,et al.  Genome‐wide significant association between alcohol dependence and a variant in the ADH gene cluster , 2012, Addiction biology.

[48]  J. Feigon,et al.  Architecture of human telomerase RNA , 2011, Proceedings of the National Academy of Sciences.

[49]  Yusuke Nakamura,et al.  Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers , 2011, Nature Genetics.

[50]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[51]  Jin Dong,et al.  [hTERT single nucleotide polymorphism is associated with increased risks of hepatocellular carcinoma and tumor metastasis]. , 2011, Nan fang yi ke da xue xue bao = Journal of Southern Medical University.

[52]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[53]  Alkes L. Price,et al.  New approaches to population stratification in genome-wide association studies , 2010, Nature Reviews Genetics.

[54]  R. O'Sullivan,et al.  Telomeres: protecting chromosomes against genome instability , 2010, Nature Reviews Molecular Cell Biology.

[55]  T. Dragani,et al.  Risk of HCC: genetic heterogeneity and complex genetics. , 2010, Journal of hepatology.

[56]  Timothy D. Veenstra,et al.  Telomerase modulates Wnt signalling by association with target gene chromatin , 2009, Nature.

[57]  S. Cichon,et al.  Genome-wide association study of alcohol dependence. , 2009, Archives of general psychiatry.

[58]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[59]  H. El‐Serag,et al.  Risk factors for the rising rates of primary liver cancer in the United States. , 2000, Archives of internal medicine.