Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes.

Autor:	Antwi SO; Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA., Heckman M; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., White L; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Yan I; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Sarangi V; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Lauer KP; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Reddy J; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida, USA., Ahmed F; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA., Veliginti S; Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Mejías Febres ED; University of Puerto Rico Medical School, San Juan, Puerto Rico., Hatia RI; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chang P; Department of Gastrointestinal Medical Oncology, The MD Anderson Cancer Center, Houston, TX, USA., Izquierdo-Sanchez L; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain., Boix L; BCLC Group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain., Rojas A; SeLiver Group, UCM Digestive Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain.; Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain., Banales JM; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain.; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain., Reig M; BCLC Group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain., Stål P; Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden., Gómez MR; SeLiver Group, UCM Digestive Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain.; Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain., Singal AG; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA., Li D; Department of Gastrointestinal Medical Oncology, The MD Anderson Cancer Center, Houston, TX, USA., Hassan MM; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Roberts LR; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA., Patel T; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.; Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Aug 07; Vol. 32 (16), pp. 2646-2655.
DOI:	10.1093/hmg/ddad099
Abstrakt:	Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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