Metabolic Liver Cancer: Associations of Rare and Common Germline Variants in One-Carbon Metabolism and DNA Methylation Genes

Authors

Samuel O Antwi
Michael Heckman
Launia White
Irene Yan
Vivekananda Sarangi
Kimberly P Lauer
Joseph Reddy
Fowsiyo Ahmed
Swathi Veliginti
Ellis D Mejías Febres
Rikita I Hatia
Ping Chang
Laura Izquierdo-Sanchez
Loreto Boix
Angela Rojas
Jesus M Banales
Maria Reig
Per Stål
Manuel Romero Gómez
Amit G Singal
Donghui Li
Manal M Hassan
Lewis R Roberts
Tushar Patel

Publication Date

8-7-2023

Journal

Human Molecular Genetics

Abstract

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.

Keywords

Humans, Liver Neoplasms, Carcinoma, Hepatocellular, DNA Methylation, Genetic Predisposition to Disease, Case-Control Studies, Germ Cells, Carbon, Polymorphism, Single Nucleotide

DOI

10.1093/hmg/ddad099

PMID

37369012

PMCID

PMC10407694

PubMedCentral® Posted Date

6-27-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes