Genome-wide association study identifies high-impact susceptibility loci for HCC in North America

Manal M Hassan; Donghui Li; Younghun Han; Jinyoung Byun; Rikita I Hatia; Erping Long; Jiyeon Choi; Robin Kate Kelley; Sean P Cleary; Anna S Lok; Paige Bracci; Jennifer B Permuth; Roxana Bucur; Jian-Min Yuan; Amit G Singal; Prasun K Jalal; R Mark Ghobrial; Regina M Santella; Yuko Kono; Dimpy P Shah; Mindie H Nguyen; Geoffrey Liu; Neehar D Parikh; Richard Kim; Hui-Chen Wu; Hashem El-Serag; Ping Chang; Yanan Li; Yun Shin Chun; Sunyoung S Lee; Jian Gu; Ernest Hawk; Ryan Sun; Chad Huff; Asif Rashid; Hesham M Amin; Laura Beretta; Robert A Wolff; Samuel O Antwi; Yehuda Patt; Lu-Yu Hwang; Alison P Klein; Karen Zhang; Mikayla A Schmidt; Donna L White; John A Goss; Saira A Khaderi; Jorge A Marrero; Francisco G Cigarroa; Pankil K Shah; Ahmed O Kaseb; Lewis R Roberts; Christopher I Amos

doi:10.1097/HEP.0000000000000800

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America

Hepatology. 2024 Feb 20. doi: 10.1097/HEP.0000000000000800. Online ahead of print.

Authors

Manal M Hassan¹, Donghui Li², Younghun Han³, Jinyoung Byun³, Rikita I Hatia¹, Erping Long⁴, Jiyeon Choi⁴, Robin Kate Kelley⁵, Sean P Cleary⁶, Anna S Lok⁷, Paige Bracci⁸, Jennifer B Permuth^{9

10}, Roxana Bucur¹¹, Jian-Min Yuan^{12

13}, Amit G Singal¹⁴, Prasun K Jalal¹⁵, R Mark Ghobrial¹⁶, Regina M Santella¹⁷, Yuko Kono¹⁸, Dimpy P Shah¹⁹, Mindie H Nguyen²⁰, Geoffrey Liu²¹, Neehar D Parikh⁷, Richard Kim⁹, Hui-Chen Wu¹⁷, Hashem El-Serag²², Ping Chang², Yanan Li², Yun Shin Chun²³, Sunyoung S Lee², Jian Gu¹, Ernest Hawk²⁴, Ryan Sun²⁵, Chad Huff¹, Asif Rashid²⁶, Hesham M Amin²⁷, Laura Beretta²⁸, Robert A Wolff², Samuel O Antwi²⁹, Yehuda Patt³⁰, Lu-Yu Hwang³¹, Alison P Klein³², Karen Zhang⁵, Mikayla A Schmidt³³, Donna L White³⁴, John A Goss³⁵, Saira A Khaderi³⁶, Jorge A Marrero¹⁴, Francisco G Cigarroa³⁷, Pankil K Shah¹⁹, Ahmed O Kaseb², Lewis R Roberts³³, Christopher I Amos³

Affiliations

¹ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
⁶ Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, Minnesota, USA.
⁷ Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
⁹ Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.
¹⁰ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.
¹¹ Princess Margaret Cancer Center and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
¹² Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹³ Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁴ Division of Digestive and Liver Diseases, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹⁵ Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA.
¹⁶ J.C. Walter Jr. Transplant Center, Houston Methodist Hospital, Houston, Texas, USA.
¹⁷ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York City, New York, USA.
¹⁸ Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, California, USA.
¹⁹ Mays Cancer Center, The University of Texas Health Science Center San Antonio MD Anderson, San Antonio, Texas, USA.
²⁰ Division of Gastroenterology and Hepatology, Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California, USA.
²¹ Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
²² Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
²³ Division of Surgery, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁴ Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁵ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁶ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁷ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁸ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁹ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida, USA.
³⁰ Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
³¹ Department of Epidemiology, Human Genetics, and Environment Science, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
³² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
³³ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
³⁴ Sections of Gastroenterology and Hepatology and Health Services Research, Baylor College of Medicine, Houston, Texas, USA.
³⁵ Division of Abdominal Transplantation, Michael E. DeBakey School of Medicine, Baylor College of Medicine, Houston, Texas, USA.
³⁶ Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA.
³⁷ Transplant Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

PMID: 38381705
DOI: 10.1097/HEP.0000000000000800

Abstract

Background and aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP).

Approach and results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC.

Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.