Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations

Wenlong Carl Chen; Jean-Tristan Brandenburg; Ananyo Choudhury; Mahtaab Hayat; Dhriti Sengupta; Yaniv Swiel; Chantal Babb de Villiers; Lucien Ferndale; Colleen Aldous; Cassandra C Soo; Sang Lee; Charles Curtis; Rob Newton; Tim Waterboer; Freddy Sitas; Debbie Bradshaw; Christian C Abnet; Michele Ramsay; M Iqbal Parker; Elvira Singh; Cathryn M Lewis; Christopher G Mathew

doi:10.1016/j.ajhg.2023.08.007

Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations

Am J Hum Genet. 2023 Oct 5;110(10):1690-1703. doi: 10.1016/j.ajhg.2023.08.007. Epub 2023 Sep 5.

Authors

Wenlong Carl Chen¹, Jean-Tristan Brandenburg², Ananyo Choudhury², Mahtaab Hayat³, Dhriti Sengupta², Yaniv Swiel⁴, Chantal Babb de Villiers⁵, Lucien Ferndale⁶, Colleen Aldous⁷, Cassandra C Soo², Sang Lee⁸, Charles Curtis⁸, Rob Newton⁹, Tim Waterboer¹⁰, Freddy Sitas¹¹, Debbie Bradshaw¹², Christian C Abnet¹³, Michele Ramsay², M Iqbal Parker¹⁴, Elvira Singh¹⁵, Cathryn M Lewis¹⁶, Christopher G Mathew¹⁷

Affiliations

¹ National Cancer Registry, National Health Laboratory Service, Johannesburg 2131, South Africa; Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; Strengthening Oncology Services Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa.
² Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
³ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa.
⁴ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; School of Electrical & Information Engineering, University of the Witwatersrand, Johannesburg 2000, South Africa.
⁵ Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa.
⁶ Department of Surgery, Grey's Hospital, Pietermaritzburg 3200, South Africa; College of Health Sciences, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4013, South Africa.
⁷ College of Health Sciences, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4013, South Africa.
⁸ Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, SE5 8AF London, UK; NIHR BioResource Centre Maudsley, South London and Maudsley NHS Foundation Trust, King's College London, SE5 8AF London, UK.
⁹ MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda; University of York, YO10 5DD York, UK.
¹⁰ Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
¹¹ Burden of Disease Research Unit, South African Medical Research Council, Cape Town 7505, South Africa; Centre for Primary Health Care and Equity, School of Population, University of New South Wales, Sydney, NSW 2052, Australia; Menzies Centre of Health Policy, School of Public Health, University of Sydney, Sydney, NSW 2006, Australia.
¹² Burden of Disease Research Unit, South African Medical Research Council, Cape Town 7505, South Africa.
¹³ Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA.
¹⁴ Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa.
¹⁵ National Cancer Registry, National Health Laboratory Service, Johannesburg 2131, South Africa; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
¹⁶ Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, SE5 8AF London, UK; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, SE1 9RT London, UK.
¹⁷ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa; Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, SE1 9RT London, UK. Electronic address: christopher.mathew@kcl.ac.uk.

Abstract

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 × 10^-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 × 10^-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, p_meta = 9.36 × 10^-10), chromosome 10 at PLCE1 (rs7099485, p_meta = 1.48 × 10^-8), and chromosome 22 at CHEK2 (rs1033667, p_meta = 1.47 × 10^-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.

Keywords: African cancer genome-wide association study; ESCC GWAS; ESCC genetics; ESCC meta-analysis; esophageal squamous cell carcinoma.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

African People
Carcinoma, Squamous Cell* / genetics
Carcinoma, Squamous Cell* / pathology
Case-Control Studies
East Asian People
Esophageal Neoplasms* / epidemiology
Esophageal Neoplasms* / genetics
Esophageal Neoplasms* / pathology
Esophageal Squamous Cell Carcinoma* / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide / genetics

Abstract

Publication types

MeSH terms

Grants and funding