Meta-Analysis

. 2023 Oct 5;110(10):1690-1703.

doi: 10.1016/j.ajhg.2023.08.007. Epub 2023 Sep 5.

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

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.

PMID: 37673066
PMCID: PMC10577073
DOI: 10.1016/j.ajhg.2023.08.007

Meta-Analysis

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

Wenlong Carl Chen et al. Am J Hum Genet. 2023.

. 2023 Oct 5;110(10):1690-1703.

doi: 10.1016/j.ajhg.2023.08.007. Epub 2023 Sep 5.

Authors

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.

PMID: 37673066
PMCID: PMC10577073
DOI: 10.1016/j.ajhg.2023.08.007

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

**Figure 1**
Admixture plot and principal component plots of ESCC-affected individuals and control individuals (A) The ADMIXTURE plot (K = 6) of ESCC-affected individuals and control individuals by study sites is shown on the top. (B) PC plot of study participants by disease phenotype status is shown on the bottom left. (C) PC plot of study participants by study site is shown by the bottom right. JCS, Johannesburg Cancer Study; UCT, University of Cape Town; UKZN, University of KwaZulu-Natal; 1KG: CEU, 1000 Genome Northern European; 1KG: CHB, Han Chinese; 1KG: YRI, Yoruba.

**Figure 2**
Quantile-Quantile plot and Manhattan plot of the ESCC GWAS (A) The QQ plot is shown on the left, with lambda for genomic control of 1.01. (B) The Manhattan plot with top hits on chromosome 9 and chromosome 2 is shown on the right.

**Figure 3**
Locuszoom plots of top hits in the African ESCC GWAS (A) rs12379660/*FAM120A* on chromosome 9. (B) rs142741123/*MYO1B* on chromosome 2. (C) rs113702517/*STAT4* on chromosome 2. (D) rs2834763/*RUNX1* on chromosome 21.

**Figure 4**
Meta-analysis Manhattan plot for African ESCC and Chinese ESCC Green arrows indicate African-GWAS-driven signals, blue arrows indicate Chinese-GWAS-driven signals.

**Figure 5**
Meta-analysis Locuszoom plots of *FAM120A*, *CHEK2*, *PLCE1*, and *SLC16A14* First column contains Locuszoom plots of the meta-analysis, using the African GWAS LD data as reference. The second column contains Locuszoom plots of the African GWAS, using African LD data as reference. The third column contains the Chinese GWAS plots, using Chinese LD data as reference.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical