Esophageal squamous cell carcinoma (ESCC) has a high incidence in sub-Saharan Africa and a poor prognosis, but little is known about the genetic contribution to ESCC susceptibility in this region. We carried out a GWAS in the South African Black (SAB) population with 1,686 ESCC cases and 3,217 controls as part of the Evolving Risk Factors for Cancer in African populations (ERICA-SA) study after ethical approval and informed consent. ESCC case samples from ERICA-SA and controls from the H3A AWI-Gen study were genotyped on the 2.3 million H3 Africa SNP Illumina array and additional SNPs imputed using the Wellcome Sanger Institute imputation service. Measures for correction of population structure included Eigen decomposition for Principal Component (PC) analysis. The final imputed dataset of 14.4M SNPs for 1,686 OSCC cases and 3,217 population controls was used in linear-mixed model analysis to test for association using GEMMA. A meta-analysis of SNP sets common to both our study and a GWAS of 2,013 Chinese ESCC cases and 2,701 controls was done using METAL. The GWAS of the SAB population identified a total of 62 SNPs with suggestive association with ESCC (P < 5x10-6), from 29 independent potential risk loci. A strong signal at genome-wide significance is located upstream of the FAM120A gene on chromosome 9 (rs1237966, p=4.58x10-8) and is supported by multiple SNPs at this locus. FAM120A encodes an RNA binding protein which is a critical component of oxidative stress-induced signalling. A strong association was also observed on chromosome 2, led by rs142741123 (p=5.49x10-8) in a region spanning the MYO1B and STAT4 genes with SNPs that are absent in non-African populations, suggesting that this is an African-specific risk locus for ESCC. There was limited support for the association of ESCC risk loci reported in other populations in our study. We did a meta-analysis of the SAB GWAS with a published GWAS of Chinese ESSC cases and controls with 4.85 million SNPs shared between the two studies. A total of 12 SNPs were associated with ESCC at genome-wide significance. These included 3 loci: chromosome 9, led by rs12379660 (p-valuemeta = 9.36x10-10), chromosome 10 led by rs7099485 (p-valuemeta = 1.48x10-8) and chromosome 22 led by rs1033667 (p-valuemeta = 1.47x10-9). The chromosome 9 locus at FAM120A is the novel locus identified in our African ESCC GWAS, the chromosome 10 locus at PLCE1 shows association only in the Chinese GWAS, and the chromosome 22 locus at CHEK2 was previously identified in the Chinese ESCC GWAS, and is supported further by the African ESCC GWAS. This study is, to our knowledge, the first cancer GWAS conducted in solely in a resident African population, and has detected two novel risk loci for ESCC at or near genome-wide significance, one of which is likely specific to African populations. It also demonstrates the power of trans-ethnic meta-analysis to identify common or distinct risk loci in populations of diverse ancestry.

Citation Format: Wenlong C. Chen, Jean-Tristan Brandenburg, Ananyo Choudhury, Mahtaab Hayat, Dhriti Sengupta, Chantal Babb de Villiers, Lucien Ferndale, Cassandra Soo, Sang H. Lee, Charles Curtis, Robert Newton, Tim Waterboer, Frederic Sitas, Michele Ramsay, Christian C. Abnet, Colleen Aldous, Mohamed I. Parker, Elvira Singh, Deborah Bradshaw, Cathryn M. Lewis, Christopher G. Mathew. Genome-wide association study of African esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 31.