Abstract 237: The genetic architecture of African esophageal cancer
Authors: Mathew Christopher G. , Chen Wenlong C. , Bye Hannah , Prescott Natalie J. , Matejcic Marco , Kerr Robyn , Singh Elvira , Lewis Cathryn M. , Villiers Chantal Babb de , Parker Mohamed I. 
Published: August 2018

Abstract
Esophageal squamous cell carcinoma (ESCC) is common in many Black populations of sub-Saharan Africa, with high incidence regions in Eastern and Southern Africa. Clinical presentation in Africa is late, and treatment is mainly palliative with a very poor prognosis. Various environmental risk factors have been identified, but the possible contribution of inherited genetic variants to disease risk is unresolved. Genetic association studies of African ESCC have been limited to the analysis of small numbers of single nucleotide polymorphisms (SNPs) in candidate genes, and carried out only in the Black and Mixed Ancestry populations of the Western Cape of South Africa. Thus far no genetic associations with ESCC have been replicated in African populations.
We tested SNPs which have been associated with ESCC in genome-wide association studies (GWAS) from Asian and European populations for association with ESCC in the South African Black population. Black cases with a histologically confirmed diagnosis of ESCC and matching population controls were recruited, after informed consent and institutional ethical approval, from the Western Cape and Gauteng provinces of South Africa. SNPs were genotyped either by individual TaqMan assays (Applied Biosystems) or in a multiplex MassARRAY (Agena Bioscience) and genotypes were tested for association. We genotyped 26 SNPs from OSCC risk loci and 10 ancestry informative markers in 880 Black South African (SAB) OSCC cases and 939 controls recruited by the Johannesburg Cancer Study. No significant associations were detected at the CASP8, ALS2CR12, ADH1C TMEM173, PLCE1, ALDH2, ATP1B2/TP53 or CHEK2 loci, although some SNPs showed the same direction of effect observed in other populations. 8 SNPs from these loci were genotyped in a further 493 cases and 820 controls from the Western Cape, and a combined test for association done in a total of 1373 cases and 1759 controls. The only SNP that was significantly associated with ESCC in the combined analysis after correction for multiple testing was rs1033667 in CHEK2 (OR = 1.18, P = 0.002).
The lack of transference of most loci from Asian and European populations in an African population could result from smaller or absent effects of these loci in Africa. Alternatively, since we are likely to be genotyping tagging SNPs rather than the actual causal variants in these studies and linkage disequilibrium (LD) is lower in African genomes, our power to detect association with tagging SNPs will be reduced. This question could be resolved by carrying out a well-powered GWAS in African ESCC using a SNP array with sufficient African content to identify known or novel associations. We are currently conducting a GWAS for ESCC by genotyping 1700 ESCC cases and 6000 controls using a 2.4M SNP array designed by the H3 Africa Consortium.
Citation Format: Christopher G. Mathew, Wenlong C. Chen, Hannah Bye, Natalie J. Prescott, Marco Matejcic, Robyn Kerr, Elvira Singh, Cathryn M. Lewis, Chantal Babb de Villiers, Mohamed I. Parker. The genetic architecture of African esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 237.