Abstract IA8: The genetics and genomics of African esophageal cancer
Authors: Mathew Christopher G. 
Published: December 2017

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 an important question which is unresolved. Also, limited data are available on the somatic mutations which are driving tumor development. This presentation will review current knowledge on the role of germline genetic variants and somatic mutations in the development of African ESCC.
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. Several positive associations have been reported, particularly in the Mixed Ancestry population, but none have achieved genome-wide levels of significance or been replicated in independent studies. We are currently testing 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 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. Our initial studies found no significant evidence of association at previously reported GWAS loci ATP1B2, CASP8, c20orf54, HEATR3, PDE4D, PLCE1, PTPN2, RUNX1, SMG6, ST6GAL1, TMEM173 and UNC5L loci. However, evidence for association was observed for the SNP rs2239815 at XBP1 on chromosome 22q12 (OR =1.41, P = 0.00087), and the SNPs rs4822983 (OR = 1.31, P = 0.0013) and rs1033667 (OR = 1.29, P = 0.0025) in CHEK2. Genotyping of a larger SNP panel in an expanded collection of cases and controls is in progress to extend these findings.
Detection of somatic mutations in ESCC tumour tissue has in the past been limited to sequencing of candidate genes and copy number studies, with TP53 mutations being detected in a minority of South African and Kenyan patients. We have carried out pilot whole exome sequencing in 10 matched blood/tumour pairs from South African ESCC patients and detected mutations in TP53, ATR, GNAS, MAGI2, FBXW7, FLT3, NFE2L2, TET2 and ZNF750. Follow up sequencing of the TP53 gene detected missense or truncating mutations in 18/26 (69%) of tumours. A recent sequencing study of 59 Malawian ESCC patients (Liu et al) observed recurrent mutations in TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1 and FBXW7, and transcriptomic profiles were used to divide ESCCs into 3 subtypes.
Priorities for the future should include well powered GWAS in high risk populations from several African countries, with collaborative studies to compare genetic risk factors across populations and meta-analysis to provide power to detect risk loci with moderate effects. Whole-exome or whole genome sequencing of substantial panels of blood/tumour pairs are needed to establish the major drivers of tumorigenesis in African ESCC and to derive mutational signatures which may provide insight into causal environmental factors.
Citation Format: Christopher G. Mathew. The genetics and genomics of African esophageal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA8.