Abstract 2637: Application of identity-by-descent (IBD) approach to genetic mapping of susceptibility locus in hereditary esophageal squamous cell carcinoma (ESCC) by high density SNP array analysis

Abstract

Abstract Background and aims: Esophageal cancer (EC) is a deadly disease with a very low 5-year survival rate. The incidence of EC shows great geographical variations with high prevalence in Northern China. Although epidemiological studies suggest that environmental factors may be etiologic factors of EC, strong evidence supporting a causative role of genetic factors in familial EC comes from i) familial aggregation of EC in Yangcheng County, ii) the distinct high EC incidence in Chaoshan migrants to Nanao, and iii) molecular genetic studies such as BRCA2 germline mutations. Recent technological advances allow the identification of long regions of homozygosity (known as IBD segments) in genomic DNAs, which represent the sharing of a common ancestor in those regions, using the high density SNP arrays. Previous studies suggest that a high rate of consanguinity, which produces germline genomic homozygosity, is associated with cancers. We aim to use the IBD approach for mapping the susceptibility locus with low-penetrance SNPs in hereditary ESCC patients in Henan, one of the highest ESCC risk regions in the world. Screening programs based on knowledge of founder mutations may reduce cancer mortality by prevention. Thus, our second aim is to assess if a founder effect exists and predisposes individuals to ESCC in Henan. Methods: Genomic DNAs were extracted from blood samples of Henan family history positive (FH+) ESCC patients and healthy normal individuals. The germline homozygosity in 30 Henan FH+ ESCC patients was explored by using Affymetrix GeneChip Human mapping SNP array (∼238K SNPs, Sty I). IBD analysis was performed using the PLink software. Results: There is longer IBD segment length associated with FH+ ESCC compared with control groups. The 27 IBD segments in FH+ ESCC samples having no overlap with control/Hapmap may encompass the potential cancer-susceptibility loci and should be further examined. However, no strong evidence for founder effect was observed by IBD approach for hereditary ESCC in Henan population. Conclusions: The increased length of germline genomic homozygosity association with hereditary ESCC in Henan is observed. Due to the small sample size in the current study, the association is considered hypothesis-generating only. The importance of these IBD segments to the etiology and development of ESCC in high risk areas require further study with an expanded sample size for validation. Acknowledgements: This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China (HKU 3/06C to M.L.L.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2637. doi:1538-7445.AM2012-2637