Abstract
BackgroundFamilial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).MethodsWe genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model‐based and model‐free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model‐based linkage analysis. Model‐based and model‐free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome‐wide associations were also tested in these families.ResultsLinkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female‐affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported.ConclusionOur linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.
Highlights
National statistics estimate 18,140 new cases of esophageal cancer, the majority adenocarcinomas, in 2014 (Siegel et al 2014)
Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
Our linkage study of Barrett’s esophagus (BE)/esophageal adenocarcinoma (EAC) pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks
Summary
National statistics estimate 18,140 new cases of esophageal cancer, the majority adenocarcinomas, in 2014 (Siegel et al 2014). Almost all EACs originate in Barrett’s epithelium, a premalignant condition in which normal stratified squamous epithelium is replaced by metaplastic specialized intestinal type columnar epithelium (Haggitt et al 1978; Hameeteman et al 1989; Reid et al 1992; Cameron et al 1995; Hirota et al 1999; Ruol et al 2000; Spechler 2002; Sharma et al 2004). Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett’s esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC)
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