Germline variant in MSX1 identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma

Abstract

The vast majority of esophageal adenocarcinoma cases are sporadic and caused by somatic mutations. However, over the last decades several families have been identified with clustering of Barrett's esophagus and esophageal adenocarcinoma. This observation suggests that one or more hereditary factors may play a role in the initiation of Barrett's esophagus and esophageal adenocarcinoma in these families. A Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma was identified. Normal DNA obtained from the proband diagnosed with Barrett's esophagus was analyzed with SNP array and exome sequencing. A custom-made panel consisting of potential germline variants was verified in the normal DNA of the affected family members. In addition, the respective tumors were analyzed for somatic loss of the wild type allele or the presence of an inactivating somatic mutation in the wild type allele. Exome sequencing revealed 244 candidate variants in the normal DNA of the proband, of which 212 variants were verified successfully. After the normal DNA of the affected family members was analyzed for the presence of the 212 potential germline variants and subsequently the respective tumors, only one potential germline variant in MSX1 (chr4: 4861985 T > G, c.359T > G, p.V120G, NM_002448) showed loss of the wild type allele in the tumor DNAs of the affected family members. A germline variant in MSX1 was identified in a Dutch family with clustering of Barrett's esophagus and esophageal adenocarcinoma. This finding indicates that the germline defect in MSX1 may be associated with Barrett's esophagus and cancer in this particular family.

Keywords: Barrett’s esophagus; Esophageal adenocarcinoma; Exome sequencing; Familial clustering; Genetic testing.

Fig. 1

Pedigree of investigated family. Black symbols indicate esophageal adenocarcinoma. Partly blocked symbols indicate Barrett esophagus and/or gastro-esophageal reflux (GER). The proband is indicated by a red arrow

Fig. 2

Flowchart of sequencing pipeline WES whole exome sequencing, Ion PGM Ion Torrent Personal Genome Machine, Sanger Sanger sequencing, G Germline DNA, T Tumor DNA

Fig. 3

Sanger sequencing results of MSX1. a Sanger sequencing of normal DNA of the proband (II.3) confirmed the presence of the heterozygote variant (c.359T > G) in MSX1. b Sanger sequencing of normal DNA of youngest brother of the proband (II.4) revealed no variant in MSX1. c Sanger sequencing of normal DNA (upper panel) and tumor DNA (lower panel) of the oldest brother of the proband (II.1) confirmed the presence of the heterozygote variant (C.359T > G) in MSX1 in normal DNA and loss of the wild type allele in tumor DNA which changed the codon 120 from Valine into Glycine (P.V120G). d Sanger sequencing of normal DNA (upper panel) and tumor DNA (lower panel) of the older sister of the proband (II.2) confirmed the presence of the heterozygote variant (c.359T > G) in MSX1 in normal DNA and loss of the wild type allele in tumor DNA, which changed the codon 120 from Valine into Glycine (p.V120G)