Identification of the potential molecular mechanism and driving mutations in the pathogenesis of familial intestinal gastric cancer by whole exome sequencing

The genetic alterations in familial intestinal gastric cancer (FIGC) have not been clearly understood. Aiming to explore the molecular basis and the driving mutations underlying the pathogenesis of FIGC, we performed exome sequencing of the blood samples of the members of an extended family with FIGC. The differences in mutation patterns between family members with gastric cancer and controls were analysed and the overlapped variants were screened by comparing previously published data for blood and tumours from gastric cancer patients. The overlapped genes harbouring insertions-deletions (INDELs) and single-nucleotide variants (SNVs) were subjected to function, pathway and network analysis. The INDELs were enriched in DNA packaging and in the neurological system process related to the biological process (BP), while SNVs were closely related to cell-function-related BPs. ESR was the significant node with marked centrality in the SNV network. ERK 1/2 was the hub node in the INDEL network, interacting with EZK and IGF2R. Sequencing analysis revealed ESR1 homozygous mutations in exon 1 (216G > C) and exon 10 (2234C > T) and EZR1 heterozygous deletion of 68-69 GT nucleotides in exon 13 of the family members. The IGF2R gene only demonstrated a mutation in exon 48 of the propositus. All hub proteins had direct or indirect interactions in the protein-protein interaction network.