Molecular Signatures of gastric cancer: An integrated approach to molecular cytogenetics, whole genome copy number and transcriptome profiles

Abstract

Signature chromosomal translocations in gastric cancer are poorly described. By integrating spectral karyotype and high-resolution genome copy number data, 45 recurrent translocations in 17 human gastric cancer cell lines were identified. Dissecting a simple rearrangement in SNU-1 cells using fluorescence in situ hybridization probe-walking confirmed a 4q32.3q35.1 deletion associated with three chromosomal fusions. Among complex rearrangements, 18q21 was most frequently aberrant (35% of cell lines) with multiple fusion partners and sustained copy number loss in >50%. This 18q21q22 translocation was mirrored in 38% of 99 primary gastric cancer adenocarcinomas. High resolution analysis of flow-sorted rearranged chromosome 18 species from four cell lines identified fusion partners and probable breakpoints. Translocation-positive and -negative lines segregated distinctly in supervised hierarchical clustering of 18q genes. Immunohistochemical staining of 18q proteins, Serpin B8 and CD226 antigen, showed overexpression in breakapart-positive primary gastric cancers. Other molecular signatures from whole genome copy number, mRNA and miRNA profiles are described.