Chromosomal breaks at FRA18C: association with reduced expression, altered oncogenic signaling and increased gastric cancer survival.

Chromosomal rearrangements are common in cancer. More than 50% occur in common fragile sites and disrupt tumor suppressors. However, such rearrangements are not known in gastric cancer. Here we report recurrent 18q2 breakpoints in 6 of 17 gastric cancer cell lines. The rearranged chromosome 18, t(9;18), in MKN7 cells was flow sorted and identified by reverse chromosome painting. High-resolution tiling array hybridization mapped breakpoints to (docking protein 6) intron 4 in FRA18C (18q22.2) and an intergenic region in 9q22.2. The same rearrangement was detected by FISH in 22% of 99 primary gastric cancers. Intron 4 truncation was associated with reduced transcription. Analysis of The Cancer Genome Atlas stomach adenocarcinoma cohort showed significant correlation of expression with histological and molecular phenotypes. Multiple oncogenic signaling pathways (gastrin-CREB, NGF-neurotrophin, PDGF, EGFR, ERK, ERBB4, FGFR1, RAS, VEGFR2 and RAF/MAP kinase) known to be active in aggressive gastric cancers were strikingly diminished in gastric cancers with low expression. Median survival of patients with low -expressing tumors was 2100 days compared with 533 days in patients with high -expressing tumors (log-rank  = 0.0027). The level of expression in tumors predicted patient survival independent of TNM stage. These findings point to new functions of human as an adaptor that interacts with diverse molecular components of signaling pathways. Our data suggest that expression is an integrated biomarker of multiple oncogenic signals in gastric cancer and identify FRA18C as a new cancer-associated fragile site.