Chromosomal breaks at FRA18C: association with reduced DOK6 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 DOK6 (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 DOK6 transcription. Analysis of The Cancer Genome Atlas stomach adenocarcinoma cohort showed significant correlation of DOK6 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 DOK6 expression. Median survival of patients with low DOK6-expressing tumors was 2100 days compared with 533 days in patients with high DOK6-expressing tumors (log-rank P = 0.0027). The level of DOK6 expression in tumors predicted patient survival independent of TNM stage. These findings point to new functions of human DOK6 as an adaptor that interacts with diverse molecular components of signaling pathways. Our data suggest that DOK6 expression is an integrated biomarker of multiple oncogenic signals in gastric cancer and identify FRA18C as a new cancer-associated fragile site. Gastric tumors often harbor a chromosome abnormality that disrupts a key signaling gene, resulting in less aggressive cancers. Oi Lian Kon from the National Cancer Centre Singapore and colleagues searched for chromosomal rearrangements in 17 gastric cancer cell lines. The researchers discovered a recurrent breakpoint in six of the cell lines that mapped to a gene called DOK6, which encodes a protein that provides a docking platform for multiple signaling molecules. They also found the abnormality in 22 of 99 tissue samples taken from gastric cancer patients. This defect led to lower expression of DOK6 and, in turn, less active oncogenic signaling pathways. Patients with low DOK6-expressing gastric cancers lived longer on average than those with high DOK6-expressing tumors. The findings point to DOK6 levels as a potential drug target and diagnostic biomarker.