Immunohistochemistry as a surrogate for molecular subtyping of gastric adenocarcinoma

The Cancer Genome Atlas Research Network recently classified gastric adenocarcinoma into 4 molecular subtypes: Epstein-Barr virus-positive tumors, microsatellite-unstable tumors, tumors with chromosomal instability, and genomically stable tumors. We theorized that immunohistochemistry might be useful in similar categorization and that that HER2 expression might relate to subtype. We stained 104 gastric adenocarcinomas for MLH1, p53, and EBER in situ hybridization. We grouped them based on staining pattern and compared the groups. Cases were categorized as follows: group 1 (EBER positive), 7 cases (7%); group 2 (MLH1 deficient), 17 cases (16%); group 3 (aberrant p53 staining, EBER negative, retained MLH1), 40 cases (38%); group 4 (unremarkable staining), 40 cases (38%). This distribution was comparable to that found by the Research Network after accounting for the TP53 mutation rate in the chromosomal instability group. Group 1 patients had significantly longer follow-up times (median, 70 months versus 13 months for other groups; P = .0324). No group 2 cases overexpressed HER2. In group 3, 3 of 40 cases were HER2 immunohistochemistry positive, but 7 of 27 were HER2 positive by fluorescence in situ hybridization. Staining offers an efficient, reasonably accurate alternative for molecular subtyping of gastric adenocarcinoma, although some cases with chromosomal instability cannot be identified. These findings have potential prognostic and therapeutic implications.