Nucleotide variants within the IQGAP1 gene in diffuse-type gastric cancers.

IQGAP1 is recognized as a negative regulator of cell-cell adhesion at adherens junctions in several cell types, including gastric mucosal cells. The histopathologic appearance of diffuse gastric carcinoma is defined by non- or poorly cohesive tumor cells, indicating abnormal intercellular adhesion. Hence, we screened 38 gastric cancers for activating point mutations in IQGAP1. In 2 of the 33 diffuse gastric cancers, there was a missense nucleotide change predicted to alter the amino acid sequence in the GAP-related domain, which includes part of the binding site for the activated small G proteins Cdc42 and Rac1. Many intronic IQGAP1 gene changes were observed, and several occurred more frequently in diffuse-type gastric cancers than in intestinal-type gastric cancers. A highly variable pentanucleotide repeat was identified in the final intron of IQGAP1. The most expanded six-repeat sequence was present exclusively in diffuse-type gastric cancers. Additionally, 19 diffuse cases and two intestinal cases exhibited silent coding region nucleotide alterations. Taken together, our results suggest that IQGAP1 coding sequence mutations are not a frequent event in gastric cancer, but do occur in a subset of diffuse-type gastric carcinomas. Additional studies analyzing other proteins involved in cell adhesion may lead to a better molecular understanding of the histopathologic appearance of diffuse gastric cancers.