Preferential Loss of Fhit Expression in Signet-Ring Cell and Krukenberg Subtypes of Gastric Cancer

Abstract

Gastric cancer of youth is predominantly a disease of women, usually of the signet-ring cell subtype, with a predilection for metastasizing to the ovaries. The metastatic ovarian tumor is named a Krukenberg tumor. However, the characteristic genetic alterations between the primary gastric cancer and its metastatic ovarian tumor have not been studied. We used laser capture microdissection to procure tissues from 7 patients with gastric cancer who had ovarian metastases (Krukenberg tumor) and tissues from 14 patients with gastric cancer without ovarian metastases. Loss of heterozygosity (LOH) analysis was performed by use of 16 polymorphic markers, which are mapped to the FHIT, APC, p16, BRCA2, E-cadherin, p53, BRCA1, and DPC4 loci. Immunohistochemical staining with anti-Fhit antibody was performed in 7 Krukenberg tumors and 92 gastric cancers without ovarian metastases. LOH at the FHIT locus was observed in six (85.7%) of the seven Krukenberg tumors. In contrast, the gastric cancers without ovarian metastases showed a lower frequency (28.6%, 4/14) of LOH at the FHIT locus (p < 0.05, odds ratio = 1/15). Anti-Fhit antibody showed that expression of Fhit was lost in each of the 7 (100%) Krukenberg tumors but in only 41 (44.6%) of the 92 patients who had gastric cancer without ovarian metastases (p < 0.05; odds ratio = 1/18.614). Further analysis showed that loss of Fhit expression is highly associated with signet-ring cell type gastric cancer (p < 0.0001, odds ratio = 62.5) but is not correlated with prognosis. Alteration of the FHIT gene is a characteristic of signet-ring cell type gastric cancer and Krukenberg tumor.