Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract

Abstract

Background: Little is known about the genetic alterations in multiple primary cancers of the gastrointestinal tract. Microsatellite instability (MSI) is frequently observed in hereditary non-polyposis colorectal cancer (HNPCC), and multiple primary cancers is a feature of this syndrome.

Aims: To identify MSI incidence, target gene mutation, and mismatch repair (MMR) protein status in patients with multiple primary cancers of the gastrointestinal tract.

Subjects: Fifty seven cancers from 22 Japanese patients with multiple primary cancers of the stomach, duodenum, colon, and rectum.

Methods: MSI was examined at 5-7 microsatellite loci. Mutation analysis for TGFbetaRII, IGFIIR, and BAX was performed in cancers with MSI. MMR protein status was examined by immunohistochemical analysis using a monoclonal antibody against hMSH2 and hMLH1.

Results: MSI was observed in 16 of 22 patients (73%) and in 29 of 57 lesions (51%). High frequency MSI (MSI-H) was found often in patients with multiple cancers in the same organ (p = 0.042), especially in multiple gastric cancer patients (p = 0.038). In contrast, patients with multiple cancers in different organs had a tendency to show low frequency MSI (MSI-L) or microsatellite stable (MSS) phenotype. Both target gene mutation and decreased expression of MMR protein were found only in seven lesions of three patients with MSI at more than four microsatellite loci.

Conclusions: These results suggest that genetic instability may play an important role in the development of multiple gastrointestinal cancers but there may be different genetic alterations between multiple gastrointestinal cancers of the same and different organs.

Figure 1

Typical results of microsatellite instability (MSI). MSI is seen as extra peaks in tumours (arrows) compared with normal tissues. In patient No 16, both gastric and colonic cancers showed MSI of BAT-26 (left). In patient No 2, all four gastric cancers showed MSI of D17S250 (right).

Figure 2

Typical results of target gene mutations. SW48 and SKUT1B are known to have mutated IGFIIR (G7+G8 and G8+G9, respectively). DU145 have wild type (G8). In patient No 16, colonic cancer showed mutated IGFIIR (G8+G9, arrow).

Figure 3

Immunostaining for hMSH2 in gastric cancer from patient No 16. Normal gastric epithelium (left) and infiltrating inflammatory cells were stained, but in cancer tissue (right) hMSH2 protein expression was very weak.