Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma

Abstract

Gastric cancer is common among the world, but genetic mechanisms of gastric carcinogenesis are not well understood. Gastric polypoid adenomas and flat dysplasias are regarded as precursor lesions. However, a detailed molecular study of these lesions has not been done to determine their role as precancerous lesions. We investigated mutations of the APC, beta-catenin, and K-ras genes, and microsatellite instability (MSI) status in 35 adenomas and 47 flat dysplasias without adenocarcinoma, 35 adenomas/dysplasias associated with adenocarcinomas, and 39 adenocarcinomas (20 diffuse type and 19 intestinal type). Somatic APC gene mutations were identified in 76% (59 of 78) of adenomas or flat dysplasias without associated adenocarcinoma, but in only 3% (1 of 30) of adenomas/dysplasias associated with adenocarcinoma, and in only 4% (3 of 69) of adenocarcinomas (P < 0.000001). No mutations of beta-catenin were found in adenocarcinomas, or adenomas/dysplasia without APC mutation. K-ras mutations were detected in 5% (4 of 82) of gastric adenomas/dysplasia without carcinoma, 3% (1 of 39) of adenocarcinomas without associated adenoma/dysplasia, and not in 32 adenocarcinomas with associated adenoma/dysplasia. High level of MSI (MSI-H) was more frequent in gastric adenoma/dysplasia associated with carcinoma (17%, 6 of 35) than in adenomas/dysplasia without carcinoma (3%, 2 of 75; P = 0.01). MSI-H was also more frequent in intestinal type adenocarcinoma (20%, 11 of 54) than in diffuse type (0%, 0 of 20; P = 0.03). APC gene mutations were present in six of nine (67%) of gastric adenomas/dysplasias with low level of MSI, but in none of the eight adenomas/dysplasia with MSI-H phenotype (P = 0.009). Our results indicate that somatic mutation of the APC gene plays an important role in the pathogenesis of gastric adenoma and dysplasia but has a limited role in neoplastic progression to adenocarcinoma. Gastric adenomas or dysplasias without APC mutations but with or without MSI may have a different biological behavior, and are precursors of intestinal-type of gastric adenocarcinomas.

Figure 1.

Somatic APC gene mutations in gastric adenomas/dysplasias and adenocarcinomas. A: Summary of the APC gene mutations in the mutation cluster region. An insertion of A into the poly(A) tract at codons 1554 to 1556 is the most common mutation. B: An insertion of T (asterisk) at codon 1556 (adenoma 1), and an insertion of A (asterisk) into the poly(A) tract (bracketwith arrow) at codons 1554 to 1556 (adenoma 2). In adenoma 2, the absence of normal sequence also indicates loss of the nonmutated APC allele. Adenoma 3 has normal APC sequence.

Figure 2.

Microsatellite instability in gastric adenocarcinoma and the associated adenoma/dysplasia. The adenoma/dysplasia component shows a different allelic shift pattern in all five markers (D2S123, D5S346, D17S250, BAT25, and BAT26) as compared to the adenocarcinoma component.

Figure 3.

Role of APC gene and MSI in gastric adenoma/dysplasia-carcinoma sequence. Adenocarcinoma can arise de novo or from pre-existing adenoma/dysplasia. Adenomas or dysplasias with APC gene mutations rarely progress to adenocarcinoma, and have a different biological behavior as compared to adenomas or dysplasias with MSI.