title: 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.
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Lee
authors.forename: Susan C
authors.initials: SC
authors.lastname: Abraham
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Nam
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Lee
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Park
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Juhng
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D017491:Genes, APC; D011905:Genes, ras; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin