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Genetic alteration of colorectal adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions in a patient with attenuated familial adenomatous polyposis.

ABSTRACT: BACKGROUND:Familial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients. METHODS:We report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with gastric mucin (i.e., MUC6, MUC5AC) showed that the tumors belonged to the gastric subtype. Somatic mutation profiles were determined by target amplicon sequencing using a next-generation sequencer. RESULTS:Germline APC variant c.5782delC was found by direct sequencing and somatic KRAS mutations in these tumors were identified by next-generation sequencing. Different KRAS mutation alleles (KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicated these dysplastic lesions developed from a distinct origin in fundic gland polyposis. Sequential mutations of the APC and KRAS were judged-based on a database search-to be characteristic of the adenoma-carcinoma sequence in colorectal carcinogenesis. CONCLUSION:The colonic adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions was indicated in FAP-associated gastric carcinogenesis.

SUBMITTER: Tanabe H

PROVIDER: S-EPMC7507424 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genetic alteration of colorectal adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions in a patient with attenuated familial adenomatous polyposis.

Tanabe Hiroki H Moriichi Kentaro K Takahashi Keitaro K Ono Yusuke Y Kobayashi Yu Y Murakami Yuki Y Iwama Takuya T Kunogi Takehito T Sasaki Takahiro T Ando Katsuyoshi K Ueno Nobuhiro N Kashima Shin S Takei Hidehiro H Mizukami Yusuke Y Fujiya Mikihiro M Okumura Toshikatsu T

Molecular genetics & genomic medicine 20200616 9

<h4>Background</h4>Familial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients.<h4>Methods</h4>We report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with g ...[more]

PMID: 32543103

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Project description:ObjectivesDuodenal cancer in familial adenomatous polyposis (FAP) arises from adenomas. Differentially expressed genes (DEGs) in the duodenal adenoma-carcinoma pathway have been identified in murine FAP models, but similar data in patients with FAP are limited. Identifying such changes may have significance in understanding duodenal polyposis therapies and identifying cancer biomarkers. We performed a genome-wide transcriptional analysis to describe the duodenal adenoma-carcinoma sequence and determine changes distinguishing patients with FAP with and without duodenal cancer.MethodsTranscriptional profiling was performed with the Affymetrix Human Transcriptome Array 2.0 on duodenal biopsies from 12 FAP patients with duodenal cancer (FAP cases) and 12 FAP patients without cancer (FAP controls). DEGs were compared between cancer-normal, adenoma-normal, and cancer-adenoma in FAP cases and between adenomas from FAP cases and FAP controls. Significant results at P < 0.05 were filtered using fold change > 2.ResultsTwo hundred twenty-four DEGs were identified at an absolute fold change > 2. In adenoma-normal, downregulation of DEGs involved in metabolism of brush border proteins (LCT), lipids (APOB/A4), reactive oxygen species (GSTA2), and retinol (RBP2) was observed. In the cancer-adenoma comparison, upregulation of DEGs involved in cell invasion/migration (POSTN, SPP1) and downregulation of DEGs involved in Paneth differentiation (DEFA5/6) were observed. In the adenoma-adenoma comparison, downregulation of several DEGs (CLCA1, ADH1C, ANXA10) in FAP case adenomas was observed. DEGs with therapeutic potential include SPP1, which is involved in both cyclooxygenase and epidermal growth factor receptor pathways targeted by the sulindac/erlotinib combination for duodenal polyposis.DiscussionWe describe DEGs in the human duodenal adenoma-carcinoma sequence in FAP, which may have prognostic and therapeutic significance. Validation studies are needed to confirm these findings.

Dataset Information

Genetic alteration of colorectal adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions in a patient with attenuated familial adenomatous polyposis.

Publications

Genetic alteration of colorectal adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions in a patient with attenuated familial adenomatous polyposis.

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