High-Resolution Array Comparative Genomic Hybridization in Sporadic and Celiac Disease–Related Small Bowel Adenocarcinomas

Abstract

Purpose: The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment.Experimental Design: Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas.Results: DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15. 33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable.Conclusions: Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401. ©2010 AACR.

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

“…Among the alterations seen in this group, deletions at chromosome 18q were the most common shared feature (58% in the CIN group, 30% of all investigated carcinomas) and were commonly associated with gains at chromosomes 20q and 7 as well as with losses of chromosomes 4q, 8p, and 17p (Table 1). Our finding of 30% 18q deletions among all investigated small bowel adenocarcinomas is in contrast with a previous matrix CGH study by Diosdado et al 38 reporting o10% of 18q deletions in 48 small intestinal adenocarcinoma, whereas the frequencies of deletions at 4q, 8p, 17p, and gains at chromosomes 7 and 20 were similar to those of our study. The reason for this discrepancy is not clear.…”

“…The reason for this discrepancy is not clear. It may be explained by sampling variation, and in part result from the high number of celiac disease-associated carcinomas (15/48) included in the study by Diosdado et al 38 (1/37 in our study), which have been shown to follow a somewhat different genetic pathway than nonceliac disease-related sporadic carcinomas. 38,39 Chromosome 18q harbors the SMAD4 gene, a mediator of TGFb signaling, which was previously described as a mutational target for a variety of cancers, including small bowel adenocarcinoma.…”

“…It may be explained by sampling variation, and in part result from the high number of celiac disease-associated carcinomas (15/48) included in the study by Diosdado et al 38 (1/37 in our study), which have been shown to follow a somewhat different genetic pathway than nonceliac disease-related sporadic carcinomas. 38,39 Chromosome 18q harbors the SMAD4 gene, a mediator of TGFb signaling, which was previously described as a mutational target for a variety of cancers, including small bowel adenocarcinoma. 7,40 The importance of SMAD4 inactivation for small bowel carcinogenesis is underlined by the fact that deletions at the SMAD4 locus were found in two carcinomas with only minimal numbers of other chromosomal imbalances (T401, T970), and that somatic intragenic mutations of SMAD4 were identified in two tumors lacking 18q loss (T246, T502; data not shown).…”

Small bowel adenocarcinomas in celiac disease follow the CIM-MSI pathway

“…Young age of onset and detection of MSI are typical for the development of SBA in the setting of HNPCC. Our data and the findings of two other studies (31,32) identifying MSI in 67 and 73% of CD-associated carcinomas, respectively, show that these features also occur in CDassociated SBAs. Therefore, CD should be included in the differential diagnosis of SBAs exhibiting MSI.…”

Losses of Chromosome 5q and 14q Are Associated with Favorable Clinical Outcome of Patients with Gastric Cancer

“…A microsatellite instability (MSI) analysis was performed as previously described [29] using the MSI Analysis System (MSI Multiplex System, Version 1.1, Promega Corp., Madison, WI) consisting of five nearly monomorphic mononucleotide markers (BAT-25, BAT-26, . Separation of polymerase chain reaction (PCR) products was performed by capillary electrophoresis using an ABI 3130 DNA sequencer (Applied Biosystems, Foster City, CA) and analysis was performed using GeneScan 3100 (Applied Biosystems, Foster City, CA).…”