High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas.
OBJECTIVE
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.


METHODS
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.
Diosdado
Begoña
B
Departments of Pathology and Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands. b.diosdado@vumc.nl
Buffart
Tineke E
TE
Watkins
Russell
R
Carvalho
Beatriz
B
Ylstra
Bauke
B
Tijssen
Marianne
M
Bolijn
Anne S
AS
Lewis
Fraser
F
Maude
Karen
K
Verbeke
Caroline
C
Nagtegaal
Iris D
ID
Grabsch
Heike
H
Mulder
Chris J J
CJ
Quirke
Phil
P
Howdle
Peter
P
Meijer
Gerrit A
GA
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002446:Celiac Disease / Q000150:complications* / Q000235:genetics; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D005260:Female; D018628:Gene Dosage; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011401:Promoter Regions, Genetic