title: High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas.
abstract: 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.
authors.affiliation: Departments of Pathology and Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands. b.diosdado@vumc.nl
authors.forename: Begoña
authors.initials: B
authors.lastname: Diosdado
authors.forename: Tineke E
authors.initials: TE
authors.lastname: Buffart
authors.forename: Russell
authors.initials: R
authors.lastname: Watkins
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Marianne
authors.initials: M
authors.lastname: Tijssen
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bolijn
authors.forename: Fraser
authors.initials: F
authors.lastname: Lewis
authors.forename: Karen
authors.initials: K
authors.lastname: Maude
authors.forename: Caroline
authors.initials: C
authors.lastname: Verbeke
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.forename: Heike
authors.initials: H
authors.lastname: Grabsch
authors.forename: Chris J J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: Phil
authors.initials: P
authors.lastname: Quirke
authors.forename: Peter
authors.initials: P
authors.lastname: Howdle
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
mesh_terms: 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