Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas.
Primary carcinomas of the small intestine are rare and the mechanism of their pathogenesis is poorly understood. Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal carcinomas. The aim of this study is to gain more insight into the development of duodenal carcinomas. Therefore, five FAP-related duodenal carcinomas were characterized for chromosomal and methylation alterations, which were compared to those observed in sporadic duodenal carcinomas. Comparative genomic hybridization (CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed in 10 primary sporadic and five primary FAP-related duodenal carcinomas. In the FAP-related carcinomas, frequent gains were observed on chromosomes 8, 17 and 19, whereas in sporadic carcinomas they occurred on chromosomes 8, 12, 13 and 20. In 60% of the sporadic carcinomas, gains in the regions of chromosome 12 were observed which were absent in the FAP-related carcinomas (P=0.04). Hypermethylation was observed in the immunoglobulin superfamily genes member 4 (IGSF4), TIMP metallopeptidase inhibitor 3 (TIMP3), Estrogen receptor 1 (ESR1), adenomatous polyposis coli (APC), H-cadherin (CDH13) and paired box gene 6 (PAX6) genes. Hypermethylation of PAX6 was only observed in FAP-related carcinomas (3/5) and not in sporadic carcinomas (P=0.02). In conclusion, in contrast to sporadic duodenal carcinomas, gains on chromosome 12 were not observed in duodenal carcinomas of patients with FAP. Identification of the genes in these regions of chromosome 12 could lead to a better understanding of the carcinogenesis pathways leading to sporadic and FAP-related duodenal carcinomas. Furthermore, hypermethylation seems to be a general feature of both FAP-related duodenal carcinomas as well as sporadic duodenal carcinomas with the exception of the PAX6 gene, which is methylated only in FAP-related carcinomas.
Berkhout
Marloes
M
Department of Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Nagtegaal
Iris D
ID
Cornelissen
Sandra J B
SJ
Dekkers
Marieke M G
MM
van de Molengraft
Fred J J M
FJ
Peters
Wilbert H M
WH
Nagengast
Fokko M
FM
van Krieken
J Han J M
JH
Jeuken
Judith W M
JW
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000235:genetics*; D002869:Chromosome Aberrations; D019175:DNA Methylation; D004379:Duodenal Neoplasms / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009693:Nucleic Acid Hybridization