Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma.
Barrett's esophagus (BE) is a metaplastic condition caused by chronic gastroesophageal reflux which represents an early step in the development of esophageal adenocarcinoma (EAC). Single-nucleotide polymorphism microarray (SNP-chip) analysis is a novel, precise, high-throughput approach to examine genomic alterations in neoplasia. Using 250K SNP-chips, we examined the neoplastic progression of BE to EAC, studying 11 matched sample sets: 6 sets of normal esophagus (NE), BE and EAC, 4 of NE and BE and 1 of NE and EAC. Six (60%) of 10 total BE samples and 4 (57%) of 7 total EAC samples exhibited 1 or more genomic abnormalities comprising deletions, duplications, amplifications and copy-number-neutral loss of heterozygosity (CNN-LOH). Several shared abnormalities were identified, including chromosome 9p CNN-LOH [2 BE samples (20%)], deletion of CDKN2A [4 BE samples (40%)] and amplification of 17q12-21.2 involving the ERBB2, RARA and TOP2A genes [3.1 Mb, 2 EAC (29%)]. Interestingly, 1 BE sample contained a homozygous deletion spanning 9p22.3-p22.2 (1.2 Mb): this region harbors only 1 known gene, basonuclin 2 (BNC2). Real-time PCR analysis confirmed the deletion of this gene and decreased the expression of BNC2 mRNA in the BE sample. Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus and that deletion of this gene occurs during the development of EAC. Thus, this SNP-chip analysis has identified several early cytogenetic events and novel candidate cancer-related genes that are potentially involved in the evolution of BE to EAC.
Akagi
Tadayuki
T
Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA. tadayuki@staff.kanazawa-u.ac.jp
Ito
Tetsuo
T
Kato
Motohiro
M
Jin
Zhe
Z
Cheng
Yulan
Y
Kan
Takatsugu
T
Yamamoto
Go
G
Olaru
Alexandru
A
Kawamata
Norihiko
N
Boult
Jessica
J
Soukiasian
Harmik J
HJ
Miller
Carl W
CW
Ogawa
Seishi
S
Meltzer
Stephen J
SJ
Koeffler
H Phillip
HP
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C484527:BNC2 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger