Multiple forms of genetic instability within a 2-Mb chromosomal segment of 3q26.3-q27 are associated with development of esophageal adenocarcinoma.
Gene amplification is one of the mechanisms to activate oncogenes in many cancers, including esophageal adenocarcinoma (EA). In the present study, we used two-dimensional restriction landmark genome scanning to clone a NotI/DpnII fragment that showed increased genomic dosage in 1 of 44 EAs analyzed. This fragment maps to 3q26.3-q27, and subsequent experiments identified two intrachromosomal amplicons within a 10-Mb DNA segment in 7 of 75 (9%) EAs. The distal amplified-core region maps centromeric to the PIK3CA locus, and a microsatellite (D3S1754) within this region exhibited significant instability (MSI), in stark contrast to the genomewide microsatellite stability found in EA. D3S1754-MSI arises in premalignant Barrett's dysplastic cells and preceded amplification of the nascent MSI allele in the corresponding EA. Seven ESTs within the amplified-core were overexpressed in amplicon-containing EAs. One of these, EST AW513672, represents a chimeric transcript that initiated from an antisense promoter sequence in the 5'UTR of a full-length LINE-1 element (L1-5'ASP). Similar chimeric transcripts encoding portions of the MET oncogene and the BCAS3 gene also were overexpressed in EAs, suggesting that L1-5'ASP activation may occur at a broad level in primary EAs. Thus, the fine dissection of a 2-Mb amplified DNA segment in 3q26.3-q27 in EA revealed multiple genetic alterations that had occurred sequentially and/or concurrently during EA development.
Lin
Lin
L
Department of Surgery Thoracic Section, University of Michigan Medical School, B560 MSRB2, Box 0686, Ann Arbor, MI 48109, USA. linlin@umich.edu
Wang
Zhuwen
Z
Prescott
Michael S
MS
van Dekken
Herman
H
Thomas
Dafydd G
DG
Giordano
Thomas J
TJ
Chang
Andrew C
AC
Orringer
Mark B
MB
Gruber
Stephen B
SB
Moran
John V
JV
Glover
Thomas W
TW
Beer
David G
DG
D020121:5' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3; D004938:Esophageal Neoplasms / Q000235:genetics*; D020224:Expressed Sequence Tags; D005784:Gene Amplification; D042822:Genomic Instability; D006801:Humans; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D014158:Transcription, Genetic
D020121:5' Untranslated Regions