title: Multiple forms of genetic instability within a 2-Mb chromosomal segment of 3q26.3-q27 are associated with development of esophageal adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Surgery Thoracic Section, University of Michigan Medical School, B560 MSRB2, Box 0686, Ann Arbor, MI 48109, USA. linlin@umich.edu
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Zhuwen
authors.initials: Z
authors.lastname: Wang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Prescott
authors.forename: Herman
authors.initials: H
authors.lastname: van Dekken
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chang
authors.forename: Mark B
authors.initials: MB
authors.lastname: Orringer
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: John V
authors.initials: JV
authors.lastname: Moran
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Glover
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
mesh_terms: 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
chemical_list: D020121:5' Untranslated Regions