Mutational and LOH analyses of the chromosome 4q region in esophageal adenocarcinoma.
OBJECTIVE
Mortality due to esophageal adenocarcinoma has risen markedly, but the molecular mechanisms underlying this carcinogenesis are still incompletely understood. Findings from loss of heterozygosity (LOH) studies have suggested that the long arm of chromosome 4 might harbor tumor suppressor genes relevant to esophageal adenocarcinoma.


METHODS
We performed LOH analysis of 4q in esophageal adenocarcinomas. Regions of LOH were further evaluated by studying two candidate tumor suppressor genes, hCDC4 and CARF, located within them.


RESULTS
54% of the adenocarcinomas examined showed allelic deletion. LOH was observed in 53, 40, 32, 38, and 27% of tumors at positions D4S1554 (the locus of CARF), D4S1572, D4S1548, D4S2934, and D4S3021, respectively. An area of allelic deletion (spanning 3 million bases) was identified at 4q31.1-3 in 37% of tumors. This region harbors a candidate tumor suppressor gene: hCDC4. However, sequencing of the coding regions of CARF and hCDC4 at 4q35 and 4q31, respectively, did not identify mutations.


CONCLUSIONS
Our findings demonstrate frequent LOH in esophageal adenocarcinoma at several loci including a novel area of allelic deletion at 4q31.1-3. The results imply that mutational or other alterations at these loci may be involved in the pathogenesis of esophageal adenocarcinoma. Candidate tumor suppressor genes located within these regions merit further study.
Sterian
Anca
A
Division of Gastroenterology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Kan
Takatsugu
T
Berki
Agnes T
AT
Mori
Yuriko
Y
Olaru
Andreea
A
Schulmann
Karsten
K
Sato
Fumiaki
F
Wang
Suna
S
Paun
Bogdan
B
Cai
Kun
K
Hamilton
James P
JP
Abraham
John M
JM
Meltzer
Stephen J
SJ
D000230:Adenocarcinoma / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D004938:Esophageal Neoplasms / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
C486724:CaRF protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases