Multistep Carcinogenesis of Esophageal Carcinoma
To investigate genetic features of esophageal cancer, we have examined a large number of squamous cell carcinomas of the esophagus (ESCs) for loss of heterozygosity (LOH) using polymorphic DNA markers representing all autosomal chromosomes. Allelic losses at frequencies of at least 30% were observed at loci on chromosomal arms on 3p (33%), 3q (30%), 5q (36%), 9p (57%), 9q (60%), 10p (33%), 13q (43%), 17p (62%), 17q (46%), 18q (38%), 19q (32%), and 21q (37%). By comparing the LOH on each chromosomal arm with the clinicopathologic parameters of patients, we found a significant correlation between LOH on 19q and regional lymph node metastasis. Interestingly, the frequency of LOH on 17q was significantly higher in tumors from female patients (12 of 14 cases) than in those from male patients (20 of 56 cases) P =0.0009 by Fisher’s exact test). Subsequent analysis of allelic losses in DNA extracts isolated from 106 lesions among 32 patients with ESCs revealed that allelic losses on 3p or 17p occurred frequently even in dysplastic lesions, and that allelic losses on these chromosomal arms were observed in cancerous tissues as well. We detected allelic losses of the short and long arms of chromosome 9 at low frequency in lesions with mild dysplasia but often in lesions with severe dysplasia and in intraepithelial cancers. Our results suggested that inactivation of tumor suppressor genes on 3p and 17p occurs at an early stage of esophageal carcinogenesis, and that genes on 9p and 9q are likely to play important roles in malignant changes.
KeywordsEsophageal Cancer Esophageal Squamous Cell Carcinoma Esophageal Carcinoma Allelic Loss Epithelial Growth Factor Receptor
Unable to display preview. Download preview PDF.
- 7.Boynton RF, Blount PL, Yin J, Brown VL, Huang Y, Tong Y, McDaniel T, Newkirk C, Resau JH, Raskind WH, Haggitt RC, Reid BJ, Meltzer SJ (1992) Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc Natl Acad Sci USA 89:3385–3388PubMedCrossRefGoogle Scholar
- 14.Goudie DR, Yuille MAR, Affara NA, Ferguson-Smith MA (1993) Mapping of the gene for multiple self-healing squamous epithelioma by haplotype analysis in families with common ancestry. Cytogenet Cell Genet 64:114Google Scholar
- 26.Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B (1996) A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 271:12125–12128PubMedCrossRefGoogle Scholar
- 27.Suzuki K, Daigo Y, Fukuda S, Tokino T, Isomura M, Isono K, Wainwright B, Nakamura Y (1997) No evidence of mutation in the human PTC gene, re-sponsible for NBCC syndrome, in human primary squamous cell carcinomas of the esophagus and lung. Jpn J Cancer Res (in press)Google Scholar
- 29.Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, David L, Holm R, Ryberg D, Haugen A, Brogger A, Borresen A-L, de la Chapelle (1993) A microsatellite instability is associated with tumors that characterize the heredi-tary non-polyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855PubMedGoogle Scholar