Loss of heterozygosity analysis of microsatellites on multiple chromosome regions in dysplasia and squamous cell carcinoma of the esophagus

Abstract

Abstract. The objective of this study was to characterize the molecular events in the carcinogenesis of esophageal squamous cell carcinoma (ESCC) and to identify biomarkers for early detection of the disease. Matched precancerous and cancerous tissues resected from 34 esophageal cancer patients from Chongqing, southern China, were compared to evaluate the extent of loss of heterozygosity (LOH). Sixteen microsatellite markers on chromosome regions 3p, 4p, 5q, 8p, 9p, 9q, 11p, 13q and 17p were used for PCR-based LOH analysis. The overall frequency of LOH at the 16 microsatellite loci was significantly increased as the pathological status of the resection specimens changed from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and SCC (P<0.001). A total of 8 markers showed LOH in the LGD samples. In addition, heterozygosity was regained at 4 loci in the SCC samples of 4 patients, respectively, in comparison to the results for these loci in the HGD samples. The overall rate of LOH increased significantly with the deterioration of the lesions, indicating that tumorigenesis of the esophageal squamous epithelia is a progressive process involving accumulative changes in LOH. The 8 loci showing allelic loss in the LGD samples may be involved in the early-stage tumorigenesis of ESCC, and LOH analysis at these loci may help improve the early detection of this disease. Regain of heterozygosity found in certain patients suggests the possibility of genetic heterogeneity in the tumorigenesis of esophageal cancer.

Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to Carcinoma

“…Intriguingly, despite shared genetic changes in paired ESCC and IEN samples, a high degree of private mutation sites showed evidence for genetic heterogeneity, 12,29 which was similar to paired Barrett's and EAC samples. 30,31 In addition, some cases showing high heterogeneity between paired IEN and ESCC samples (3 pairs with <5% SNV overlap) implied the possibility of multifocal lesions in the esophagus.…”

“…[6][7][8][9] However, most studies of precancerous lesions of ESCC were limited to hotspot genes or the allelic loss of tumor-suppressor genes. [10][11][12] The panoramic genetic architecture of the carcinogenesis process is unknown.…”

Genomic and Epigenomic Aberrations in Esophageal Squamous Cell Carcinoma and Implications for Patients

“…Other alterations detected in dysplasia include hypermethylation at promoters of tumor suppressor genes ( CDKN2A , CLDN3 , and MT1G ) 93,94 and loss of heterozygosity of microsatellite markers. 95–98 Together, these findings indicate that even though IEN and ESCC are histologically distinct, they share many pathogenic genomic abnormalities. These might be used as biomarkers for early detection and risk stratification.…”

Squamous Dysplasia—The Precursor Lesion for Esophageal Squamous Cell Carcinoma

“…Nucleic acid-based studies of precursors have shown increased allelic loss (pointing to potential tumor suppressor gene inactivation sites) with increasing grade of dysplasia at a wide variety of microsatellite loci (i.e., 3p, 4p, 5q, 8p, 9p, 9q, 10p, 11p, 13q, and 17p) (24–27). Mutation studies in esophageal squamous precursors have been limited to TP53 , where missense mutations were evident early in esophageal carcinogenesis (four of 11 samples with dysplasia vs one of three normal epithelia) (28).…”