Allelic loss in esophageal precancerous and cancerous lesions from a high risk area in China

Abstract

Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer death in China, but its etiology remains largely unknown. Carcinogenesis of ESCC is considered a multistage process evolving from basal cell hyperplasia (BCH) to dysplasia, carcinoma in situ, and invasive cancer. Although loss of heterozygosity (LOH) analyses of ESCC have shown frequent allelic losses on chromosomes 3p, 5q, 6p, 9p, 13q, 17q, 17p and 18q, the genetic changes involved in the progression of ESCC remain unclear. In the present study, LOH on these chromosomal regions was investigated in 29 precancerous lesions and 29 ESCC microdissected specimens collected from Linzhou, an area in northern China with an exceptionally high incidence of ESCC, using 15 polymorphic microsatellite markers. Loss of heterozygosity was detected in all stages of precancerous lesions and ESCC. The overall frequency of LOH in BCH (9.7%) was significantly lower than that in the more histopathologically advanced lesions. Although BCH can progress to dysplasia or even invasive cancer, this event is considered reversible and its progression to advanced stage takes much longer than the late carcinogenic events. In BCH, allelic loss was detected at 3p14-p21, 5q21-q22, 9p21, 17p13 and 17q21, with the highest frequency (37.5%) detected at 17q21 using marker D17S855 which is located in intron 20 of BRCA1 gene. From dysplasia onwards, LOH was detected in additional loci (5q15-q23, 13q13.1-q14.3, 17p12-p13 and 18q21.1). Although a trend of increased losses was noted from dysplasia (31.8%) to carcinoma in situ (39.5%) and invasive cancer (42.6%), no statistical significance was observed among these lesions. Allelic loss at 6p21, where candidate tumor suppressor genes p21WAF1 and HLA are located, was detected only in invasive cancer. Our results suggest that genetic instability resulting from the alteration of the BRCA1 gene may play a role in initiation of ESCC, and that other genetic changes which begin to accumulate at dysplasia may be responsible for irreversible progression to cancer. Allelic loss at 6p21 may be associated with the progression in late stage. Our findings support a multistage model of esophageal carcinogenesis. (This study was supported by the Research Grants Council of Hong Kong, China, Project No. HKU 7057/99M and HKU CRCG 21374067/07419/20200/420/01).