| 1 BACKGROUNDEsophageal cancer (EC), especially the esophageal squamous cell carcinoma (SCC), is one of the six most common malignant diseases in the world, with a remarkable geographical distribution. The ratios of EC incidence between high- and low-incidence areas could be as high as 500:1. Linzhou and nearby counties in Henan province have been well recognized as the highest incidence and mortality areas for SCC in the world. Although SCC usually occurs in the old patients (≥50 years old), the young SCC patients (≤40 years old) have been frequently identified and the incidence seems increasing in recent years. The young SCC patients have been characterized with more poorly differentiated SCC type and a poor prognosis because of early diffuse infiltrative growth and vassel invasion, the 5-year survival rate is lower than the older counterpart. However, the information for the molecular changes is very limited in young SCC patients. In particular, gastric cardia adenocarcinoma (GCA) is also one of the most common malignant digestive diseases in this area and the incidence of GCA in young patients is about 1-3%. A remarkable epidemiological characteristic for GCA is its very similar geographic distribution with SCC and its differences with distal gastric cancer in respect of epidemiology, risk factors, histogenesis and clinical characteristics. The underlying molecular changes, however, are largely unknown.Comparative genomic hybridization (CGH) is a relatively new molecular cytogenetic technique. It combines fluorescent hybridization in situ with digital image analysis and allows the identification of the entire genome for regional variations of DNA sequence copy number (gain, loss, and amplification of DNA sequences) in a single experiment. This technique can detect recurrent copy number changes and may highlight chromosomal regions containing genes that contribute to cancer development and /or progression. Recent studies by us and other laboratories indicate that regional variations of DNA sequence copy number occur frequently in SCC and GCA. However, CGH changes in young patients with SCC and GCA have not been characterized. The present study was undertaken to characterize the spectrum of DNA sequences gains and losses in young SCC and GCA and to compare the CGH changes with that from old SCC and GCA patients in the same area, and to locate novel sites of genetic alterations related with young SCC and GCA.2 MATERIALS AND METHODSForty six patients with SCC and twenty four patients with GCA enrolled in this study were from Linzhou Center Hospital and Yaocun Esophageal Cancer Hospital. Of the 46 cases patients with SCC, the member of the young, middle and old patients were: 10 cases young patients (7 male and 3 female, with a mean age 39±1 years old); 16 cases middle patients (9 male and 7 female, with a mean age 55±4 years old); 20 cases old patients (9 male and 11 female, with a mean age 64±2 years old). For GCA, the member of the young, middle and old patients were: 9 cases patients ( 3 male and 6 female, with a mean age 37±2 years old); 10 cases middle patients (8 male and 2 female, with a mean age 54±5 years old); 5 cases old patients (3 male and 2 female, with a mean age 67±4 years old). All the patients were not received either chemotherapy or radiotherapy before operation. Tumor tissue specimens were frozen immediately and kept in a freezer at -80℃until use. All the specimens were confirmed with histopathology. CGH analysis was used to analyze the whole genome DNA copy number changes in SCC and GCA from the young and old patients. A comparison was performed for the CGH results among the young, middle and old SCC or GCA. The x~2 Test was applied for the statistics (P<0.05 was considered significant).3 RESULTS3.1 CGH changes in the young patients with SCC and GCASCC: In young SCC samples, the most frequently detected gain was on chromosome 3q, 5p, and 7p (4/10, 40%), followed by 5q and 8q (3/10, 30%), the chromosomal aberrant frequency on chromosome 12p, 13q, 20p was very similar (20%, 2/10). The most frequently detected loss was on 16q (5/10, 50%), and followed in turn (from high to low) by 22q (4/10,40%), 3p, 4p, 4q and 16p (3/10,30%).GCA: In young GCA samples, the most frequently detected gain was on chromosome 12p, 12q, 13q, 19q (4/9, 44%), followed by (from high to low) 5p (3/9, 33%), 5q, 3q, 8q, 15q, 19p (2/9, 22%). The most frequently detected loss was on 10q (5/9, 56%), the following detected DNA copy number loss (from high to low) was on 4q (4/9, 44%), 4p, 10p, 14q, 20q (3/9,33%), 7q, 18q and 20p (2/9, 22%).3.2 CGH changes in the old patients with SCC and GCASCC: In middle SCC samples (41~59 years old), the most frequently detected gain was on chromosome 8q (12/16, 75%), followed by 3q (11/16, 69%), 7q (9/16, 56%), 5p, 7p (8/16, 50%). The most frequently detected loss was on 3p (9/16, 56%), 8p, 13p, 13q (7/16, 44%), 9q (6/16, 38%), 9p (5/16, 31%). In old SCC samples (>60 years old), the most frequently detected gain was on chromosome 8q (15/20, 75%), followed by 3q (13/20, 65%), 5p (10/20, 50%), 1q (9/20, 45%). The most frequently detected loss was on 3p (12/20, 60%), 5q, 11q (8/20,40%), 4p, 9q, 1p (7/20, 35%).GCA: In the middle GCA samples (41-59 years old), the most frequently detected gain was on chromosome 8q (7/10, 70%), followed by 3q, 20q (5/10, 50%), 7p, 7q, 20p (4/10, 40%), 2q, 8p (3/10, 30%), 2p, 5p (2/10, 20%). The most frequently detected loss was on 1p, 19p (6/10, 60%), 17p (4/10, 40%), 17q, 19q (3/10, 30%). In the old GCA samples (>60 years old), the most frequently detected gain was on chromosome 1q, 6q (3/5, 60%), 1p, 6p, 12q, 18p, 18q, 20p, 20q (2/5, 40%). The most frequently detected loss was on 17p, 19p, 19q (3/5, 60%), 1p, 4p, 6p, 16p, 17q (2/5, 40%).3.3 Comparison of CGH changes between the young and old patients with SCC and GCASCC: The common gain sites in young, middle and old patients were very similar, all of their changes included 3q, 5p and 8q; however, the profile of loss was different, the highest loss sites occurred in young patients were 16q and 22q, but 3p, 8p, 13p, 13q in middle age and 3p, 5q and 11q in old patients.GCA: The frequent gain sites in young GCA patients were on 12p, 12q, 13q, 19q, but 8q, 3q, 20q in middle patients and 1q, 6q in old patients, respectively. The common loss sites in young GCA patients were 10q and 4q, 1p, 19p and 17p, 19p, 19q in middle and old patients, respectively.SCC and GCA: The chromosome imbalance in young SCC and GCA patients was different, the most frequently detected gains and losses in young SCC were on 3q, 5p, 7p and 16q, 22q, respectively; however, the most frequent detected gains and losses in young GCA were on 12p, 12q, 13q, 19q and 10q, 4q, respectively. The chromosomal imbalance in middle and old SCC and GCA patients was different: the most frequently detected gains and losses in middle and old SCC patients were on 8q, 5p, 3q and 3p, respectively; however, the frequently detected gains in middle and old GCA patients were on 8q, 3q, 20q, 7p, 7q, 20p and 1q, 6q, respectively; the most frequently detected losses in middle and old GCA patients were 1p, 19p, 17p and 17p, 19p, 19q, respectively.4 CONCLUSIONS4.1 The chromosome sites at 3q, 5p, 7p may harbor oncogenes related with the young patients with SCC; however, 16q, 22q may include the tumor suppress genes related with the young patients with SCC.4.2 The chromosome sites at 12p, 12q, 13q ,19q may harbor oncogenes related with the young patients with GCA; 10q and 4q may include the tumor suppress gene related with the young patients with GCA.4.3 The chromosome sites at 8q, 3q, 5p may harbor oncogenes related with the middle and old patients with SCC, 3p may include the tumor suppress gene related with the middle and old patients with SCC.4.4 The chromosome sites at 8q, 3q, 20q, 7p, 7q, 20p may harbor oncogenes related with the middle patients with GCA; 1q, 6q may harbor oncogenes related with the old patients with GCA; 1p, 19p, 17p may include the tumor suppress gene related with the middle patients with GCA, 1q, 6q may include the tumor suppress gene related with the old patients with GCA.4.5 Different profile of DNA gains is observed between the young and old patients with GCA, suggesting that there may be different oncogenes involved in these patients with different ages; different profile of DNA loss is observed between the young and old patients both with SCC and GCA, suggesting that there may be different tumor suppressor genes involved in these patients with different ages, which may precede genetic clues with esophageal and gastric carcinogenesis.4.6 Different profile of DNA gains and losses is observed between the young, middle and old patients with SCC and GCA, suggesting that there may be different oncogenes and tumor suppressor genes involved in SCC and GCA, there may be different mechanisms between SCC and GCA.
|
PDF Full Text Request