Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene.
Gap junctional intercellular communication is often impaired in cancers, and the genes which encode the connexin gap junction proteins are considered to be tumor-suppressor genes. In this study, we analyzed the presence of mutations in the connexin 37 (Cx37) gene in 22 human hepatic angiosarcomas, 6 and 4 of which were associated with exposure to vinyl chloride and Thorotrast, respectively. The other 12 samples were from patients with no history of exposure to these 2 agents. In 9 samples, a proline (ACC) to serine (ACT) amino acid change in codon 319 was detected. However, DNA from non-tumorigenic tissue of the same patients also showed this amino acid change, suggesting that this is a polymorphism rather than a mutation. Subsequent analysis of 84 DNA samples from normal donors revealed the frequencies of Pro/Pro, Pro/Ser and Ser/Ser alleles to be 65.5%, 23.8% and 10.7%, respectively, while among the group of angiosarcoma patients the corresponding figures were 59.1%, 31.8% and 9. 1%, respectively. Thus, there was no correlation between the polymorphism at codon 319 and hepatic angiosarcoma occurrence. However, among the 6 cases of vinyl chloride-associated angiosarcoma, the percentages of the polymorphic alleles were 33.3%, 66.7% and 0%, respectively. While the number of samples was too small to allow us to conclude that the Ser319 allele in Cx37 predisposes to this rare type of human cancer, it may be noted that codon 319 is located at the cytoplasmic tail of Cx37, where most regulatory sequences reside, and that it could be a site of phosphorylation for some protein kinases, which may in turn affect the function of Cx37, including intercellular communication.
Saito
T
T
Unit of Multistage Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Krutovskikh
V
V
Marion
M J
MJ
Ishak
K G
KG
Bennett
W P
WP
Yamasaki
H
H
D002273:Carcinogens / Q000009:adverse effects; D003043:Cocarcinogenesis; D017630:Connexins / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D009154:Mutation; D009784:Occupational Diseases / Q000139:chemically induced / Q000235:genetics; D016273:Occupational Exposure; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics; D012694:Serine / Q000235:genetics; D013911:Thorium Dioxide / Q000009:adverse effects; D014752:Vinyl Chloride / Q000009:adverse effects; D000097006:Gap Junction alpha-4 Protein
D002273:Carcinogens; D017630:Connexins; D004273:DNA, Neoplasm; D011392:Proline; D012694:Serine; D013911:Thorium Dioxide; D014752:Vinyl Chloride; D000097006:Gap Junction alpha-4 Protein