Abnormal nucleotide repeat sequence in the TGF‐βRII gene in hepatocellular carcinoma and in uninvolved liver tissue

Replication error (RER)-related genetic alterations are associated with a subset of hepatocellular carcinomas (HCCs) with multiple primary cancers. This study investigated whether mutations in the nucleotide repeats of three putative target genes of RER are associated with hepatocarcinogenesis. The genes examined were those encoding transforming growth factor β type II receptor (TGF-βRII), BCL-2-associated X protein (BAX), and insulin-like growth factor II receptor (IGF-IIR). Tumour and non-tumour hepatic tissues were examined in 48 HCC patients, 34 with solitary HCC and 14 who had double cancer with gastric cancer. Four double-cancer cases showed an abnormal signal in the single nucleotide repeat (A)10 of the TGF-βRII gene. These four were among the six RER-positive cases in this series. The genotypes of the poly A tract of the TGF-βRII gene in the liver tumour tissue of the four cases with an abnormal signal were (A)9/10, (A)9/10, (A)9/10, and (A)9/9. Five uninvolved liver tissue specimens from these four patients showed (A)9/10 and (A)9/9, (A)9/10, (A)10/10 and (A)9/9, respectively. The genotype in the stomach cancer specimens of these four patients was (A)10/10, indicating no germline mutation of the TGF-βRII gene. There were no mutations in the nucleotide repeats of the BAX and IGF-IIR genes in any of the liver tissue specimens. Abnormality of the nucleotide repeat in the TGF-βRII gene occurred in the uninvolved liver tissue as well as the HCC tissue in some HCC patients. Such genetic instability may be gene-specific and tissue-specific in carcinogenesis. Copyright © 2001 John Wiley & Sons, Ltd.