Gene mutation of transforming growth factor beta1 type II receptor in hepatocellular carcinoma.
Alteration of transforming growth factor beta1 (TGF-beta1) type II receptor (RII) appears to cause unresponsiveness to TGF-beta1 in tumorigenic cells. Defect in the mononucleotide repeat sequence, i.e., poly A region of TGF-beta1RII gene has been reported to be related to replication error-positive cancer cells. We examined if there is any TGF-beta1RII mutation in a coding microsatellite in hepatocellular carcinoma (HCC). Genomic DNAs were extracted from formalin-fixed, paraffin-embedded liver tissues obtained at surgery or autopsy in 3 normal individuals and 96 patients with hepatitis C virus-induced chronic liver disease; 3 with chronic hepatitis, 20 with liver cirrhosis and 73 with HCC. The DNA was PCR-amplified at 2 segments of TGF-beta1RII: poly A region which includes the (A)10 microsatellite sequence, and poly GT region. PCR products were directly sequenced. DNA from normal and patients with chronic liver disease contained the 10 wild-type adenines but 3 cases with liver cirrhosis in whom there were only 9 adenines within poly A tract. This microdeletion of one A resulted in a frameshift and truncated a predicted length of amino acids. In HCC lesions, the same deletion was noted in 4 cases (25%) of well-differentiated type, 10 (40%) of moderately differentiated type, 18 (53%) of poorly differentiated type. None of the lesions had mutations within the GT region. Our findings indicate that one adenine deletion of poly A microsatellite tract within TGF-beta1RII is frequently detected in patients with HCC, and the mutation may cause the abrogation of the function of TGF-beta1RII gene.
Furuta
K
K
First Department of Internal Medicine, and Research Center for Infectious Disease, Aichi Medical University, Japan.
Misao
S
S
Takahashi
K
K
Tagaya
T
T
Fukuzawa
Y
Y
Ishikawa
T
T
Yoshioka
K
K
Kakumu
S
S
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D004261:DNA Replication; D018900:Dinucleotide Repeats; D006526:Hepatitis C / Q000150:complications / Q000235:genetics / Q000473:pathology; D018937:Hepatitis C Antibodies / Q000097:blood; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D011061:Poly A / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid
D018937:Hepatitis C Antibodies; D018125:Receptors, Transforming Growth Factor beta; D011061:Poly A; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II