Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma.
In the present study, we evaluated a series of sporadic ovarian carcinomas for mutations within the entire coding region of TbetaR-II. Using reverse transcription-PCR and "Cold" single-strand conformational polymorphism analysis, 6 of 24 samples (25%) were found to contain code-altering mutations in TbetaR-II: (a) four mutations resulting in amino acid substitutions in the highly conserved serine/threonine kinase domain; (b) one mutation resulting in a conservative amino acid change in the transmembrane domain; and (c) a 1-bp insertion in the polyadenylic acid microsatellite region resulting in a reading frameshift. In addition, six cases (25%) exhibited a common bp substitution (C-->T at nucleotide 1322) in both tumor and patient-matched normal tissues. This is the first report of such TbetaR-II mutations in primary human ovarian carcinomas. Immunohistochemical analysis demonstrated a loss of expression of TbetaR-II in 5 of 22 available tumors (23%; 4 of which also had mutations in the coding region) and decreased expression of TbetaR-II in 10 of 22 available tumors (44%; 1 of which had a mutation in the coding region). Thus, the loss or decreased expression of TbetaR-II seems to be a common event in sporadic ovarian carcinomas, and mutational inactivation, due to either frameshift mutations in the polyadenylic acid microsatellite region or point mutations in conserved functional domains, is one mechanism by which this occurs.
Lynch
M A
MA
Division of Environmental Health Sciences, School of Public Health, College of Medicine and Public Health, The Ohio State University, Columbus 43210-1240, USA.
Nakashima
R
R
Song
H
H
DeGroff
V L
VL
Wang
D
D
Enomoto
T
T
Weghorst
C M
CM
D000328:Adult; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D003062:Codon; D017124:Conserved Sequence; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D016019:Survival Analysis
D003062:Codon; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II