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Structural alterations of transforming growth factor‐β receptor genes in human cervical carcinoma
Author(s) -
Chen Taiping,
de Vries E.G.E,
Hollema H.,
Yegen H.A.,
Vellucci V.F.,
Strickler H.D.,
Hildesheim A.,
Reiss M.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990702)82:1<43::aid-ijc9>3.0.co;2-0
Subject(s) - transversion , exon , biology , transforming growth factor , cancer research , mutation , germline mutation , gene , microbiology and biotechnology , genetics , endocrinology
The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor‐β (TGFβ)‐mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGFβ resistance, we screened the 7 exons of the type II ( TβR‐II ) TGFβ receptor and the 9 exons of the type I (TβR‐I) TGFβ receptor genes for mutations in 16 paraffin‐embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G→T transversion in exon 3 of TβR‐II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor. In one tumor, a silent A→C transversion mutation that may affect mRNA splicing was present in exon 6 of TβR‐I . In addition, 7 of 16 cases were heterozygous for a G→A polymorphism in intron 7 of TβR‐I . Finally, we identified a 9 base pair in‐frame germline deletion in exon 1 of TβR‐I resulting in loss of 3 of 9 sequential alanine residues at the N‐terminus in 6 of 16 cases. Analysis of specimens from case‐control studies indicated that carriers of this del(GGC) 3 TβR‐I variant allele may be at a increased risk for the development of cervical carcinoma ( p =0.22). Furthermore, the response of cells expressing the variant receptor to TGFβ was diminished. Our results support the notion that diverse alterations in the TGFβ signaling pathway may play a role in the development of cervical cancer. Int. J. Cancer 82:43–51, 1999. © 1999 Wiley‐Liss, Inc.