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Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas
1Wood Hudson Cancer Research Laboratory, Newport, KY 41071-4701, USA. tchen@woodhudson.org
Abstract:
Ovarian carcinomas (OCs), particularly recurrent OCs, are frequently resistant to transforming growth factor (TGF)-beta-mediated growth inhibition. Mutations in the TGF-beta receptor type II (TbetaR-II) gene are only evident in a minority of OCs, suggesting that other alterations of the TGF-beta signaling pathway may be involved in OC. Using PCR, cold single-strand conformation polymorphism, and DNA sequencing, we now show that 33% of primary OCs (10 of 30) harbor somatic changes in exons 2, 3, 4, and 6 of the TGF-beta receptor I (TbetaR-I) gene. Most of the changes are missense mutations and clustered largely in the catalytic domain of the receptor kinase. Interestingly, seven additional cases (23.3%) showed heterozygous carriers of an allelic variant [a 9-nucleotide deletion, del(GGC)(3)] in exon 1 of the TbetaR-I gene. This is in contrast with 10.6% of del(GGC)(3) heterozygous carriers in a recent report of a large normal population (n = 735; B. Pasche et al., Cancer Res., 59: 5678-5682, 1999). These results indicate that TbetaR-I is frequently mutated in OC and suggest that resistance to TGF-beta-mediated growth inhibition may frequently involve alterations of the TbetaR-I gene.
Insights
Transforming growth factor-beta (TGF-β) resistance in ovarian cancer is common. This study found frequent mutations in the TGF-β receptor I (TβR-I) gene in ovarian carcinomas, suggesting its role in treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ovarian carcinomas (OCs) often exhibit resistance to transforming growth factor-beta (TGF-β)-mediated growth inhibition, particularly in recurrent cases.
- While mutations in TGF-β receptor type II (TβR-II) are infrequent, other pathway alterations are suspected in OC development and progression.
Purpose of the Study:
- To investigate the frequency and nature of alterations in the TGF-β receptor I (TβR-I) gene in primary ovarian carcinomas.
- To determine the potential role of TβR-I gene mutations in TGF-β signaling pathway resistance in OCs.
Main Methods:
- Polymerase chain reaction (PCR) was employed to analyze specific exons of the TβR-I gene.
- Cold single-strand conformation polymorphism and DNA sequencing were used to detect somatic mutations and allelic variants.
- Genotyping focused on exons 2, 3, 4, and 6 for mutations and exon 1 for a specific 9-nucleotide deletion (del(GGC)(3)).
Main Results:
- Somatic changes in the TβR-I gene were identified in 33% (10 of 30) of primary OCs, predominantly missense mutations within the catalytic kinase domain.
- An increased frequency of heterozygous carriers for the TβR-I exon 1 variant (del(GGC)(3)) was observed in OCs (23.3%) compared to the general population (10.6%).
- These mutations and variants suggest a significant involvement of the TβR-I gene in OC pathogenesis.
Conclusions:
- The TGF-β receptor I (TβR-I) gene is frequently altered in ovarian carcinomas.
- Mutations in TβR-I likely contribute to the observed resistance to TGF-β-mediated growth inhibition in OCs.
- Targeting TβR-I alterations may represent a therapeutic strategy for overcoming TGF-β resistance in ovarian cancer.