Transforming growth factor-beta receptor type I gene is frequently mutatedin ovarian carcinomas

Ovarian carcinomas (OCs), particularly recurrent OCs, are frequently resist ant to transforming growth factor (TGF)-beta -mediated growth inhibition. M utations in the TGF-beta receptor type II (T betaR-II) gene are only eviden t in a minority of OCs, suggesting that other alterations of the TGF-beta s ignaling pathway mag be involved in OC. Using PCR, cold single-strand confo rmation polymorphism, and DNA sequencing, we now show that 33% of primary O Cs (10 of 30) harbor somatic changes in exons 2, 3, 4, and 6 of the TGF-bet a receptor I (T betaR-I) gene. Most of the changes are missense mutations a nd clustered largely in the catalytic domain of the receptor kinase, Intere stingly, seven additional Eases (23.3%) showed heterozygous carriers of an allelic variant Ca P-nucleotide deletion, del(GGC)(3)] in exon 1 of the T b etaR- gene. This is in contrast with 10.6% of del(GGC)(3) heterozygous carr iers 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 T betaR -I is frequently mutated in OC and suggest that resistance to TGF-beta -med iated growth inhibition may frequently involve alterations of the T betaR-I gene.