
<ArticleTitle>Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases.</ArticleTitle>
<AbstractText>Carcinoma cell lines are frequently refractory to transforming growth factor-beta (<prot>TGF beta</prot>)-mediated cell cycle arrest. Whether and how TGF beta signaling is disrupted in the majority of human tumors, however, remains unclear. To investigate whether <prot>TGF beta</prot> signaling might be disrupted by inactivation of the key signaling molecule, the <prot><prot><prot>TGF beta</prot> type I</prot> (<prot>T beta R-I</prot>)</prot> receptor, and whether or not <prot>T beta R-I</prot> inactivation is associated with late stage disease, we conducted a comprehensive structural analysis of the <prot>T beta R-I</prot> gene in fine-needle aspirates of 23 head-&#38;-neck cancer metastases. We encountered 4 different mutations of <prot>T beta R-I</prot>, 3 of which have not been previously identified. In 1 case, we found a somatic intragenic 4-bp deletion predicting for a truncation of the receptor protein. This is the first example of a true loss-of-function mutation of<prot> T beta R-I</prot> in a human epithelial neoplasm. In 2 other cases, we identified missense mutations located between the juxtamembrane- and serine-threonine kinase domains. One of these resulted in an alanine-to-threonine substitution (A230T), which disrupts receptor signaling activity by causing rapid protein degradation within the endoplasmatic reticulum. This represents a novel mechanism of inactivation of a <prot>TGF beta</prot> signaling intermediate. Finally, we identified a serine-to-tyrosine substitution at codon 387 (S387Y) in a metastasis but not in the corresponding primary tumor. We had previously shown this S387Y mutant to be predominantly associated with breast cancer metastases and to have a diminished ability to mediate TGF beta-dependent signaling. In aggregate, these findings provide further support for the hypothesis that inactivation of the TGF beta signaling pathway occurs in a significant subset of human cancers.</AbstractText>
