Novel inactivating mutations of transforming growth factor-? type I receptor gene in head-and-neck cancer metastases

Abstract

Carcinoma cell lines are frequently refractory to transforming growth factor‐β (TGFβ)‐mediated cell cycle arrest. Whether and how TGFβ signaling is disrupted in the majority of human tumors, however, remains unclear. To investigate whether TGFβ signaling might be disrupted by inactivation of the key signaling molecule, the TGFβ type I (TβR‐I) receptor, and whether or not TβR‐I inactivation is associated with late stage disease, we conducted a comprehensive structural analysis of the TβR‐I gene in fine‐needle aspirates of 23 head‐&‐neck cancer metastases. We encountered 4 different mutations of TβR‐I, 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 TβR‐I 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 TGFβ 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 TGFβ‐dependent signaling. In aggregate, these findings provide further support for the hypothesis that inactivation of the TGFβ signaling pathway occurs in a significant subset of human cancers.