Mutation and downregulation of the transforming growth factor beta type II receptor gene in primary squamous cell carcinomas of the head and neck

In the present study, we analyzed 28 squamous cell carcinomas of the headand neck (SCCHN) for mutations in the coding region of TbetaR-II using'Cold' SSCP and automatic DNA sequencing analyses. Twenty-one percent(6/28) of the SCCHN examined contained TbetaR-II mutations compared withpatient-matched normal tissues. These alterations included five missensemutations (A:T-->G:C transitions in codons 250, 401, 448 and 488, and aG:C-->T:A transversion in codon 373), and a 38- bp deletion betweennucleotides 1825 to 1862. In addition to these code- altering mutations,one case exhibited a silent mutation (A:T-->G:C transition in codon 451)and three cases contained one of two potential population polymorphisms(codons 354 and 389). In contrast to colon and gastric cancers exhibitingmicrosatellite instability (MI) or replication errors (RER+), no 'indirect'frameshift mutations were identified within a 10-bp polyadenine repeatpresent in the TbetaR-II coding sequence. All of the mutations in thepresent study occurred within the highly conserved serine/threonine kinasedomain and represent the first report of such 'direct' TbetaR-II mutationsin primary human tumors. In addition, we analyzed a subset of SCCHN andcorresponding normal samples for TbetaR-II mRNA expression using semi-quantitative multiplex RT-PCR. Expression of TbetaR-II was decreased by 24%to 74% in 20 of 23 SCCHN (87%) compared with patient-matched normaltissues. Taken together, the results from this study suggest thatalterations in the nucleic acid sequence and mRNA expression of TbetaR- IIare prevalent events in the development of SCCHN, which may deregulate cellcycle control.