MUTATION AND DOWN-REGULATION 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 h ead and neck (SCCHN) for mutations in the coding region of TPR-II usin g 'Cold' SSCP and automatic DNA sequencing analyses, Twenty-one percen t (6/28) of the SCCHN examined contained TPR-II mutations compared wit h patient-matched normal tissues, These alterations included five miss ense mutations (A:T-->G:C transitions in codons 250, 401, 448 and 488, and a G:C-->T:A transversion in codon 373), and a 38-bp deletion betw een nucleotides 1825 to 1862, In addition to these code-altering mutat ions, one case exhibited a silent mutation (A:T-->G:C transition in co don 451) and three cases contained one of two potential population pol ymorphisms (codons 354 and 389), In contrast to colon and gastric canc ers exhibiting microsatellite instability (MI) or replication errors ( RER+), no 'indirect' frameshift mutations were identified within a 10- bp polyadenine repeat present in the TPR-II coding sequence, All of th e mutations in the present study occurred within the highly conserved serine/threonine kinase domain and represent the first report of such 'direct' TPR-II mutations in primary human tumors, In addition, we ana lyzed a subset of SCCHN and corresponding normal samples for TPR-II mR NA expression using semi-quantitative multiplex RT-PCR, Expression of TPR-II was decreased by 24% to 74% in 20 of 23 SCCHN (87%) compared wi th patient-matched normal tissues, Taken together, the results from th is study suggest that alterations in the nucleic acid sequence and mRN A expression of TPR-II are prevalent events in the development of SCCH N, which may deregulate cell cycle control.