These findings demonstrate that ras mutations are a marker for aggressive cancer behavior and indicate a possible role of ras genotyping to identify thyroid carcinoma subsets associated with poor prognosis.

The phosphatidylinositol 3V-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients. (Cancer Res 2005; 65(22): 10199-207)

The development of human malignancies can involve the aberrant regulation of intracellular signal transduction pathways that regulate cell-extracellular matrix interactions. Purpose: In the current study, we aimed to evaluate focal adhesion kinase (FAK) at both genetic and protein expression levels in head and neck squamous cell carcinomas (HNSCC) and to explore the prognostic significance of FAK. Experimental Design: A total of 211tissue specimens, including 147 primary tumors, 56 lymph node metastases, 3 benign hyperplasias, and 5 dysplasias, were analyzed using immunohistochemistry. The fak gene dosage was determined in 33 tumors. Correlations among DNA, protein, and clinicopathologic variables were analyzed. Results: FAK protein was overexpressed in HNSCCs compared with corresponding normal mucosa. High expression levels were found in 62% of the samples. Positive immunostaining was also detected in benign hyperplasias and preinvasive dysplastic lesions. All lymph node metastases examined showed FAK overexpression, with significant correlation with the expression in matched primary tumor. DNA copy number ratios for fak were higher in 39% of the tumors compared with normal mucosa. However, elevated FAK expression did not correlate with gains on DNA level, and not all cases with an amplification of the fak gene displayed protein overexpression. Similar data were obtained in five HNSCC-derived cell lines, in which FAK mRNA levels were precisely correlated with FAK protein levels. FAK protein overexpression in tumors correlated with nodal metastases. Conclusions: These findings suggest an involvement of FAK in the onset and progression of HNSCC and provide aninsight into a mechanism of FAK activation alternative to gene amplification.Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of tumors worldwide. Despite recent advancements in diagnosis and treatment, the overall survival has undergone little improvement over the past few decades (1, 2). The major cause of the lethal progression of this type of cancer is the spreading of the malignant cells to regional lymph nodes, which represents a major prognostic indicator and serves as a guide for therapeutic strategies. Although many efforts have been devoted to better understand the molecular mechanisms involved in the progression of this type of cancer, accurate and reliable biomarkers that predict patients at highest risk for lymphatic metastases have yet to be defined.Loss of adhesion of the epithelial cells to the extracellular matrix is one of the fundamental pathways that promote tumor cell migration, invasion, and metastasis. A key factor involved in the control of cell-extracellular matrix interactions is the focal adhesion kinase (FAK), an intracellular tyrosine kinase protein that is localized to cellular focal contact sites (3). FAK is activated and tyrosine phosphorylated upon integrins clustering (4). Evidences also suggest that FAK is a key component of growth factor receptor signaling pathways, such as those activa...

BRAF(V600E)'alone' does not represent a marker for poor outcome, however, when associated with alterations in other genes identifies a subset of PTCs with increased risk of recurrence and decreased survival.