Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers.

CONTEXT: Fatty acid synthase (FASN) is an enzyme that plays a critical role in de novo synthesis of fatty acids. FASN is overexpressed in variety of human cancers, but its role has not been elucidated in papillary thyroid carcinoma (PTC). OBJECTIVE: Our objective was to investigate the role of FASN and its relationship with phosphatidylinositol 3-kinase/AKT activation in a large series of PTC in a tissue microarray format followed by studies using PTC cell lines and Nude mice. DESIGN: Analysis of apoptosis and cell cycle were evaluated by flow cytometry and DNA fragmentation assays. FASN and phospho-AKT protein expression was determined by immunohistochemistry and Western blotting. RESULTS: Our data show that expression of FASN is associated with activated AKT (phospho-AKT) in a subset of PTC. Treatment of PTC cell lines (NPA-187, ONCO-DG-1, and B-CPAP) with C-75, an inhibitor of FASN, suppresses growth and induces apoptosis in all cell lines. Treatment of PTC cells with C-75 or expression of FASN small interfering RNA causes down-regulation of FASN and inactivation of AKT activity. Furthermore, treatment of PTC cell lines with C-75 results in apoptosis via the mitochondrial pathway involving the proapoptotic factor Bad, activation of Bax, activation of caspases, and down-regulation of antiapoptotic proteins. Finally, treatment of NPA-187 xenografts with C-75 results in growth inhibition of tumors in Nude mice via down-regulation of FASN expression and inactivation of AKT. CONCLUSIONS: Our results suggest that FASN and activated AKT pathway may be a potential target for therapeutic intervention for the treatment of PTC.

Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population.

BACKGROUND: The xenobiotic enzyme system that enables us to detoxify carcinogens exhibits identifiable genetic polymorphisms that are highly race specific. We hypothesized that polymorphisms of these genes may be associated with risk of thyroid cancer. To evaluate the role of genetic polymorphisms of xenobiotic genes in thyroid cancer, we conducted a hospital-based case-control study in Saudi population. METHODS: 223 incident papillary thyroid cancer cases and 513 controls recruited from Saudi Arabian population were analyzed for the association between polymorphisms in genes encoding folic acid metabolizing enzymes MTHFR and six xenobiotics-metabolizing enzymes including CYP1A1 T3801C, C4887A, GSTP1 A1578G, C2293T, GSTM1, GSTT1, NAT2 G590A, NQO*1 C609T, using PCR-RELP. RESULTS: Among selected genes, CYP1A1 C4887A genotypes CA, AA and variant allele A demonstrated significant differences and greater risk of developing thyroid cancer comparing to wild type genotype CC (CA vs. CC; p < 0.0001, OR = 1.91, 95% CI = 1.36-2.70, AA vs. CC; p < 0.001, OR = 3.48, 95% CI = 1.74-6.96 and CA+AA vs. CC; p < 0.0001, OR = 2.07, 95% CI = 1.49-2.88). GSTT1 null showed 3.48 times higher risk of developing thyroid cancer (p < 0.0001, 95% CI = 2.48-4.88) while GSTM1 null showed protective effect (p < 0.05, OR = 0.72, 95% CI = 0.52-0.99). Remaining loci demonstrated no significance with risk. CONCLUSION: Of the 9 polymorphisms screened, we identified GST, GSTM1 and CYP1A1 C4887A, may be of importance to disease process and may be associated with papillary thyroid cancer risk in Saudi Arabian population.

High rate of persistent/recurrent disease among patients with differentiated thyroid cancer in Saudi Arabia: factors affecting nonremission.

BACKGROUND AND OBJECTIVES: A fairly high number of patients with differentiated thyroid cancer (DTC) in our center had locally advanced disease at presentation and/or persistent disease after standard treatment. Therefore, we conducted a retrospective study to find the rate of successful ablation and remission and the factors affecting these outcomes. METHODS: The study included 100 consecutively treated patients (20 males, 80 females; median age 36 years) diagnosed with DTC. Univariate and multivariate logistic regression was used to evaluate the effect of risk factors on the persistence or recurrence of thyroid cancer. All patients underwent total thyroidectomy and had cervical lymph node dissection when indicated. All patients received sodium iodide I 131 ablation once or twice post surgery. Patients were followed clinically by neck ultrasound, (123)I whole body scan and by thyroglobulin measurements and other diagnostic tests as needed. RESULTS: Over a median follow-up of 7.6 years (range 7-10 years), ablation occurred in 93%, remission in 50%, disease persisted without remission in 41%, and 9% had recurrence after at least 1 year of remission. Papillary thyroid cancer was found in 76%, the follicular variant in 14%, other variants (tall cell and sclerosing types) in 2%, Hurthle cell carcinoma in 4%, and pure follicular thyroid cancer in 4%. Compared with patients in remission, patients with persistent/recurrent disease were older (mean 41 versus 31 years, P=.003), had higher postoperative thyroglobulin (193 versus 29 ng/mL, P=.04) and more advanced TNM staging (P=.005). Risk factors significant for non-remission were age >40 years (odds ratio 4.1, 95% CI 1.5-10.9 years, P=.003) and TNM stage other than 1 (odds ratio 5.5, 95% CI 1.9-16.3, P=.001). Only TNM Stage 1 was significant for remission in the multivariate analysis. CONCLUSION: The low remission rate in our DTC patients is probably due to more advanced disease at time of presentation. Early detection may, therefore, be essential in improving outcome.

Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population.

CONTEXT: Genetic aberration in phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been detected in numerous and diverse human cancers. PIK3CA, which encodes for the catalytic subunit of p110alpha of PI3K, is amplified in some cases of papillary thyroid cancer (PTC). Mutations in the PIK3CA have also been identified in thyroid cancers and, although relatively common in anaplastic thyroid carcinoma, are uncommon in PTC. OBJECTIVE: The objective of the study was to investigate genetic alterations like PIK3CA gene mutation, PIK3CA amplification, RAS, and RAF mutations and to further explore the relationship of these genetic alterations with various clinicopathological characteristics in Middle Eastern PTC. DESIGN: We used the fluorescence in situ hybridization technique for analysis of PIK3CA amplification from 536 PTC cases, and selected amplified samples were further validated by real-time quantitative PCR. Mutation analysis was done by direct DNA sequencing of PIK3CA, N2-RAS, and BRAF genes. RESULTS: PIK3CA amplification was seen in 265 of 499 PTC cases analyzed (53.1%); PIK3CA gene mutations in four of 207 PTC (1.9%); N2-RAS mutations in 16 of 265 PTC (6%); and BRAF mutations in 153 of 296 PTC (51.7%). N-RAS mutations were-associated with an early stage (P = 0.0465) and lower incidence of extrathyroidal extension (P = 0.027), whereas BRAF mutations were-associated with metastasis (P = 0.0274) and poor disease-free survival (P = 0.0121) in PTCs. CONCLUSION: A higher incidence of PIK3CA alterations and the possible synergistic effect of PIK3CA alterations and BRAF mutations suggest their major role in Middle Eastern PTC tumorigenesis and argue for therapeutic targeting of PI3K/AKT and MAPK pathways.