No abstract

Distant metastasis is a main cause of death in follicular thyroid carcinoma (FTC) patients. Factors related to distant metastasis in FTC had been known as age, primary tumor size, and invasiveness. Ras mutations were also supposed to be associated with poor clinical outcomes. We analyzed Ras mutations in FTC with a distant metastasis (FTC M1, n=28), size matched-FTC without a distant metastasis (FTC M0, n=28), follicular adenoma (FA, n=17), and nodular hyperplasia (NH, n=12) to figure out the roles of Ras mutations in follicular thyroid carcinogenesis and metastasis. In addition, we assess the relationship between Ras mutations and clinical outcomes in FTC patients. NRAS, HRAS, and KRAS mutations were assessed using direct sequencing method. Among 85 patients, 39 patients (46%) had Ras mutations. NRAS codon 61 mutation (n=21; 25%) was the most common point mutation. HRAS codon 61, KRAS codon 12/13, and KRAS codon 61 mutations were found in 7, 6, and 4 patients, respectively. NRAS codon 12/13 mutation was found in only 1 patient, and HRAS codon 12/13 mutation was not found. Ras mutations were significantly more common in the FTC than FA or NH groups. Especially, NRAS codon 61 mutation was associated with distant metastasis in patients with FTC. However, there was no significant difference in survival between the Ras mutation positive-FTC and Ras mutation negative-FTC patients. Ras mutation, especially NRAS codon 61 mutation, was significantly associated with the presence of distant metastases. NRAS codon 61 mutation status might be a potential prognostic factor in FTC patients. Citation Format: MinJi Jeon, Eun Kyung Jang, Dong Eun Song, So Young Sim, Eui Young Kim, Yun Mi Choi, Ji Min Han, Won Gu Kim, Tae Yong Kim, Young Kee Shong, Won Bae Kim. N-ras codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4009. doi:10.1158/1538-7445.AM2014-4009

Context: Slits, representative axon guidance molecules, and their Roundabout (Robo) transmembrane receptors are identified as key regulators of many cancers. One genome-wide liknage analysis suggested Slit-Robo Rho GTPase activating protein 1 gene as a candidate gene in papillary thyroid carcinoma (PTC) susceptibility. Objective: To identify the role of Slit-Robo signaling in PTC. Results : Slits(Slit 1-3) and Robos (Robo 1-4) were expressed in all of thyroid cancer cells and Slit2, Slit3, Robo1 and Robo4 presented higher expression than others. The mRNA expression of Slits and Robos was higher in fresh frozen PTC tissues than matched normal tissues. When we conducted immunohistochemical staining of Slit2 and Robo1 in thyroid tissues, the positivity of Slit2 and Robo1 were higher in PTC tissues than benign or normal tissues. However, negative Slit2 expression was significantly associated with cervical lymph node (LN) metastasis, distant metastasis and cervical recurrence of PTC (P <.001) irrespective of BRAF mutation status. In cellular assays, Slit2 treatment inhibited proliferation of thyroid cancer cells as dose dependent manner and also significantly suppressed cell migration by inhibiting activation of beta-catenin and inducing E-cadherin. Slit2 treatment also significantly suppressed beta-catenin activation induced by Wnt3A in luciferase reporter assay. Conclusions : Low expression of Slit2 was associated with poor prognostic factors in PTC. This present study demonstrated the potential of Slit2 as a novel prognostic and therapeutic factor in PTC. Citation Format: MinJi Jeon, Won Gu Kim, Seonhee Lim, Eun Kyung Jang, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2015-2042