Abstract 5233: Associations between somatic mutations and clinical manifestations in South American Hispanic patients with papillary thyroid cancer
Authors: Estrada-Florez Ana P. , Bohorquez Mabel E. , Duque Carlos S. , Donado Jorge , Mateus Gilbert , Bolaños Fernando , Velez Alejandro , Estrada Erika , Polanco-Echeverry Guadalupe , Sahasrabudhe Ruta , Garcia Elisha , Echeverry Magdalena , Carvajal-Carmona Luis G. 
Published: August 2018

Abstract
Papillary thyroid cancer (PTC) is the second most commonly diagnosed tumor in U.S. Hispanic women, representing ~9% of all incident female cancer cases in this minority. In Colombia, a country with a predominantly Hispanic population, PTC is the fifth most commonly diagnosed cancer in women. Several studies, predominantly in non-Hispanic whites (NHW), have associated the RAS-RAF gene and TERT promoter mutations with severe PTC clinical manifestations. We investigated associations between mutations in these genes and clinicopathologic data (age, gender, histologic type, tumor features and AJCC stage) in 143 Colombian cases (76 with classical variant PTC, CVPTC and 65 with follicular variant PTC, FVPTC). DNA from archival samples was isolated using standard methods and mutation status at hotspots in BRAF (V600E), NRAS (Q61R, Q61K), HRAS (Q61R, Q61K), and TERT (C228T, C250T) were assessed using Sanger sequencing. Clinicopathologic data between mutation carriers and noncarriers and with data from NHWs in the TCGA were carried out with t-tests and odds ratios (OR). BRAF V600E was detected in 59% of all cases, a rate that is similar to NHW (64%; P=0.29). When we stratified the data by subtype, we found a similar V600E frequency in CVPTC in Colombian cases than in NHWs (67% vs 68%; P=0.87) but a borderline significantly higher frequency of the mutation in FVPTC (49% vs 29%; P=0.06). TERT promoter mutations were found in 17% of all cases, a rate that is significantly higher than in NHW (10%, p= 0.03). 5% of cases had mutations in HRAS/NRAS, which is lower than in NHW (11%; P=0.04). Given the low RAS gene mutation frequency, comparisons with clinical data were carried out only with BRAF and TERT data. BRAF/TERT mutation-positive samples (BRAF+/TERT+, n=18) were compared to mutation-negative cases for either or both genes (n=123). BRAF+/TERT+ tumors were more common in CVPTC than in FVPTC (17% vs. 7%; OR=4.1; P=0.02), and in cases with tumors &gt;2cm (20% vs. 6%; OR=4.0; P=0.03), with capsular invasion (18% vs. 5%; OR=5.6; P=0.02), with lymph node metastasis (19% vs. 6%; OR=7.1; P=0.006), with extrathyroidal extension (23% vs. 6%; OR=4.8; P=0.03), and advanced AJCC stage (29% vs. 4%; OR= 8.7; P=5.00 x 10-4). PTC is considered a relatively benign malignancy with good prognosis and survival in the U.S., but we found a high fraction of Colombian cases in advanced AJCC stage (32%) and with distant metastasis (6%), suggesting that most cases were not the result of incidental findings, a common phenomenon in developed countries where most PTCs are likely the result of overdiagnosis. In summary, we present the first report of BRAF/RAS/TERT mutations in Hispanics with PTC from Latin America, demonstrate the utility of these mutations to identify cases with severe disease, and generate a body of data that will be important for the establishment of PTC precision medicine in the region.
Citation Format: Ana P. Estrada-Florez, Mabel E. Bohorquez, Carlos S. Duque, Jorge Donado, Gilbert Mateus, Fernando Bolaños, Alejandro Velez, Erika Estrada, Guadalupe Polanco-Echeverry, Ruta Sahasrabudhe, Elisha Garcia, Magdalena Echeverry, Luis G. Carvajal-Carmona. Associations between somatic mutations and clinical manifestations in South American Hispanic patients with papillary thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5233.