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      BRAF and TERT mutations in papillary thyroid cancer patients of Latino ancestry

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          Abstract

          Papillary thyroid cancer (PTC) is the second most commonly diagnosed malignancy in U.S. Latinas and in Colombian women. Studies in non-Latinos indicate that BRAF and TERT mutations are PTC prognostic markers. This study aimed to determine the prevalence and clinical associations of BRAF and TERT mutations in PTC Latino patients from Colombia. We analyzed mutations of BRAF (V600E) and TERT promoter (C228T, C250T) in tumor DNA from 141 patients (75 with classical variant PTC, CVPTC; 66 with follicular variant PTC, FVPTC) recruited through a multi-center study. Associations between mutations and clinical variables were evaluated with Fisher exact tests. Survival was evaluated with Kaplan–Meier plots. Double-mutant tumors ( BRAF+/ TERT+, n = 14 patients) were more common in CVPTC ( P = 0.02). Relative to patients without mutations ( n = 48), double mutations were more common in patients with large tumors ( P = 0.03), lymph node metastasis ( P = 0.01), extra-thyroid extension ( P = 0.03), and advanced stage ( P = 6.0 × 10 −5). In older patients, TERT mutations were more frequent (mean age 51 years vs 45 years for wild type TERT, P = 0.04) and survival was lower (HR = 1.20; P = 0.017); however, given the small sample size, the decrease in survival was not statically significant between genotypes. Comparisons with published data in US whites revealed that Colombian patients had a higher prevalence of severe pathological features and of double-mutant tumors (10 vs 6%, P = 0.001). Mutations in both oncogenes show prognostic associations in Latinos from Colombia. Our study is important to advance Latino PTC precision medicine and replicates previous prognostic associations between BRAF and TERT in this population.

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          Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer.

          BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. To investigate the relationship between BRAF V600E mutation and PTC-related mortality. Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. Patient deaths specifically caused by PTC. Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.
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            Cancers with increasing incidence trends in the United States: 1999 through 2008.

            Despite declines in incidence rates for the most common cancers, the incidence of several cancers has increased in the past decade, including cancers of the pancreas, liver, thyroid, and kidney and melanoma of the skin, as well as esophageal adenocarcinoma and certain subsites of oropharyngeal cancer associated with human papillomavirus (HPV) infection. Population-based incidence data compiled by the North American Association of Central Cancer Registries were used to examine trends in incidence rates from 1999 through 2008 for the 7 cancers listed by sex, age group, race/ethnicity, and stage at diagnosis. Joinpoint regression was used to calculate average annual percent changes in incidence rates (1999-2008). Rates for HPV-related oropharyngeal cancer, esophageal adenocarcinoma, cancer of the pancreas, and melanoma of the skin increased only in whites, except for esophageal adenocarcinoma, which also increased in Hispanic men. Liver cancer rates increased in white, black, and Hispanic men and in black women only. In contrast, incidence rates for thyroid and kidney cancers increased in all racial/ethnic groups, except American Indian/Alaska Native men. Increases in incidence rates by age were steepest for liver and HPV-related oropharyngeal cancers among those aged 55 [corrected] to 64 years and for melanoma of the skin in those aged 65 years and older. Notably, for HPV-related oropharyngeal cancer in men and thyroid cancer in women, incidence rates were higher in those aged 55 to 64 years than in those aged 65 years and older. Rates increased for both local and advanced stage diseases for most cancer sites. The reasons for these increasing trends are not entirely known. Part of the increase (for esophageal adenocarcinoma and cancers of the pancreas, liver, and kidney) may be linked to the increasing prevalence of obesity as well as increases in early detection practices for some cancers. These rising trends will exacerbate the growing cancer burden associated with population expansion and aging. Additional research is needed to determine the underlying reasons for these increasing trends. CA Cancer J Clin 2012. © 2012 American Cancer Society. Copyright © 2012 American Cancer Society, Inc.
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              Cancer Statistics for Hispanics/Latinos, 2018

              Cancer is the leading cause of death among Hispanics/Latinos, who represent the largest racial/ethnic minority group in the United States, accounting for 17.8% (57.5 million) of the total population in the continental United States and Hawaii in 2016. In addition, more than 3 million Hispanic Americans live in the US territory of Puerto Rico. Every 3 years, the American Cancer Society reports on cancer occurrence, risk factors, and screening for Hispanics in the United States based on data from the National Cancer Institute, the North American Association of Central Cancer Registries, and the Centers for Disease Control and Prevention. For the first time, contemporary incidence and mortality rates for Puerto Rico, which has a 99% Hispanic population, are also presented. An estimated 149,100 new cancer cases and 42,700 cancer deaths will occur among Hispanics in the continental United States and Hawaii in 2018. For all cancers combined, Hispanics have 25% lower incidence and 30% lower mortality compared with non-Hispanic whites, although rates of infection-related cancers, such as liver, are up to twice as high in Hispanics. However, these aggregated data mask substantial heterogeneity within the Hispanic population because of variable cancer risk, as exemplified by the substantial differences in the cancer burden between island Puerto Ricans and other US Hispanics. For example, during 2011 to 2015, prostate cancer incidence rates in Puerto Rico (146.6 per 100,000) were 60% higher than those in other US Hispanics combined (91.6 per 100,000) and 44% higher than those in non-Hispanic whites (101.7 per 100,000). Prostate cancer is also the leading cause of cancer death among men in Puerto Rico, accounting for nearly 1 in 6 cancer deaths during 2011-2015, whereas lung cancer is the leading cause of cancer death among other US Hispanic men combined. Variations in cancer risk are driven by differences in exposure to cancer-causing infectious agents and behavioral risk factors as well as the prevalence of screening. Strategies for reducing cancer risk in Hispanic populations include targeted, culturally appropriate interventions for increasing the uptake of preventive services and reducing cancer risk factor prevalence, as well as additional funding for Puerto Rico-specific and subgroup-specific cancer research and surveillance.
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                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                September 2019
                22 August 2019
                : 8
                : 9
                : 1310-1317
                Affiliations
                [1 ]Genome Center and Department of Biochemistry and Molecular Medicine , School of Medicine, University of California, Davis, California, USA
                [2 ]Grupo de Citogenética , Filogenia y Evolución de Poblaciones, Facultad de Ciencias y Facultad de Ciencias de la Salud, Universidad del Tolima, Ibagué, Tolima, Colombia
                [3 ]Facultad de Ciencias para la Salud , Universidad de Caldas, Manizales, Caldas, Colombia
                [4 ]Dinamica IPS , Medellín, Antioquia, Colombia
                [5 ]Hospital Pablo Tobón Uribe , Medellín, Antioquia, Colombia
                [6 ]Hospital Federico Lleras Acosta , Ibagué, Tolima, Colombia
                [7 ]Universidad Surcolombiana , Neiva, Huila, Colombia
                [8 ]University of California Davis Comprehensive Cancer Center , Sacramento, California, USA
                [9 ]Fundación de Genética y Genómica , Medellín, Antioquia, Colombia
                Author notes
                Correspondence should be addressed to L G Carvajal-Carmona: lgcarvajal@ 123456ucdavis.edu
                Article
                EC-19-0376
                10.1530/EC-19-0376
                6765322
                31454788
                bcb3353d-780f-4115-a00a-bf380c46d27c
                © 2019 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 08 August 2019
                : 22 August 2019
                Categories
                Research

                cancer risk factors,somatic mutations,hispanics,braf,tert
                cancer risk factors, somatic mutations, hispanics, braf, tert

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