ABSTRACT
INTRODUCTION: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant inherited disease with an estimated prevalence of 2-10:100 000. The main locations of tumors are parathyroid glands (HPT), gastroenteropancreatic tract (GEPT), and anterior pituitary gland (PT). The aim of our investigation was to describe the phenotype and genotype of Argentinian patients with MEN1. METHODS: A total of 68 index patients diagnosed with at least two of the three main tumors or one tumor and a relative with MEN1, and 84 first-degree relatives were studied. We sequenced the coding region (exons 2-10); the promoter, exon 1; and the flanking intronic regions of the MEN1 gene, following the Sanger method. We used MLPA in index patients without mutation. RESULTS: Prevalence of tumors: HPT 87.5%, GEPT 49% (p< 0.001). No statistical differences in the prevalence of HPT vs. PT (68%). Prevalence of pathogenic variants: 90% in familial cases and 51% in sporadic cases. Of the different 36 pathogenic variants, 13 (36.2%) were frameshift micro-rearrangement, 8 (22.2%) were missense, 9 (25%) were nonsense, 3 (8.3%) were mutations in splicing sites, 2 (5.5%) were large deletions and, 1 in-frame micro-rearrangement. We found 7 novel pathogenic variants. Thirty-nine percent (n = 33) of first-degree relatives of 23 families were found to be mutation carriers. CONCLUSION: The phenotype and genotype of Argentinian patients was similar to other MEN1 populations. A high frequency of PT and the identification of seven novel mutations are underscored.
Introducción: La neoplasia endocrina múltiple tipo 1 (NEM1) es una enfermedad hereditaria autosómica dominante con una prevalencia estimada de 2-10:100 000. Las localizaciones principales de los tumores son glándulas paratiroides (HPT), tracto gastroenteropancreático (TGEP) y glándula pituitaria (TP). El objetivo de nuestra investigación fue describir el fenotipo y genotipo de pacientes argentinos con NEM1. Métodos: Estudiamos 68 casos índices diagnosticados por presentar al menos dos de los tres tumores principales, o un tumor y un pariente con NEM1, y 84 familiares de primer grado. Secuenciamos la región codificante (exones 2-10); el promotor, exón 1; y las regiones intrónicas flanqueantes del gen MEN1 siguiendo el método de Sanger. Utilizamos MLPA en pacientes índice sin mutación. Resultados: Prevalencia de tumores: HPT 87.5%, TGEP 49% (p < 0.001), sin diferencias estadísticas entre las prevalencias de HPT vs TP (68%). Prevalencia de variantes patogénicas: 90% en casos familiares y 51% en esporádicos. Hallamos 36 variantes patogénicas, 7 (20%) fueron noveles. Fueron 13 (36.2%) microarreglos con cambio en el marco de lectura, 9 (25%) variantes sin sentido, 8 (22.2%) con cambio de sentido, 3 (8.3%) en sitio de unión de empalme, 2 (5.5%) grandes deleciones y 1 microarreglo sin cambio en el marco de lectura. El 39 % (n = 33) de los parientes de primer grado en 23 familias fueron portadores de mutaciones. Conclusión: El fenotipo y genotipo de los pacientes argentinos con NEM1 fue similar al de otras poblaciones. Destacamos una alta frecuencia de TP y de variaciones patogénicas noveles.
Subject(s)
Genotype , Multiple Endocrine Neoplasia Type 1 , Phenotype , Humans , Argentina/epidemiology , Male , Multiple Endocrine Neoplasia Type 1/genetics , Multiple Endocrine Neoplasia Type 1/epidemiology , Female , Adult , Middle Aged , Adolescent , Young Adult , Child , Aged , Mutation , Child, Preschool , Parathyroid Neoplasms/genetics , Parathyroid Neoplasms/epidemiology , Proto-Oncogene ProteinsABSTRACT
INTRODUCTION: The determination of thyroglobulin levels by immunoassay and imaging studies is subject to interference by antithyroglobulin antibodies in up to 30% of cases, suggesting a need to find alternative methods for the follow-up of a significant number of thyroid cancer patients. OBJECTIVES: Assess the sensitivity, specificity, and predictive values of thyroglobulin messenger RNA levels measured by quantitative Real Time-PCR (qRT-PCR) in the blood of patients followed for differentiated thyroid cancer. METHODS: This is a prospective study of Tg-mRNA levels measured with qRT-PCR. A peripheral blood sample was taken in patients with excellent response (69) and with structural incomplete response to treatment (23). Results were analysed using the Unity Real-Time program and expressed as fg/µg RNA. A Receiver Operating Characteristic curve was constructed to assess Tg-mRNA cut-off values. RESULTS: Tg-mRNA levels were not significantly different between the group with excellent response [0.10â¯fg/µg RNA (0.08-0.17)] and the group with incomplete structural response [0.133â¯fg/µg RNA (0.07-0.33)] (Pâ¯<â¯.06). Test sensitivity was 69.6%, specificity was 59.4%, negative predictive value was 85.4% and positive predictive value 36.4% CONCLUSIONS: Our experience shows that this technique could be useful as a rule-out test in selected cases, but its low sensitivity and specificity preclude its usefulness as a first-line test.
Subject(s)
Adenocarcinoma, Follicular , Thyroid Neoplasms , Follow-Up Studies , Humans , Prospective Studies , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Thyroglobulin/genetics , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/geneticsABSTRACT
INTRODUCTION: The determination of thyroglobulin (Tg) levels by immunoassay is subject to interference by antithyroglobulin antibodies in up to 30% of cases, suggesting a need to find alternative methods for the follow-up of a significant number of thyroid cancer patients. OBJECTIVES: Assess the sensitivity, specificity, and predictive values of thyroglobulin messenger RNA (Tg-mRNA) levels measured by quantitative Real Time-PCR (qRT-PCR) in the blood of patients followed for differentiated thyroid cancer. METHODS: This is a prospective study of Tg-mRNA levels measured with qRT-PCR. A peripheral blood sample was taken in patients with excellent response (n=69) and with structural incomplete response to treatment (n=23). Results were analysed using the Unity Real-Time program and expressed as fg/µg RNA. A Receiver Operating Characteristic curve was constructed to establish Tg-mRNA cut-off values. RESULTS: Tg-mRNA levels were not significantly different between the group with excellent response [0.10fg/µg RNA (0.08-0.17)] and the group with incomplete structural response [0.133fg/µg RNA (0.07-0.33)] (p<0.06). Test sensitivity was 69.6%, specificity was 59.4%, negative predictive value was 85.4% and positive predictive value was 36.4%. CONCLUSIONS: Our experience shows that this technique could be useful as a rule-out test in selected cases, but its low sensitivity and specificity preclude its usefulness as a first-line test.
