RESUMO
Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.
RESUMO
INTRODUCTION: Among the U.S. population, the p81L SDHD (11q23) gene mutation is present in 6-36% of patients with sporadic carotid body tumor (CBT), but in familial cases is high as 80%. That is why the P81L mutation is used as a screening method for carotid body tumor in the U.S. METHODS: We included 25 patients who underwent resection of a CBT from January 2010 to June 2015. After informed consent, a blood sample was taken for genetic testing on real-time polymerase chain reaction, in order to identify p81L mutation in the SDHD gene. The information was analyzed with descriptive statistics, using central tendency and description measures. RESULTS: In our group, 92% were females, a mean age of 55.5 years, and 52% were Shamblin type II. The most common place of residence was Mexico City, 8% of the patients had family history, about 20% of the patients had a contralateral tumor and 16% had antecedent of another kind of tumor, 4 (16%) p81L SDHD gene mutations were detected, all of them were heterozygous. CONCLUSIONS: The p81L mutation in the SDHD gene was found in the Mexican population in higher grade that in the U.S. population, which explain the high incidence of this pathology in our country, but we need more studies about this subject.
INTRODUCCIÓN: La mutación p81L del gen SDHD (11q23) se encuentra presente en el 6-36% de los pacientes con tumores del cuerpo carotídeo (TCC) esporádicos y hasta en el 80% de los que presentan TCC familiares. En los EE.UU. se usa como método de cribado para TCC. MÉTODO: Se incluyeron 25 pacientes consecutivos operados de resección de TCC entre enero de 2010 y junio de 2015. Se les tomó muestra sanguínea venosa que se sometió a reacción en cadena de la polimerasa en tiempo real para identificar la mutación p81L del gen SDHD (11q23). La información se analizó con estadística descriptiva mediante medidas de tendencia central y dispersión. RESULTADOS: Del grupo en estudio, el 92% eran mujeres, la edad promedio era de 55.5 años y el 52% tenían tumor Shamblin tipo II. El lugar de residencia más frecuente fue la Ciudad de México. El 8% presentaban antecedentes familiares, el 20% tumor bilateral y el 16% presentaron un tumor en otra región. Se encontró la mutación p81L del gen SDHD (11q23) en el 16% de los pacientes de forma heterocigota. CONCLUSIONES: La mutación p81L del gen SDHD se encuentra presente en la población mexicana en un grado más elevado que lo reportado en los EE.UU., lo que podría explicar la alta incidencia en nuestro medio.
Assuntos
Tumor do Corpo Carotídeo/genética , Mutação , Succinato Desidrogenase/genética , Tumor do Corpo Carotídeo/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-IdadeRESUMO
Introduction: Among the U.S. population, the p81L SDHD (11q23) gene mutation is present in 6-36% of patients with sporadic carotid body tumor (CBT), but in familial cases is high as 80%. That is why the P81L mutation is used as a screening method for carotid body tumor in the U.S. Methods: We included 25 patients who underwent resection of a CBT from January 2010 to June 2015. After informed consent, a blood sample was taken for genetic testing on real-time polymerase chain reaction, in order to identify p81L mutation in the SDHD gene. The information was analyzed with descriptive statistics, using central tendency and description measures. Results: In our group, 92% were females, a mean age of 55.5 years, and 52% were Shamblin type II. The most common place of residence was Mexico City, 8% of the patients had family history, about 20% of the patients had a contralateral tumor and 16% had antecedent of another kind of tumor, 4 (16%) p81L SDHD gene mutations were detected, all of them were heterozygous. Conclusions: The p81L mutation in the SDHD gene was found in the Mexican population in higher grade that in the U.S. population, which explain the high incidence of this pathology in our country, but we need more studies about this subject.
Introducción: La mutación p81L del gen SDHD (11q23) se encuentra presente en el 6-36% de los pacientes con tumores del cuerpo carotídeo (TCC) esporádicos y hasta en el 80% de los que presentan TCC familiares. En los EE.UU. se usa como método de cribado para TCC. Método: Se incluyeron 25 pacientes consecutivos operados de resección de TCC entre enero de 2010 y junio de 2015. Se les tomó muestra sanguínea venosa que se sometió a reacción en cadena de la polimerasa en tiempo real para identificar la mutación p81L del gen SDHD (11q23). La información se analizó con estadística descriptiva mediante medidas de tendencia central y dispersión. Resultados: Del grupo en estudio, el 92% eran mujeres, la edad promedio era de 55.5 años y el 52% tenían tumor Shamblin tipo II. El lugar de residencia más frecuente fue la Ciudad de México. El 8% presentaban antecedentes familiares, el 20% tumor bilateral y el 16% presentaron un tumor en otra región. Se encontró la mutación p81L del gen SDHD (11q23) en el 16% de los pacientes de forma heterocigota. Conclusiones: La mutación p81L del gen SDHD se encuentra presente en la población mexicana en un grado más elevado que lo reportado en los EE.UU., lo que podría explicar la alta incidencia en nuestro medio.