Avaliação de painel multigenes em mulheres brasileiras com câncer de mama / Evaluation of a multigene panel in Brazilian women with breast cancer

Introdução: Apenas 5-10% dos casos de câncer de mama estão relacionados a variantes genéticas herdadas e mutações nos genes BRCA1 e BRCA2, relacionadas à Síndrome do câncer de mama e ovário hereditário (SMOH), são identificadas na maioria desses casos. Além dos genes BRCA1 e BRCA2, outros genes também estão associadas a um risco elevado e moderado para o câncer de mama, como TP53, STK11, CDH1, PTEN, ATM, CHEK2 e PALB2 e fazem parte do grupo de genes acionáveis com estratégias de manejo clínico e prevenção bem estabelecidos. A implementação do Sequenciamento de Nova Geração (NGS) vem permitindo a análise simultânea de múltiplos genes através dos painéis multigenes com maior rapidez na análise e menor custo quando comparada ao sequenciamento de um gene único e, atualmente, vem sendo amplamente utilizado em Oncologia para identificação das síndromes de predisposição hereditária ao câncer. Objetivo: O objetivo desse estudo é avaliar a contribuição do painel multigenes na detecção de mutações germinativas em outros genes, além de BRCA1 e BRCA2, em pacientes com critérios clínicos para câncer de mama hereditário. Pacientes e Métodos: Um painel NGS de 94 genes foi realizado em 321 pacientes com diagnóstico atual ou prévio de câncer de mama que apresentavam critérios clínicos para SMOH, e que realizaram o teste genético para os genes BRCA1 e BRCA2 no Laboratório de Diagnóstico Genômico do A.C.Camargo Cancer Center, entre agosto de 2016 e maio de 2018. Resultados: A análise dos dados do painel das 321 pacientes resultou em um total de 84 variantes patogênicas/provavelmente patogênicas (VP/PP) que foram identificadas em 81 pacientes e a positividade do teste genético foi de 25,2% (n=81/321). Três pacientes (n=3/81 ­ 3,7%) apresentaram duas VP/PP em genes distintos e foram diagnosticadas com Síndrome da Neoplasia Hereditária Multialélica (MINAS). Do total de VP/PP, 42,9% (n=36/84) foram identificadas em genes de alta penetrância para câncer de mama (BRCA1, BRCA2 e TP53) e 21,4% (n=18/84) em genes de penetrância moderada (ATM, PALB2 e CHEK2). O restante, correspondente a 35,7% (n=30/84) das VP/PP, foram identificadas em genes de baixa penetrância para câncer de mama e foram considerados como achados incidentais, uma vez que não apresentaram correlação genótipo-fenótipo. Em relação ao subtipo molecular do câncer de mama, o subtipo triplo negativo apresentou frequência de VP/PP de 31,6% (n=25/79), com predomínio de mutações no gene BRCA1 (12,6% - n=10/79). Entre o subtipo luminal, 18,7% (n=29/155) apresentavam VP/PP e destes, mutações em genes não-BRCA1/2 predominaram com frequência de 12,2% (n=19/155). Para o subtipo Luminal B HER2, 40% (n=16/40) apresentaram uma VP/PP, com predomínio do gene ATM (12,5% - n=5/40). Finalmente, o subtipo hiperexpressor de HER2 apresentou frequência de VP/PP de 30,8% (n=4/13), sem predominância de genes específicos. Variantes de significado incerto foram identificadas em 77,6% (n=249/321) das pacientes e dessas, 24,5% (n=61/249) apresentaram também ao menos uma VP/PP. Conclusão: O painel 94 genes contribuiu para identificar VP/PP em outros genes além de BRCA1/2, aumentando a positividade do teste genético de 9,9% (BRCA1/2) para 25,2%. Considerando-se apenas os genes acionáveis, o aumento na positividade do teste em nossa coorte foi de 6,9%. Esses resultados indicam que mulheres com critérios clínicos para SMOH podem se beneficiar da realização de um painel multigenes, pois o mesmo permite identificar variantes patogênicas em outros genes de predisposição ao câncer de mama, incluindo os genes acionáveis, que impactam diretamente no acompanhamento desses pacientes e familiares, uma vez que são genes com estimativas de risco para câncer estabelecidas e estratégias de rastreamento e prevenção bem definidas

Introduction: Only 5-10% of breast cancer are related to inherited genetic variants and BRCA1 and BRCA2 mutations, associated to the Hereditary Breast and Ovarian Cancer Syndrome (HBOC), are responsible for the majority of cases. In addition to BRCA1 and BRCA2, other genes are also associated with a high and moderate risk for breast cancer, such as TP53, STK11, CDH1, PTEN, ATM, CHEK2 and PALB2, considered actionable genes, once they have well-established guidelines for clinical management and prevention. The implementation of Next Generation Sequencing (NGS) has allowed to sequence multiple genes simultaneously, faster and lower-cost when compared to the sequencing of a single gene and, currently, it has been widely used in Oncology for identification of hereditary cancer predisposition syndromes. Objective: The aim of this study is to evaluate the contribution of the multigene panel in detection of germline mutations in other genes besides BRCA1/2 in patients with clinical criteria for hereditary breast cancer. Patients and Methods: A NGS panel of 94 cancer predisposition genes was performed on 321 patients with current or previous diagnosis of breast cancer and clinical criteria for HBOC, who were referred for BRCA1/2 testing between August 2016 and May 2018. Results: Panel analysis of 321 patients resulted in a total of 84 pathogenic/likely pathogenic (P/LP) variants were identified in 81 patients and the positivity rate of the genetic test was 25.2% (n=81/321). Three patients (n=3/81 - 3.7%) had two P/LP variants in different genes and were diagnosed with the multilocus inherited neoplasia alleles syndrome (MINAS). Of the total deleterious mutations, 42.9% (n=36/84) were identified in high-risk breast cancer genes (BRCA1/2 and TP53) and 21.4% (n= 8/84) in moderate-penetrance genes (ATM, PALB2 and CHEK2). The remainder of the mutations, corresponding to 35.7% (n=30/84), were identified in low-risk genes and were considered unexpected findings, since they did not demonstrate a genotype-phenotype correlation. Regarding the molecular subtype of breast cancer, triple negative breast cancer had a mutation frequency of 31.6% (n=25/79), with a predominance in BRCA1 (12.6% - n=10/79). Among the luminal subtype, 18.7% (n=29/155) had deleterious mutations and of these, mutations in non-BRCA1/2 genes predominated with a frequency of 12.2% (n=19/155). For Luminal B HER2-positive subtype, 40% (n=16/40) had a P/LP variants, with a predominance of ATM gene (12.5% - n=5/40). Finally, HER2-enriched subtype presented a mutation frequency of 30.8% (n=4/13). Variants of uncertain significance were identified in 77.6% (n = 249/321) of the patients and of these, 24.5% (n=61/249) also had at least one P/LP variant. Conclusion: The NGS panel contributed to identify P/LP variants in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.9% (BRCA1/2) to 25.2%. Considering only the actionable genes, the increase in positivity in our cohort was 6.9%. These results indicate that women with clinical criteria for HBOC may benefit from a multigene panel testing, as it allows to identify P/LP variants in other breast cancer susceptibility genes, including actionable genes, that directly impact the clinical management of these patients and family members, since they are genes with established risk assessment and well-defined screening and prevention strategies

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance.

OBJECTIVE: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. RESULTS: We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. CONCLUSIONS: PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

ABSTRACT Objective Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

Pesquisa na área medica na Universidade Federal de Juiz de Fora: como melhorar a participação do aluno / Universidade Federal de Juiz de Fora medical research how to improve stdents´invollvement

É importante para a formação acadêmica a participação dos alunos nos projetos de pesquisa desenvolvidos pela Universidade Federal de Juiz de Fora (UFJF). Despertar nos discentes a possibilidade de buscar conhecimentos através da pesquisa pode promover o desenvolvimento pessoal e da entidade, transformando-a em um polo exportador de saber, bem como dar condições aos alunos de buscarem cada vez mais uma melhor qualificação. Assim , aplicamos um questionário a alunos do 3º ao 9º periodos da Faculdade de Medicina da UFJF, contendo 9 perguntas que foram respondidas individualmente. Notamos que a grande maioria (78%) não participa de atividades de pesquisa; a maior parte dos que participam o fazem para enriquecimento curricular (59%); a indicação pessoal foi a principal forma de participação nos projetos (51%). A principal causa apontada para não participarem foi a falta de oportunidade (67%) . Apresentamos também os principais meios do aluno participar em atividades de pesquisa, as possibilidades de financiamento e qual o atual conhecimento do discente sobre o assunto. Concluimos que deve haver uma melhoria no número de vagas e de projetos acessíveis aos discentes e uma ampla divulgação dos projetos da UFJF, em tempo hábil, para propiciar uma efetiva participação do aluno.