Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Investigação de assinaturas mutacionais em adenocarcinomas gástricos e avaliação de Seu possível impacto prognóstico / Investigation of mutational signatures in gastric adenocarcinoma and evaluation of its possible prognostic impact

Adenocarcinomas gástricos (AdGs) são neoplasias de grande agressividade e alta incidência no Brasil. Os altos índices mundiais de mortalidade dos AdGs se devem aos poucos sinais clínicos da doença em seus estágios iniciais, o que leva uma detecção tardia na maioria dos casos. Sendo o AdG uma doença de forte componente genético e ambiental em sua etiologia, a busca por processos causadores de mutações somáticas que contribuem para a sua formação e progressão pode permitir avanços no prognóstico e na determinação de abordagens terapêuticas. Devido à escassez de estudos que associam características moleculares à clínica, além da inexistência de dados moleculares em grande escala obtidos da população brasileira, este trabalho teve por objetivo analisar o perfil mutacional de amostras de AdG em busca de assinaturas moleculares que possam ser associadas a aspectos clínicos de interesse Foram identificadas seis assinaturas mutacionais, através do signeR, para uma coorte de 756 amostras. O subtipo molecular MSI, a ausência de metástase linfonodal (N0) e de recidiva (Tumor Free) demonstraram associação com três assinaturas signeR-S1, singeR-S2 e signeR-S4, associadas aos processos de falha no mecanismo de reparo de DNA (via MMR) e desaminação espontânea da 5-metil-citosina. De maneira complementar, este grupo de assinaturas também demonstraram-se associados com uma melhor sobrevida, maior número de células T CD8+, além de uma expressão aumentada de genes de perfil citotóxico. Estes resultados, em conjunto, sugerem que o grupo de pacientes enriquecidos para estas assinaturas, possuem um contexto imunológico favorável à imunoterapia (AU)

Gastric Adenocarcinomas (GAs) are highly aggressive neoplasms with a high in- cidence in Brazil. The hight world mortality rates of GA are due to few clinical signs of the disease in its early stages which lead to late detection. Because of a strong genetic and environmental component in GA etiology, the search for the causative somatic mutations processes that contribute to their initiation and pro- gression may allow advances in prognosis and in the establishment of therapeutic approaches. Due to the lack of studies that associate molecular characteristics with clinical features, as well as the lack of large scale molecular studies in the Brazilian population, this study aims to analyze the mutational profile of GAs samples from Brazilian and global populations, looking for molecular signatures that may be associated with relevant clinical aspects. The signeR algorithm de- tected six mutational signatures in a cohort of 756 samples. Three signatures (signeR-S1 S2 and S4) were associated with failure in DNA repair mechanisms (MMR pathway) and spontaneous deamination of 5-methylcytosine and had cor- relation with microsatellite instability (MSI) molecular subtype. Those signatures were also associated with better clinical outcomes like the absence of lymph node metastasis (N0) and longer disease-free survival. Furthermore, those signatures were also associated with a particular lymphocyte infiltration pattern, enriched for T CD8+ lymphocytes, and a higher expression of cytotoxic genes. Together, these results suggest that the group of patients enriched for these signatures may have a favorable prognosis due to better anti tumoral effector immune response and that could be further improved with immunotherapy (AU)