Síndrome de Li-Fraumeni : caracterização clínica e molecular de pacientes com o fenótipo da síndrome

A Síndrome de Li-Fraumeni (LFS) é uma doença autossômica dominante associada a mutações germinativas no gene TP53 e caracterizada por uma predisposição ao desenvolvimento de um amplo espectro de tumores em idade precoce. Os tumores mais comuns relacionados à LFS são carcinoma adrenocortical (CAC), câncer de mama pré-menopáusico, sarcomas ósseos e de partes moles e tumores cerebrais. Atualmente, o critério de Chompret revisado em 2015 é o critério considerado de maior utilidade clínica para diagnóstico molecular da LFS. O objetivo principal desta tese foi caracterizar os pacientes com suspeita clínica de LFS no sul do Brasil, região conhecida pela prevalência mais alta de uma variante patogênica (VP) germinativa fundadora do gene TP53 conhecida como R337H (c.1010G>A; p.(Arg337His). No período de julho de 2015 até janeiro de 2019, foram identificados 211 pacientes não relacionados, que preenchiam os critérios revisados de Chompret, foram identificados. Destes, 191, todos com pelo menos um diagnóstico de câncer, foram recrutados para estudo molecular e clínico. A análise molecular incluiu avaliação de toda a sequência codificadora de TP53 e pesquisa de rearranjos gênicos. Vinte e seis (13,6%) probandos apresentaram VP germinativas de TP53, todas alterações pontuais de sequência. A idade média ao diagnóstico do primeiro tumor nesses 26 portadores foi 13,65 anos e 18 (69,23%) são portadores da VP R337H. Em complementação à análise molecular, foi realizada uma caracterização das variantes de significado incerto (VUS) encontradas nos pacientes testados nesta tese e em análises anteriores, bem como em uma instituição parceira, Hospital do Amor no estado de São Paulo. A análise criteriosa de 12 VUS, e a reclassificação de algumas destas, reforça a necessidade de cautela e frequente revisão das informações acerca de VUS para garantir que a conduta clínica mais adequada para o paciente e seus familiares seja proposta. Os achados deste estudo demostram a heterogeneidade clínica da LFS no Sul do Brasil, evidenciam algumas particularidades da variante fundadora R337H na região e apontam para a necessidade de estudos maiores e colaborativos com outros centros para melhor definir e a prevalência da LFS, o espectro clínico e a penetrância dos diferentes tipos de VP de TP53 no Brasil.Li-Fraumeni Syndrome (LFS) is an autosomal dominant disease associated with pathogenic germline variants in the TP53 gene and is characterized by a predisposition to develop a broad spectrum of tumors at an early age. The most common LFS related tumors are adrenocortical carcinoma (ACC), premenopausal breast cancer, bone and soft tissue sarcomas, and brain tumors. Currently, the Chompret criteria, revised in 2015, is considered of greatest clinical utility for molecular diagnosis of LFS. The main objective of this thesis was to characterize patients with clinical criteria of LFS in southern Brazil, a region known for the highest prevalence of a TP53 germline pathogenic variant known as R337H (c.1010G> A; p. (Arg337His)). From July 2015 to January 2019, 211 unrelated patients who met the revised Chompret criteria were identified, out of which 191 were recruited for molecular and clinical study, all with at least one cancer diagnosis. The molecular analysis include evaluation of the entire TP53 coding sequence and screening for gene rearrangements. Twenty-six (13.6%) probands had TP53 pathogenic germline variants (PV), all point sequence changes. Mean age of the first tumor in these 26 carriers was 13.65 years and 18 of them (69.23%) had the PV R337H. In addition, characterization of the variants of uncertain significance (VUS) found in the patients tested in this thesis and previous analyzes, was performed, together with a partner institution, Hospital do Amor in the state of São Paulo. The careful analysis of 12 VUS, and the reclassification of some of these, reinforces the need for caution and frequent review of information about VUS to ensure that the most appropriate clinical management for the patient and family members is proposed. The findings of these study demonstrate the clinical heterogeneity of LFS in southern Brazil, highlights some particularities of the founder PV R337H in the region and point to the need for larger and collaborative studies with other centers to better define the prevalence of the LFS, the clinical spectrum and the penetrance of the different types of pathogenic variants of TP53 in Brazil

Papilomavírus humanos (HPV) oncogênicos tipos 16 e 18 : freqüência e fatores associados

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Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adre nocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diag nosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chom pret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p. Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and indepen dent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligo merization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H het erozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants