RESUMO
Lynch syndrome (LS) accounts for 3-5% of all colorectal cancers (CRC) and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR), mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs) in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2), and 11 variants of unknown significance (VUS) were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45), whereas the three MMR genes (MSH6, PMS1 and PMS2) accounted for 11% (5/45). We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.
Assuntos
Adenosina Trifosfatases/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Adolescente , Adulto , Brasil , Neoplasias Colorretais Hereditárias sem Polipose/genética , Variações do Número de Cópias de DNA , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteínas MutL , Adulto JovemRESUMO
Improvements in multimodal therapy for osteosarcoma (OS) have increased event-free and overall survival. But have also led to a greater number of recurrences in uncommon sites. We report a young adult with OS who developed late bilateral renal relapse. Late recurrences to the kidneys have a more aggressive clinical behavior and poor prognosis documented by 15 cases of OS metastastic to the kidney in the literature. Two of those patients had a long survival after chemotherapy and surgery. This suggests that the disease can be controlled with early detection and treatment.