Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants.

Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir-Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.

The Brazilian TP53 mutation (R337H) and sarcomas.

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.

Impactos Psicossociais e na Qualidade de Vida do Tratamento Oncológico em Crianças e Adolescentes / Psychosocial and Quality-of-Life Impacts of Cancer Treatment in Children and Adolescents / Impactos Psicosociales y en la Calidad de Vida del Tratamiento del Cáncer en Niños y Adolescentes

Introdução: Tão importante quanto o diagnóstico e o tratamento do câncer pediátrico são os cuidados relacionados ao impacto psicossocial, educacional e emocional. Objetivo: Avaliar em crianças e adolescentes com diagnóstico de câncer os impactos psicossociais, de qualidade de vida e da presença de acompanhante durante os procedimentos. Método: Estudo transversal, descritivo, com pacientes de 8 a 18 anos e diagnóstico de neoplasia maligna. Os pacientes responderam aos questionários: PedsQL 4.0 Qualidade de Vida (8 a 12 anos), PedsQL 3.0 Módulo de Câncer (8 a 12 anos), PedsQL 4.0 Qualidade de Vida (13 a 18 anos), PedsQL 3.0 Módulo de Câncer (13 a 18 anos) e outro sobre acompanhantes elaborado pelos autores. Resultados: Foram incluídos 25 pacientes pediátricos oncológicos que se sentiam mais felizes na presença de um acompanhante e menos ansiosos durante os procedimentos. Foi percebido grande impacto na qualidade de vida. No questionário Qualidade de Vida, não houve diferença significativa (p=0,627) entre os grupos de pacientes com 8 a 12 anos e 13 a 18 anos, porém o grupo com 8 a 12 anos teve impacto significativamente maior no questionário Módulo de Câncer (p=0,0094). Conclusão: O impacto psicossocial e na qualidade de vida é razoavelmente grande em pacientes pediátricos oncológicos. Além disso, os mais jovens parecem sofrer um impacto psicossocial maior. Os pacientes se dizem mais felizes com a presença de acompanhante, e mais ansiosos na sua ausência.

Introduction: As important as the diagnosis and treatment of pediatric cancer are the care related to psychosocial, educational, and emotional impact. Objective: To evaluate in children and adolescents diagnosed with cancer the psychosocial and quality-of-life impacts and the presence of a companion during the procedures. Method: Cross-sectional descriptive study of patients aged 8 to 18 years of age diagnosed with malignant neoplasms. Patients responded the questionnaires PedsQL 4.0 Quality of Life (8 to 12 years), PedsQL 3.0 Cancer Module (8 to 12 years), PedsQL 4.0 Quality of Life (13 to 18 years), PedsQL 3.0 Cancer Module (13 to 18 years) and another about companions created by the authors. Results: There were 25 pediatric oncology patients included who felt happier in the presence of a companion, and less anxious during the procedures. A great impact on quality of life was perceived. In the Quality-of-Life questionnaire, no significant difference (p=0.627) between the groups of patients aged 8 to 12 years and 13 to 18 years were found, but the group aged 8 to 12 years had a significantly higher impact on the Cancer Module questionnaire (p= 0.0094). Conclusion: The impact on quality of life and psychosocial is fairly large in pediatric oncology patients. The youngest appear to suffer great psychosocial impact. Patients claim they are happier in the presence of a companion, and more anxious in its absence

Introducción: Tan importante como el diagnóstico y tratamiento del cáncer pediátrico, son los cuidados sobre el impacto psicosocial, educativo y emocional. Objetivo: Evaluar en niños y adolescentes diagnosticados de cáncer el impacto psicosocial y en la calidad de vida y la presencia de un acompañante durante los procedimientos. Método: Estudio transversal descriptivo de pacientes de 8 a 18 años con diagnóstico de neoplasia maligna. Los pacientes respondieron a los cuestionarios: PedsQL 4.0 Calidad de Vida (8 a 12 años), PedsQL 3.0 Módulo de Cáncer (8 a 12 años), PedsQL 4.0 Calidad de Vida (13 a 18 años), PedsQL 3.0 Módulo de Cáncer (13 a 18 años) y otro sobre cuidadores elaborado por los autores. Resultados: Se incluyeron 25 pacientes de oncología pediátrica que se sentían más felices con la presencia de un acompañante y menos ansiosos al realizar procedimientos. Se percibió un gran impacto en la calidad de vida. En el cuestionario de Calidad de Vida, no hubo diferencia significativa (p=0,627) entre los grupos de pacientes de 8 a 12 años y de 13 a 18 años, pero el grupo de 8 a 12 años tuvo un impacto significativamente mayor en el cuestionario del Módulo de Cáncer (p=0,0094). Conclusión: El impacto en la calidad de vida y psicosocial es razonablemente grande en los pacientes oncológicos pediátricos. Los de menor edad parecen sufrir un mayor impacto psicosocial. Los pacientes dicen sentirse más felices con la presencia de un acompañante, y más ansiosos en su ausencia.

p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers.

Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186). Cancer-affected carriers had been diagnosed either with adrenocortical carcinoma (ACC, n = 29) or breast cancer (BC, n = 43). Allelic discrimation using TaqMan assay was used for genotyping MDM2 SNP 309 (rs2279744) as well as MDM4 (rs1563828) and USP7 (rs1529916) polymorphisms. We found significantly higher MDM2 SNP 309 GG genotype and G allele frequencies in the LFS cohort than in controls. Furthermore, median age at first diagnosis was earlier in MDM2 SNP309 GG carriers when compared to other genotypes for both cancers (ACC: age 1 vs. 2 years; BC: age 35 vs. 43 years, respectively), although not statistically different. The allelic and genotypic frequencies for all SNPs did not differ between cancer affected and unaffected carriers, neither between patients with ACC or BC. In conclusion, our results suggest that MDM2 SNP 309 may contribute to the LFL phenotype and also to an earlier age at diagnosis of ACC and BC cancer in carriers of the R337H founder mutation.