Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes.

BACKGROUND: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. METHODS: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. RESULTS: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk. CONCLUSION: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

Imunoexpressão de WT1, ß-cateinina, E-caderina e APC em tumor de Wilms esporádico / Expression of WT1, p53, Beta-catenina, E-cadherina and APC in sporadic Wilms tumor

O tumor de Wilms é uma neoplasia embrionária, constituída classicamente por três componentes histológicos: blastema, epitélio e mesênquima (estroma), os quais podem ser encontrados em diferentes proporções em cada tumor. ... Este estudo tem como principal objetivo determinar a freqüência da expressão das proteínas WT1, p53, Beta-catenina, E-caderina e APC nos diferentes componentes histológicos do tumor de Wilms, assim como correlacionar estes achados com o prognóstico. Para estudar a expressão dos marcadores, foi utilizado a imunoistoquímica, através da construção de Tissue Macroarray (TMA), o qual permite a análise de muitas amostras teciduais em uma única lâmina, otimizando custo e tempo. Nos nossos resultados, WT1 e p53 foram mais freqüentemente expressos no componente blastema (WT1: 97% e p53: 63% dos casos) e epitélio (WT1: 87% e p53: 58% dos casos), quando comparados com o estroma (WT1: 13% e p53: 22% dos casos) e com o tecido renal não tumoral (ausência de expressão em todos os casos estudados). ... A imunoexpressão nuclear ocorreu principalmente nos componentes blastematoso e estromal. Houve imunoexpressão de E-caderina na membrana em 47% dos casos, em citoplasma em 44% e em núcleo em 12%. O acúmulo em núcleo foi encontrado principalmente nos componentes blastema e mesênquima, 21 e 25% respectivamente. A imunoexpressão do APC ocorreu em núcleo em 95% dos tumores avaliados, em citoplasma em 9% e nenhum apresentou expressão em membrana. Nos componentes blastematoso e epitelial houve imunopositividade nuclear em 100% dos casos avaliados. No componente mesenquimal a positividade nuclear ocorreu em 89% dos casos. Os pacientes com estádios precoces tiveram mais freqüentemente positividade do WT1. Não houve associação dos outros fatores clínicos, epidemiológicos e evolução dos pacientes com expressão dos marcadores estudados.

Wilms tumor is a triphasic malignant neoplasm compromised of variable proportions of epithelial, blastemal and mesenchymal (stromal) elements. Different components have different clinical behavior. Patients with tumors predominant epithelial and/or stromal has more frequently low stage while predominant blastema has advanced disease. This study was undertaken to evaluate the expression of WT1, beta-catenins, E-cadherin and APC in Wilms tumor and correlate this expression with clinical characteristics, histologic cell type and prognosis. We studied the immunohistochemical expression of WT1, p53, beta-catenins, E-cadherin in different component of Wilms tumor using a tissue array. WT1 and p53 were more often expressed on blastema component (WT1: 97% and p53: 63% of cases) and on epithelial (WT1: 87% and p53: 58% of cases), when compare with the stromal component (WT1: 13% and p53: 22% of cases) and the normal renal tissue where it was not expressed. Immunopositivity of WT1 and p53 were significantly correlated. Immunopositivity of ß-catenina was seen in 85 % at the membrane (85%), 94% cytoplasm and 24% nuclear. Nuclear immunoexpression was detected specially on blastema and stromal component. Immunohistochemical expression of E-cadherina was detected in 47% at the membrane, 44% cytoplasm and 12% nuclear. Nuclear expression was seen more often at the blastema and stromal component (21%, 25% respectively). Immunopositivity of APC occurs at 95% on nucleus, cytoplasm (9%) and none at membrane. Among the blastema and the epithelial component 100% was positive on nucleus. On the stromal component 89% was positive at the nucleus. Immunoexpression of WT1 was correlated with local stage. The expression status of WT1, E-cadherin, ßcatenina, APC in this cohort was not of prognostic value.

Estudo dos fatores de prognóstico em crianças e adolescentes portadores de tumor de Ewing ósseo do Centro de Tratamento e Pesquisa Hospital do Câncer / Study of prognostic factors in children and adolescents with bone Ewing's tumor at the Cancer Hospital Treatment and Research Center

O tumor de Ewing é a segunda mais freqüente neoplasia primária de osso entre crianças e adolescentes. Com a associação de múltiplos agentes quimioterápicos, o prognóstico desses pacientes tem melhorado significativamente nos últimos anos. A identificação dos fatores de risco para recidiva, permite direcionar o tratamento mais intensivo para o grupo de pacientes com fatores de pior prognóstico. Como descrito na literatura, não existem dúvidas que a presença de metástase detectável macroscopicamente ao diagnóstico, é um importante fator de pior prognóstico. Outros fatores de prognóstico que têm sido descritos na literatura são idade, sítio do tumor primário, volume tumoral, nível sérico de desidrogenase láctica (DHL), resposta histológica à quimioterapia, diferenciação neural. Este estudo teve como principal objetivo, identificar os fatores que influenciaram o prognóstico dos 105 pacientes com tumor de Ewing, tratados em uma única instituição, em um período de 12 anos Uunho de 1984 a dezembro de 1996). A média de idade foi 11 anos; 49% eram do sexo feminino e 51% do sexo masculino. Oitenta por cento dos pacientes eram brancos. Dos 105 pacientes 4 7 tinham tumor primário em sítio axial e 58 em extremidades. Trinta e quatro pacientes foram considerados como metastáticos ao diagnóstico. Em 7 4 pacientes o nível sé rico de DHL foi avaliado, destes pacientes 17 tinham níveis elevados (>370U/L). O tratamento foi realizado com administração de quimioterapia em todos os pacientes, cirurgia do tumor primário em 7 4 e radioterapia local em 40 pacientes. Resposta histológica a terapia neoadjuvante foi determinada através do método de Huvos, sendo 52 casos avaliados. A sobrevida global em 5 anos foi 50°/o e a sobrevida livre de eventos foi 47°/o. A análise univariada mostrou como fatores prognóstico: nível de DHL aumentado (HR=4.40 Cl 95% 2.25-8.62; p<0.0001 ), ausência de reposta clínica à quimioterapia (HR=8.40 CI 95°/o 0.04-0.15; p<0.0001 ), necrose tu moral (grade 1+11) (HR=1.65 CI 95°/o 0.09-0.58; p=0.008), presença de metástases (HR=1.20 Cl 95°/o 1.15-3.45;p=0.014). Na análise múltipla os únicos fatores de prognóstico independentes foram DHL sérico (HR=2.20,CI 95% 1.43-6.26 p=0.003) e ausência de resposta clínica à quimioterapia (HR= 11.30 CI 95% 4.87 -26.22; p<0.0001 ). Nível de DHL sérico foi o fator de prognóstico pré-tratamento mais importante neste estudo. Por ser um método sensível, simples e de baixo custo deveria ser considerado como fator capaz de estratificar os pacientes em grupos de riscos para recidiva e direcionar o tratamento.

Ewing's tumor is the second most frequent bane neoplasm in children and adolescents. Local therapy alone was used before the 1970 and it was associated with an approximately 1 0°/o 5-years event-free survival rate. With the addition of multidrug chemotherapy regimens in the last years, the prognosis has significantly improved. The identification of risk factors for relapse provides important information for the selection of the most intensive treatment for a group of patient with worst factors. Accordjng to the literature, there are no doubts that in Ewing, s tumor the metastatic disease at presentation is particularly an adverse prognosis. Other factors have been reported to influence survival in Ewing tumor, age, tumor site, tumor volume, rum laotate dehydrogenase (LDH), histological response to chemotherapy, neural differentiation. The aim of this study was to review the 12-t years experience of a single institution applying a combined modality of treatment of Ewing's tumor, and to identify prognostic factors. Mean age was 11 years; 49% female and 51% male; 80°/o were white. Primary sites were axial 47 cases and extremity 58. At diagnosis 71 had localized disease and 34 were metastic LDH leveis at diagnosis were evaluated in 72 and high LDH values ( >370 U/L) were observed in 17. Treatment included initial chemotherapy in all cases surgery of the primary site in 7 4 and radiation in 40. Histological effect of preoperative treatment according to the Huvos systêm was evaluated in 52 cases. Five years overall survival was 50% and event free survival was 47%. Univariate analysis showed as prognostic factors: raised LDH (HR=4.40 CI b~ 2.25-8.62; p<0.0001 ), no clinicai response to chemotherapy (HR=8.40 CI 95% 0.04-0.15; p<0.0001), tumor necrosis HUVOS (grade 1+11) (HR=1.65 Cl 95% 0.09-0.58; p=0.008), metastases (HR=1.20 Cl 95% 1.15-3.45;p=0.014) Cox multiple regression analysis showed that raised serum LDH leveis (HR=2.20,CI 95% 1.43-6.26 p=0.003) and no clinicai response to chemotherapy (HR= 11.30 CI 95% 4.87 -26.22; p<0.0001) were independent prognostic factors. The se rum levei of LDH was the most important pretreatment prognostic factor in this series. LDH levei, at the time of diagnosis, should be considered as a factor to treat patients in different groups. lt is a sensitive, simple and cost effective method