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.