Wilms' tumor (WT) is a heterogeneous neoplasia characterized by a number of genetic abnormalities, involving tumor suppressor genes, oncogenes and genes related to the Wnt signaling pathway. Somatic biallelic inactivation of WT1 is observed in 5-10% of sporadic WT. Somatic mutations in exon 3 of CTNNB1, which encodes β-catenin, were initially observed in 15% of WT. WTX encodes a protein that negatively regulates the Wnt/β-catenin signaling pathway and mediates the binding of WT1. In this study, we screened germline and somatic mutations in selected regions of WT1, WTX and CTNNB1 in 43 WT patients. Mutation analysis of WT1 identified two single-nucleotide polymorphisms, one recurrent nonsense mutation (p.R458X) in a patient with proteinuria but without genitourinary findings of Denys-Drash syndrome (DDS) and one novel missense mutation, p.C428Y, in a patient with Denys-Drash syndrome phenotype. WT1 SNP rs16754A>G (R369R) was observed in 17/43 patients, and was not associated with significant difference in age at diagnosis distribution, or with 60-month overall survival rate. WTX mutation analysis identified five sequence variations, two synonymous substitutions (p.Q1019Q and p.D379D), a non-synonymous mutation (p.F159L), one frameshift mutation (p.157X) and a novel missense mutation, p.R560W. Two sequence variations in CTNNB1 were identified, p.T41A and p.S45C. Overall survival of bilateral cases was significantly lower (p=0.005). No difference was observed when survival was analyzed among patients with WT1 or with WTX mutations. On the other hand, the survival of two patients with the CTNNB1 p.T41A mutation was significantly lower (p=0.000517) than the average.

Li-Fraumeni syndrome is a rare hereditary cancer predisposition syndrome associated with germline pathogenic variants in TP53 gene. The phenotype may vary from classical to variant forms, known as Li-Fraumeni-like phenotypes. We searched for pathogenic variants in TP53 in a 14 year-old female diagnosed with fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma. The proband is a heterozygote carrier of the TP53 c.467G>A (p.Arg156His) in exon 5, and her mother is an asymptomatic carrier. Analysis of tumor DNA disclosed an additional somatic mutation in TP53, c.461G>A; p.Gly154Asp. The TP53 germline and somatic pathogenic variants may have acted as possible driver mutations, resulting in genomic instability and tumor development. The fibrolamellar subtype of hepatocellular carcinoma may be part of the broad spectrum of tumors associated with Li-Fraumeni phenotype.

reLato de caso case reportSirenomelia é um defeito congênito muito raro do campo primário do desenvolvimento, definido pela substituição dos membros inferiores, normalmente pareados por um único membro mediano. Geralmente, associa-se a graus variados de anomalias gênito-urinárias. Relatamos três casos necropsiados dessa entidade, incluindo estudo radiológico do membro inferior único, associados a agenesia renal bilateral, de ureteres e da bexiga, atresia retal, ânus imperfurado, testículos abdominais e ausência de genitália externa, além de outros defeitos congênitos infrequentemente observados, que somente puderam ter seus diagnósticos firmados por meio da necropsia.

We have screened BRCA2 c.156_157insAlu founder mutation in a cohort of 168 women with diagnosis of breast cancer referred for genetic counseling because of risk of being carriers of hereditary breast and ovarian cancer syndrome. Portuguese founder mutation BRCA2 c.156_157insAlu was identified in three unrelated breast cancer probands. Genotyping identified a common haplotype between markers D13S260 and D13S171, and allele sizes were compatible to those described in the Portuguese families. Allele sizes of marker D13S1246, however, were concordant in two families, suggesting that the haplotype may be larger in a subset of families. Tumor phenotypes in Brazilian families seem to reinforce the high prevalence of breast cancer among affected males. However, an apparent excess of gastrointestinal and tongue neoplasias were also observed in these families. Although these tumors are not part of the phenotypic spectrum of hereditary breast and ovarian cancer syndrome, they might be accounted for by other risk alleles contained in the founder haplotype region.