Association of the germline TP53 R337H mutation with breast cancer in southern Brazil

<p>Abstract</p> <p>Background</p> <p>The germline <it>TP53</it>-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT) in southern Brazil; it has low penetrance and limited tissue specificity in most families and therefore is not associated with Li-Fraumeni syndrome. However, other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may also contribute to breast tumorigenesis in a genetic background-specific context.</p> <p>Methods</p> <p>We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing <it>TP</it>53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H.</p> <p>Results</p> <p>The R337H mutation was found in three patients but in none of the controls (p = 0.0442). Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant <it>TP53 </it>allele rather than the wild-type allele. Polymorphisms were identified within the <it>TP53 </it>(R72P and Ins16) and <it>MDM2 </it>(SNP309) genes that may further diminish <it>TP53 </it>tumor suppressor activity.</p> <p>Conclusion</p> <p>These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant <it>TP53 </it>alleles can differentially influence tumor susceptibility.</p

Relatorio de estagio

Trabalho de Conclusão de Curso - Universidade Federal de Santa Catarina. Curso de Agronomia

mRNA expression of matrix metalloproteinases (MMPs) 2 and 9 and tissue inhibitor of matrix metalloproteinases (TIMPs) 1 and 2 in childhood acute lymphoblastic leukemia : potential role of TIMP1 as an adverse prognostic factor

This study evaluates the mRNA expression profile of genes TIMP1, TIMP2, MMP2 and MMP9 in diagnostic bone marrow samples from 134 consecutive ALL children by real-time quantitative PCR. A significant association was observed between higher expression levels of MMP9 and low risk group and absence of extramedullary infiltration and higher expression levels of TIMP2 and MMP2 with T-ALL. TIMP1 gene expression values higher than the median were associated with a significantly lower 5-year event free-survival in univariable (P = 0.04) and multivariable analysis (P = 0.01). Our data address new information in the complex interaction of the migration/adhesion genes and childhood ALL3413237FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2001/13206-9; 2002/03182-8; 2005/50731-5Childhood TIMPPrognostic facto

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient’s clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth.236481493CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação2010/07020-