The Brazilian founder mutation TP53 p.R337H is uncommon in Portuguese women diagnosed with breast cancer.

Since the first studies reporting the TP53 p.R337H mutation as founder mutation in Southern and Southeastern Brazil, there has been controversy on its origin. Preliminary analysis of a small subset of Brazilian mutation carriers revealed that the haplotype incided on a Caucasian background. The vast majority of carriers identified today reside in Brazil or, if identified in other countries, are Brazilian immigrants. To our knowledge, the only two exceptions of carriers without a recognizable link with Brazil are two European families, from Portugal and Germany. Haplotype analysis in the Portuguese family revealed the same haplotype identified in Brazilian individuals, but in the German family, a distinct haplotype was found. Knowing that a significant proportion of women with breast cancer (BC) in Southern Brazil are p.R337H carriers, we analyzed p.R337H in a Portuguese cohort of women diagnosed with this disease. Median age at diagnosis among the first 573 patients tested was 60 years and 100 (17.4%) patients had been diagnosed at or under the age of 45 years. Mutation screening failed to identify the mutation in the 573 patients tested. These results are in contrast with the mutation frequency observed in a study including 815 BC-affected women from Brazil, in which carrier frequencies of 12.1 and 5.1% in pre- and postmenopausal women were observed, respectively. These findings suggest that the Brazilian founder mutation p.R337H, the most frequent germline TP53 mutation reported to date, is not a common germline alteration in Portuguese women diagnosed with BC.

Mutation spectrum in South American Lynch syndrome families.

BACKGROUND: Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system. METHODS: We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included. RESULTS: Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia. CONCLUSION: The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent.

Mechanisms and role of microRNA deregulation in cancer onset and progression.

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms.

Mechanisms and role of microRNA deregulation in cancer onset and progression

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms.