Câncer de mama hereditário e rastreamento em população de alto risco / Hereditary breast cancer and screening in high-risk population

Estima-se que para o câncer de mama, assim como para grande parte dos tumores malignos conhecidos, 5 a 10% sejam de caráter hereditário. A história de câncer em familiares de primeiro grau e a presença de alguns fatores específicos de risco, como câncer de mama bilateral, história familiar de câncer de mama e ovário, e câncer de mama em indivíduo do sexo masculino, são indicadores importantes de risco de câncer de mama hereditário. Os avanços em técnicas de biologia molecular nas últimas décadas resultaram na identificação de genes que, quando alterados, aumentam significativamente o risco de desenvolver câncer de mama, de ovário e outros tumores. Destacam-se os genes supressores tumorais BRCA1 e BRCA2, além de outros genes de predisposição ao câncer de mama identificados, que são igualmente importantes no risco da doença, embora correspondam a uma parcela menor dos casos hereditários. A possibilidade de identificar pacientes e familiares com elevado risco de desenvolvimento de câncer torna possível o emprego de uma abordagem preventiva e de detecção precoce do câncer. Além disso, a identificação de um indivíduo não portador de uma alteração genética em uma família de risco permite a tranquilização dele e elimina gastos/complicações com intervenções preventivas desnecessárias. Famílias de alto risco de desenvolvimento de câncer hereditário apresentam alta prevalência de câncer de mama, além de neoplasia com instalação precoce e com maior agressividade. Dessa forma, o rastreamento nesses casos deve ser diferente, objetivando alcançar a redução da morbidade e mortalidade associadas ao câncer nessa população.

It is estimated that for breast cancer, as well as for the great majority of malignant tumors, 5 to 10% are due to an inherited predisposition. Family history of cancer in first degree relatives and the presence of some specific risk factors, such as bilateral breast cancer, family history of breast and ovarian cancer, and breast cancer in a male person, are important indicators of risk for hereditary breast cancer. Advances in molecular biology in recent decades have resulted in the identification of genes that, when altered, increase significantly the risk of developing breast cancer, ovarian cancer and other tumors, for example, the tumor suppressor genes BRCA1 and BRCA2, as well as other genes predisposing to breast cancer identified, which are equally important in the risk for the disease, although a smaller portion of match cases hereditary. The ability to identify patients and relatives with high risk for developing cancer makes possible the use of a preventive approach and an early detection of cancer. In addition, the identification of a non-carrier individual in a family of high risk allows him to reassures the modification individual and eliminates expenses/complications with unnecessary preventive interventions. The typical profile of a patient with higher risk is high prevalence of breast cancer, earlier ages at cancer diagnosis and the worst prognosis and evolution of the tumor. In this way, follow up for these patients must be different in order to achieve the reduction of morbidity and mortality associated with cancer in this population.

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.

Genomic rearrangements in BRCA1 and BRCA2: a literature review

Women with mutations in the breast cancer genes BRCA1 or BRCA2 have an increased lifetime risk of developing breast, ovarian and other BRCA-associated cancers. However, the number of detected germline mutations in families with hereditary breast and ovarian cancer (HBOC) syndrome is lower than expected based upon genetic linkage data. Undetected deleterious mutations in the BRCA genes in some high-risk families are due to the presence of intragenic rearrangements such as deletions, duplications or insertions that span whole exons. This article reviews the molecular aspects of BRCA1 and BRCA2 rearrangements and their frequency among different populations. An overview of the techniques used to screen for large rearrangements in BRCA1 and BRCA2 is also presented. The detection of rearrangements in BRCA genes, especially BRCA1, offers a promising outlook for mutation screening in clinical practice, particularly in HBOC families that test negative for a germline mutation assessed by traditional methods.

Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil

In 2004, a population-based cohort (the Núcleo Mama Porto Alegre - NMPOA Cohort) was started in Porto Alegre, southern Brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (GCRA) program. Women from that cohort who reported a positive family history of cancer were referred to GCRA. Of the 9218 women enrolled, 1286 (13.9 percent) reported a family history of cancer. Of the 902 women who attended GCRA, 55 (8 percent) had an estimated lifetime risk of breast cancer ³ 20 percent and 214 (23.7 percent) had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for Li-Fraumeni-like syndrome (122 families, 66.7 percent). The overall prevalence of a hereditary breast cancer phenotype was 6.2 percent (95 percentCI: 5.67-6.65). These findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. The large proportion of women who attended GCRA (72.3 percent) indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers.