RESUMO
Approximately 5-10% of breast carcinomas and 10% of ovarian carcinomas are ascribable to a genetic susceptibility. Of these, about 40% are related to genetic mutations in the genes BRCA1 and BRCA2. Despite the increasing demand for genetic testing arising from the patients and their relatives, the genetic testing can be offered yet only to individuals belonging to high-risk families in which the probability that there is a germline mutation in a BRCA gene is high and thus cancer occurrence is likely the expression of a highly penetrant genetic predisposition. In this article, we review how the current knowledge on the biological mechanisms underlying BRCA1 and BRCA2 dysfunction may contribute to the understanding of breast and ovarian cancer predisposition. The most currently employed methods for genetic testing are critically overviewed, together with some indications for the interpretation of the test outcome and the clinical management of mutation carriers.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Análise Mutacional de DNA/métodos , Mutação , Proteína BRCA1/fisiologia , Proteína BRCA2/fisiologia , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Prognóstico , Fatores de RiscoRESUMO
Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T)11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Endodesoxirribonucleases/biossíntese , Endodesoxirribonucleases/genética , Exodesoxirribonucleases/biossíntese , Exodesoxirribonucleases/genética , Repetições de Microssatélites , Mutação , Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Saccharomyces cerevisiae/biossíntese , Proteínas de Saccharomyces cerevisiae/genética , Idoso , Alelos , Pareamento Incorreto de Bases , Proteínas de Ciclo Celular/biossíntese , Linhagem Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Reparo do DNA , Sequência de DNA Instável , Proteínas de Ligação a DNA/biossíntese , Éxons , Feminino , Humanos , Imuno-Histoquímica , Íntrons , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Proteínas Nucleares/biossíntese , Células Tumorais CultivadasRESUMO
Familial aggregations of breast/ovarian cancer cases frequently depend on BRCA1/2 pathogenic mutations. Here we counselled 120 Italian breast/ovarian cancer families and selected 73 probands for BRCA1/2 mutation screening. Through this analysis we defined the prevalence of BRCA1/2 pathogenic mutations occurring in Italian breast/ovarian cancer families, enlarged the spectrum of Italian BRCA1/2 mutations by 15% and report on the identification of 13 novel variants, including two deleterious truncating mutations and two potentially pathogenic missense mutations, on the BRCA1 and BRCA2 genes. Finally in hereditary breast cancer families with three or more female breast cancer cases we observed a low mutation prevalence and a significant association with BRCA2 mutations.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Itália/epidemiologia , Masculino , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etiologia , Linhagem , PrevalênciaRESUMO
Mutations of the ATM and NBS1 genes are responsible for the inherited Ataxia-Telangiectasia and Nijmegen Breakage Syndrome, both of which are associated with a predisposition to cancer. A related syndrome, the Ataxia-Telangiectasia-like disorder, is due to mutations of the MRE11 gene. However, the role of this gene in cancer development has not been established. Here we describe an often homozygous mutation of the poly(T)11 repeat within human MRE11 intron 4 that leads to aberrant splicing, impairment of wild-type MRE11 expression and generation of a truncated protein. This mutation is present in mismatch repair-deficient, but not proficient, colorectal cancer cell lines and primary tumours and is associated with reduced expression of the MRE11--NBS1--RAD50 complex, an impaired S-phase checkpoint and abrogation of MRE11 and NBS1 ionizing radiation-induced nuclear foci. Our findings identify MRE11 as a novel and major target for inactivation in mismatch repair-defective cells and suggest its impairment may contribute to the development of colorectal cancer.