RESUMO
PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.
Assuntos
Neoplasias da Mama/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Proteína BRCA2/fisiologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , LinhagemRESUMO
We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Penetrância , RNA Helicases/genética , Adulto , Códon sem Sentido , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , LinhagemRESUMO
We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.
Assuntos
Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Alelos , Proteínas Mutadas de Ataxia Telangiectasia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , LinhagemRESUMO
Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure, and susceptibility to cancer. FA has eight known complementation groups and is caused by mutations in at least seven genes. Biallelic BRCA2 mutations were shown recently to cause FA-D1. Monoallelic (heterozygous) BRCA2 mutations confer a high risk of breast cancer and are a major cause of familial breast cancer. To investigate whether heterozygous variants in other FA genes are high penetrance breast cancer susceptibility alleles, we screened germ-line DNA from 88 BRCA1/2-negative families, each with at least three cases of breast cancer, for mutations in FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG. Sixty-nine sequence variants were identified of which 25 were exonic. None of the exonic variants resulted in translational frameshifts or nonsense codons and 14 were polymorphisms documented previously. Of the remaining 11 exonic variants, 2 resulted in synonymous changes, and 7 were present in controls. Only 2 conservative missense variants, 1 in FANCA and 1 in FANCE, were each found in a single family and were not present in 300 controls. The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular , Anemia de Fanconi/genética , Estudos de Casos e Controles , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Éxons , Proteína do Grupo de Complementação C da Anemia de Fanconi , Proteína do Grupo de Complementação D2 da Anemia de Fanconi , Proteína do Grupo de Complementação E da Anemia de Fanconi , Proteína do Grupo de Complementação F da Anemia de Fanconi , Proteína do Grupo de Complementação G da Anemia de Fanconi , Proteínas de Grupos de Complementação da Anemia de Fanconi , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Íntrons , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas/genética , Proteínas de Ligação a RNA/genéticaRESUMO
The genes predisposing to familial breast cancer are largely unknown, but 5 of the 6 known genes are involved in DNA damage repair. RAD50 is part of a highly conserved complex important in recognising, signalling and repairing DNA double-strand breaks. Recently, a truncating mutation in the RAD50 gene, 687delT, was identified in 2 Finnish breast cancer families. To evaluate the contribution of RAD50 to familial breast cancer, we screened the whole coding region for mutations in 435 UK and 46 Finnish familial breast cancer cases. We identified one truncating mutation, Q350X, in one UK family. We screened a further 544 Finnish familial breast cancer cases and 560 controls for the 687delT mutation, which was present in 3 cases (0.5%) and 1 control (0.2%). Neither Q350X nor 687delT segregated with cancer in the families in which they were identified. Functional analyses suggested that RAD50 687delT is a null allele as there was no detectable expression of the mutant protein. However, the wild-type allele was retained and expressed in breast tumors from mutation carriers. The abundance of the full-length RAD50 protein was reduced in carrier lymphoblastoid cells, suggesting a possible haploinsufficiency mechanism. These data indicate that RAD50 mutations are rare in familial breast cancer and either carry no, or a very small, increased risk of cancer. Altogether, these results suggest RAD50 can only be making a very minor contribution to familial breast cancer predisposition in UK and Finland.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Hidrolases Anidrido Ácido , Idoso , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Dano ao DNA , Análise Mutacional de DNA , Reparo do DNA , Enzimas Reparadoras do DNA , Proteínas de Ligação a DNA , Feminino , Finlândia , Humanos , Pessoa de Meia-Idade , Reino UnidoRESUMO
Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.