Cancer Predisposition Genes BRCA1 Research Articles

Rad52 gene mutations in breast/ovarian cancer families and sporadic ovarian carcinoma patients

Rad52 encodes a protein which is required for recombinational repair of double-strand breaks. It is also associated with breast cancer predisposition genes BRCA1 and BRCA2. Mutations in the genes Rad51 or Rad52 result in severe defects in genetic recombination and the repair of double-strand DNA breaks. In order to examine if Rad52 mutations might be involved in sporadic ovarian cancer, we analyzed two stop mutations (Ser346ter and Tyr415ter) in 142 Austrian ovarian carcinoma patients and 128 healthy volunteers. In addition, we analyzed these two mutations in 105 breast/ovarian cancer families (160 members) to examine if the mutations in Rad52 are associated with the occurrence of cancer and with mutations in the BRCA1 and BRCA2 genes. Our results show that these two mutations are rare in all three groups examined. There are no statistically significant differences in the frequencies of the Rad52 mutations between the control group and sporadic ovarian cancer patients and between the control groups and familial breast/ovarian cancer patients, indicating that these two mutations of the Rad52 do not play a major role in the initiation of sporadic ovarian carcinoma and familial breast/ovarian cancer.

Patents and public health. European institutions are challenging Myriad Genetics's patent monopoly on the brca1 gene.

An increasing number of international research and governmental institutions are challenging several gene patents, arguing that the patent holders’ absolute control of diagnostic methods is not in the public's best interests. Most notably, the Institut Curie, a cancer research centre in Paris, is leading the fight against Myriad Genetics, a US biotechnology company that plans to install a monopoly on all genetic work associated with the breast and ovarian cancer predisposition gene brca1 . The critics of Myriad's wide‐ranging patent rights maintain that the company's absolute control not only prohibits further research on the diagnosis of and therapies against breast cancer, but also has a detrimental effect on public health. Physician examining mammographs. ![][1] > Critics of Myriad's wide‐ranging patent rights maintain that it not only prohibits further research on diagnostics and therapies but also has a detrimental effect on public health Since the European Commission adopted a directive allowing human genes to be patented in July 1998, many such patents have been granted and indeed challenged, including the battles over the insulin, relaxin and hematopoietin genes. In 2001, seven years after Myriad Genetics first identified the sequence of brca1 , the European Patent Office (EPO) granted the company three patents covering all potential diagnostic and therapeutic applications based on the gene's sequence. Several European research centres and associations quickly contested the first two patents in an attempt to fight Myriad's monopoly. More recently, in August 2002, the Institut Curie, the Institut Gustave‐Roussy, the Assistance‐Publique‐Hopitaux de Paris together with almost all European genetics societies and many scientific institutions and governments turned up the heat and filed a joint opposition notice to the third patent. As this protects the isolated gene and the corresponding protein, and includes all imaginable future therapeutic uses, such as gene therapy and screening of drugs or transgenic animals, … [1]: /embed/graphic-1.gif

Regional methylation of the 5' end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells.

In mammalians, demethylation of specific promoter regions often correlates with gene activation; inversely, dense methylation of CpG islands leads to gene silencing, probably mediated by methyl-CpG binding proteins. In cell lines and cancers, inhibition of tissue-specific genes and tumor suppressor genes expression seems to be related to such hypermethylation. The 5' end of the breast cancer predisposition gene BRCA1 is embedded in a large CpG island of approximately 2.7 kb in length. In human sporadic breast cancers, the down-regulation of BRCA1 does not seem to be related to BRCA1 gene alterations. Southern blot analysis and the bisulfite sequencing method indicate that the BRCA1 CpG island is regionally methylated in all human tissues analyzed and unmethylated in the gametes, suggesting a role for DNA methylation in the control of gene expression. We have therefore investigated the potential role of methyl-CpG binding proteins in the regulation of BRCA1 gene expression. In vitro, partial methylation of constructs containing this region strongly inhibits gene expression in the presence of MeCP2 protein. Moreover, in the five human cell lines analyzed, chemically induced hypomethylation is associated with BRCA1 gene activation. These data suggest that methyl-CpG binding proteins might be associated with the control of BRCA1 gene expression and that methyl-DNA binding proteins may participate in the regulation of gene expression in mammalian cells.

Regional methylation of the 5’ end CpG island ofBRCA1is associated with reduced gene expression in human somatic cells

In mammalians, demethylation of specific promoter regions often correlates with gene activation; inversely, dense methylation of CpG islands leads to gene silencing, probably mediated by methyl-CpG binding proteins. In cell lines and cancers, inhibition of tissue-specific genes and tumor suppressor genes expression seems to be related to such hypermethylation. The 5′ end of the breast cancer predisposition gene BRCA1 is embedded in a large CpG island of ∼2.7 kb in length. In human sporadic breast cancers, the down-regulation of BRCA1 does not seem to be related to BRCA1 gene alterations. Southern blot analysis and the bisulfite sequencing method indicate that the BRCA1 CpG island is regionally methylated in all human tissues analyzed and unmethylated in the gametes, suggesting a role for DNA methylation in the control of gene expression. We have therefore investigated the potential role of methyl-CpG binding proteins in the regulation of BRCA1 gene expression. In vitro, partial methylation of constructs c...

Psychological and Behavioral Implications of Screening for Breast or Ovarian Cancer Predisposition Genes BRCA1 and BRCA2

Recently discovered mutations in 2 genes, BRCA1 and BRCA2, account for most hereditary cases of breast cancer. Individuals with mutations in either BRCA1 or BRCA2 carry an elevated lifetime risk of breast or ovarian cancer. Genetic testing for these mutations now allows individuals to learn if they are at heightened cancer risk. This genetic testing may have entered the health care system without the development of adequate notification protocols. This paper reviews the psychological and behavioral sequelae of being at increased risk for breast or ovarian cancer due to personal or family history. Similar issues relating to the BRCA1 and BRCA2 genetic screening and the notification process also are discussed.