Molecular biology in radiation oncology - Radiation oncology perspective of BRCA1 and BRCA2

The breast cancer susceptibility genes, BRCA1 and BRCA2 are used to illustr ate the application of molecular biology to clinical radiation oncology. Id entified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that exa mine the structure of the DNA and the proteins made by the normal and mutan t alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. I n addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected. therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic scree ning and counseling. The localization of the protein in the nucleus, the ex pression in relation to cell cycle and the association with RAD51 led to th e discovery that the two BRCA genes may be involved in transcriptional regu lation and DNA repair. The defect in DNA repair can increase radiosensitivi ty which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes), This is supported by the early reports of a hi gh rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be obser ved for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the r ole of the normal BRCA genes in DNA repair might help define a novel mechan ism For radiation sensitization by interfering with the normal gene functio n using a variety of molecular or biochemical therapies.