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© 2000 American Society for Clinical Oncology
Are BRCA1- and BRCA2-Associated Breast Cancers Different?From the Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Kenneth Offit, MD, Department of Human Genetics, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email offitk{at}mskcc.org
AFTER THE DISCOVERY and molecular characterization of BRCA1 and BRCA2 genes in 1994 and 1995, clinical studies have sought to better define the role of genetic testing in presymptomatic diagnosis and prevention. More recently, a number of studies have focused on the potential role of BRCA testing in the management of patients already affected with breast or ovarian cancer. This final session of the American Society of Clinical Oncology 2000 Categorical Course on cancer genetics focuses on the clinical characteristics of BRCA-associated tumors. Specifically, an emerging literature has documented that BRCA1- and BRCA2-associated breast cancers may have different clinical, histologic, immunophenotypic, and prognostic implications. It is possible that by mixing together BRCA1- and BRCA2-associated breast cancers, different characteristics of these tumors (eg, expression of estrogen receptors in BRCA2-associated tumors) may be obscured. This introduction will provide an overview of the biology of the protein products of the BRCA1 and BRCA2 genes. This understanding is important to provide a framework for the discussion of the distinct histologic, immunophenotypic, and clinical features of hereditary breast cancers associated with mutations of these two genes.
BRCA1 and BRCA2 share similar names and an associated phenotype of breast and ovarian cancers. However, the function of the proteins coded by BRCA1 and BRCA2 seem to be quite distinct. Emerging evidence suggests that the functions of these proteins are also interrelated in a shared biochemical pathway that mediates genomic integrity after DNA damage. The protein products of the BRCA1 and BRCA2 genes are both located in the nucleus. Both the brca1 and brca2 proteins are large, containing 1,863 and 3,418 amino acids, respectively. (Note: current nomenclature refers to the BRCA1 gene in capital letters, whereas the brca1 protein is written in lower case.) Mouse models, resulting from targeted mutations in BRCA1 or BRCA2 or homozygous mutations of these genes, result in a phenotype that includes marked defects in cell division, chromosomal instability, and other evidence of defects in DNA repair pathways.1,2 Late in 1999, an important series of experiments related the protein products of the BRCA1 and BRCA2 genes with the ATM protein kinase.3 Homozygous mutations of the ATM gene are associated with the clinical syndrome ataxia telangiectasia. In this syndrome, children are affected with a disorder characterized by neurologic abnormalities, dilation of blood vessels, immune deficiencies, and premature aging. ATM homozygotes also show evidence of chromosomal instability and approximately a 100-fold increased risk for cancers. The ATM sequence bears a similarity to yeast genes that serve cell-cycle checkpoint and DNA repair functions. It was demonstrated that ATM phosphorylates BRCA1, activating a process of DNA repair through homologous recombination in cooperation with the BRCA2 gene product.3 Other proteins, including the product of mRAD51, and other molecules participate in this biochemical pathway (Fig 1). 4 It was demonstrated that ATM resides in a nuclear complex containing BRCA1, and that after exposure of cells to DNA damage (radiation therapy), phosphorylation of BRCA1 occurred. Interestingly, DNA damage induced by agents other than gamma radiation (eg, hydroxyurea) seemed not to involve an ATM-mediated DNA repair pathway.5 It had earlier been reported that both the BRCA1 and BRCA2 protein products were associated with mRAD51, the mammalian homologue of an important bacterial gene required for repair of double-strand breaks in DNA.2,5
It was shown that there was an increased number of chromosomal abnormalities after DNA repair in murine cells that were deficient in BRCA1 and BRCA2.6 From the models that have been proposed, it is clear that the functions of the Brca1 and Brca2 proteins are related but distinct. Both of these molecules colocalize, along with mRAD51, to the nucleus of cells and to the synaptonemal complexes of mitotic cells. Unlike BRCA1, BRCA2 binds with relatively high stoichiometry to mRAD51.2,5 This specificity of binding is felt to be caused by important differences in conserved regions of exon 11 of BRCA1 compared with BRCA2. Similarly, BRCA1 seems to have functions relating to cell cycle checkpoints that are distinctive from the functions of BRCA2. BRCA1 copurifies with the RNA polymerase 2 holoenzyme7,8 and also interacts physically with transcriptional activators such as p53 and c-myc. Disruption of the BRCA1 protein has a marked effect on the ability to block the cycling of cells with damaged DNA, and this effect is much more marked than in cells with disruptive BRCA2 proteins.9 In this regard, it is interesting that simultaneous knockout of p53 and p21 results in partial rescue of the lethality of BRCA1 knockouts in embryonic mice.1 Expression of BRCA1 in human cells is associated with p53-independent mechanisms of apoptosis.10 In addition BRCA1 is required for transcription-coupled repair of oxidative DNA damage.11
Despite these apparent functional differences, genetic epidemiologic evidence links mutations of BRCA1 and BRCA2 with a very similar phenotype, hereditary breast and ovarian cancer. Additional genetic epidemiologic evidence implicates heterozygous mutations of ATM with an increased risk of breast cancer in young women, although this role has yet to be confirmed by molecular epidemiologic investigations. Although much remains to be understood about the biochemistry of the interactions of the protein products of ATM, BRCA1, and BRCA2, and the mRAD51-associated protein, it is clear that these roles are distinct. Therefore, perhaps, it is not surprising that there may emerge significant differences in breast and ovarian cancer risks associated with inherited mutations of these genes. Similarly, further study of the biology of the protein products of these genes may provide a rationale for the different prognostic as well as therapeutic utility of testing for germline mutations of these genes in women newly diagnosed with cancer. If, for example, patients with BRCA1-associated breast cancers are more likely to suffer ipsilateral relapse, surgical management of these patients may be modified. Similarly, if BRCA2-associated tumors are more likely to be estrogen-receptor positive than their BRCA1-linked counterparts, then there would provide a greater rationale for tamoxifen-based chemotherapy. Finally, biologic differences may also have implications for differential chemotherapeutic approaches. For example, if BRCA1-associated ovarian cancers are especially susceptible to platinum-based DNA damage, this may have therapeutic implications. Greater insight into the biology of other hereditary cancers, eg, colon cancer, has set a precedent for the clinical integration of this information.12 This session focuses on distinct patterns that have emerged that suggest histologic, immunophenotypic, and clinical differences between BRCA1- and BRCA2-associated hereditary breast tumors. Further studies of the subtle but distinctive differences between BRCA1- and BRCA2-associated breast cancers will facilitate a more rational approach to the management of these patients.
1. Ludwig T, Chapman DL, Papaioannou VE, et al: Targeted mutations of breast cancer susceptibility gene homologs in mice: Lethal phenotypes of BRCA1, BRCA2, BRCA1/BRCA2, BRCA1/p53, and BRCA2/p53 nullizygous embryos. Genes Dev 11: 1226-1241, 1997 2. Sharan SK, Morimatsu M, Albrecht U, et al: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking BRCA2. Nature 386: 804-810, 1997[Medline]
3.
Cortez D, Wang Y, Qin J, et al: Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double strand breaks. Science 286: 1162-1166, 1999 4. Boyd J: Hereditary ovarian cancer: Molecular genetics and clinical implications. ASCO Educational Book, Spring:531-540, 2000 5. Scully R, Chen J, Plug A, et al: Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88: 265-275, 1997[Medline] 6. Xu X, Weaver Z, Linke SP, et al: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform deficient cells. Molec Cell 3: 389-395, 1999[Medline]
7.
Scully R, Anderson SF, Chao DM, et al: BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci USA 94: 5605-5610, 1997 8. Anderson S, Schlegel B, Nakajima T, et al: BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via helicase A. Nat Genet 19: 1-3, 1998[Medline]
9.
Ruffner H, Verma IM: BRCA1 is a cell cycle-regulated nuclear phosphoprotein. Proc Natl Acad Sci USA 94: 7138-7143, 1997 10. Harkin DP, Bean JM, Miklos D, et al: Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97: 575-586, 1999[Medline]
11.
Gowen LC, Avrutskaya AV, Latour AM, et al: BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281: 1009-1012, 1998
12.
Offit K: Genetic prognostic markers for colorectal cancer. N Engl J Med 342: 124-125, 2000
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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