Breast Disease - Volume 10, issue 1-2

Authors: Klausner, Richard

Article Type: Editorial

DOI: 10.3233/BD-1998-101-201

Citation: Breast Disease, vol. 10, no. 1-2, pp. 1-1, 1998

Authors: Liu, Edison T.

Article Type: Introduction

DOI: 10.3233/BD-1998-101-202

Citation: Breast Disease, vol. 10, no. 1-2, pp. 2-2, 1998

Authors: Newman, Beth | Liu, Edison T.

Article Type: Research Article

Abstract: In a very real sense, the search for a breast cancer susceptibility gene reflects the rapid evolution of molecular genetics as a field and the power of molecular technology to accelerate the pace of discovery. This search began with the study of blood proteins through biochemical analysis; the number of loci accessible was limited, and very few consistent results were obtained (1). Then came recombinant DNA technology. The number of available markers, and the information they provide, has grown rapidly over the years. The same is true for the development of new, high-throughput genotyping methods and associated informatics systems and …statistical methods, making gene mapping more feasible. For BRCA1, it took five years and 183 markers to identify the chromosomal location as 17q21 (2). It took an additional four years before BRCA1 was cloned (3). In contrast, BRCA2 was localized to chromosome 13q12-13 two months before the cloning of BRCA1 was reported; less than two years later, BRCA2 was cloned (4,5). Characterization of these two genes is still underway, in part, because of unanticipated complexity. This complexity plays out at multiple levels, including the relationship between phenotype and genotype within and between the populations studied, biological function(s), and social consequences. The reviews presented in this issue reflect the breadth of impact that the discovery of the BRCA genes has had on science, medicine, and law. As with most great discoveries, the identification of BRCA1 has forced us to question the fundamentals of our belief systems: what is a mutation, what is a tumor suppressor, what is righteous, and what is ethical? Show more

DOI: 10.3233/BD-1998-101-203

Citation: Breast Disease, vol. 10, no. 1-2, pp. 3-10, 1998

Authors: Lee, Wen-Hwa | Chew, Helen K. | Farmer, Andrew A. | Chen, Phang-Lang

Article Type: Research Article

Keywords: breast cancer, tumor suppressor genes, DNA repair, cell growth and differentiation, genetic disease

DOI: 10.3233/BD-1998-101-204

Citation: Breast Disease, vol. 10, no. 1-2, pp. 11-22, 1998

Authors: Baer, Richard

Article Type: Research Article

Abstract: The primary amino acid sequence of BRCA1 offers few clues about the mechanism by which it suppresses tumor formation in normal breast and ovarian tissues. In an effort to unravel its biological functions, investigators have sought to identify the proteins that interact with BRCA1 in vivo. These efforts have already uncovered two interacting proteins: the BRCA1-associated RING domain (BARD1) protein, a novel polypeptide that bears a striking structural resemblance to BRCA1, and hRAD51, a human homolog of the bacterial recA gene product. As proliferating cells enter S phase of the cell cycle, the BRCA1, hRAD51, and BARD1 polypeptides aggregate in …discrete nuclear domains, commonly described as “BRCA1 nuclear dots”. However, when S phase cells sustain DNA damage, the dots are mobilized such that BRCA1 and its associated proteins relocate to sites of replicating DNA. Thus, as a participant in the cellular response to DNA damage, BRCA1 may suppress tumor formation by preserving the integrity of genomic DNA. Show more

DOI: 10.3233/BD-1998-101-205

Citation: Breast Disease, vol. 10, no. 1-2, pp. 23-32, 1998

Authors: Snouwaert, John N. | Gowen, Lori C. | Lee, Victoria | Koller, Beverly H.

Article Type: Research Article

Abstract: BRCA1 is a nuclear phosphoprotein that is expressed in a cell cycle regulated manner in virtually all normal dividing cells. Inheritance of a mutated copy of the BRCA1 gene increases a woman’s risk for developing breast and ovarian cancer (1–3). Since the tumors that arise in these individuals consistently fail to express the wild-type allele, BRCA1 is believed to encode a tumor suppressor. Loss of the remaining functional BRCA1 allele, therefore, is one of the steps leading to neoplastic transformation of some types of epithelial cells. The isolation of the murine homologue of the human BRCA1 gene opened up the …possibility of using a powerful genetic approach to study the role of this gene in both normal development and tumor formation. This genetic approach involves in vitro manipulation of the genome of embryonic stem (ES) cells, stable tissue culture cell lines derived from mouse blastocysts. After introducing mutations into the murine homologue of the BRCA1 gene Brca1 in these cell lines, four groups have generated mouse lines carrying the same mutations (4–7). Surprisingly, mice carrying a single mutant Brca1 allele do not display the increased risk for breast tumors seen in humans carrying similar mutations. However, while loss of BRCA1 appears to be a one of the many events involved in tumorgenesis in humans, these mouse lines demonstrate that gene expression is essential for development; as homozygosity for each of the Brca1 mutations results in postimplantation embryonic lethality. The survival of Brca1 deficient embryos is extended by one or two days in the absence of p53 and p21 (7,8). Show more

DOI: 10.3233/BD-1998-101-206

Citation: Breast Disease, vol. 10, no. 1-2, pp. 33-44, 1998

Authors: Hacia, Joseph G. | Brody, Lawrence C. | Collins, Francis S.

Article Type: Research Article

Abstract: The development of technologies to identify quickly, efficiently, and inexpensively all possible heterozygous mutations and sequence variants in patient samples will play a crucial role in the future of medical genetics. In addition to the continued refinement of more established mutation detection protocols, several innovative methodologies recently have emerged with the potential to increase sample throughput as well as decrease the cost of mutational analysis. The allelic heterogeneity of BRCA1 mutations serves as an example of the considerable technical challenge in developing diagnostic tests for all possible sequence variants in large genes. We describe recent advances in methologies that have …previously been or could be readily adapted for use in BRCA1 mutation detection. Special emphasis is placed on the use of high density oligonucleotide arrays (DNA chips) as tools for detecting sequence variations in BRCA1. Show more

DOI: 10.3233/BD-1998-101-207

Citation: Breast Disease, vol. 10, no. 1-2, pp. 45-59, 1998

Authors: Monteiro, Alvaro N.A. | Humphrey, Jeffrey S.

Article Type: Research Article

Abstract: Germ-line mutations in BRCA1 account for the majority of families with breast and ovarian cancer predisposition. BRCA1 encodes a 1,863 amino acid protein with no ascribed function. Due to its size and the fact that mutations are evenly scattered along the sequence, screening for mutations is particularly challenging. Here we review recently published yeast-based assays that may form the basis of an alternative diagnostic test for BRCA1. Although individually limited, these assays may, when combined, become a useful method to screen for cancer predisposing mutations. In any event, the yeast-based assays could complement results from direct sequencing providing functional information …about unique mutations. Show more

Keywords: breast cancer, tumor suppressor gene, BRCA1, functional assay, mutation, diagnostics

DOI: 10.3233/BD-1998-101-208

Citation: Breast Disease, vol. 10, no. 1-2, pp. 61-70, 1998

Authors: Struewing, Jeffery P.

Article Type: Research Article

Abstract: A restricted number of mutant BRCA1 alleles are present at high frequency in the Ashkenazi Jewish population: 185delAG and 5382insC and, perhaps, 188del11. These mutations have provided a means to re-estimate the penetrance function of an abnormal BRCA1 allele to be in the range of 50–60% for breast cancer, and 8–16% not colorectal, cancers in BRCA1 carriers. Further studies in the Ashkenazi population may provide one approach to identifying the environmental or genetic cofactors that modify the impact of an abnormal BRCA1 gene.

DOI: 10.3233/BD-1998-101-209

Citation: Breast Disease, vol. 10, no. 1-2, pp. 71-75, 1998

Authors: Osborne, C. Kent | Elledge, Richard M. | Brown, Powel H. | Hilsenbeck, Susan G.

Article Type: Research Article

DOI: 10.3233/BD-1998-101-210

Citation: Breast Disease, vol. 10, no. 1-2, pp. 77-88, 1998

Authors: Tait, David L. | Jensen, Roy A. | Holt, Jeffrey T. | Johnson, David H. | Gralow, Julie | King, Mary-Claire

Article Type: Research Article

Abstract: As an initial step toward gene therapy for ovarian cancer, we conducted a Phase 1 trial to assess the pharmacokinetics and toxicity of intraperitoneal BRCA1sv retroviral vector therapy. Gene transfer and expression were documented by PCR, southern blot, RT-PCR and nuclease protection assays. Pharmacokinetics were assessed by PCR and southern blots detecting vector DNA, and toxicity was evaluated by clinical exam and fluid analysis. Three of twelve patients developed an acute sterile peritonitis which spontaneously resolved within 48 hours. Plasma and peritoneal antibodies to the retroviral envelope protein were detected only in patients treated with the highest dose levels but …not in others, despite repeat dosing for an interval of up to four months. Eight patients showed stable disease for 4 to 16 weeks. Three patients showed tumor reduction with diminished miliary tumor implants at reoperation (two patients) and radiographic shrinkage of measurable disease (one patient). Ovarian cancer may provide an imporant model for retroviral gene therapy studies due to vector stability, minimal antibody response, and access to tumor by intraperitoneal therapy. Show more

DOI: 10.3233/BD-1998-101-211

Citation: Breast Disease, vol. 10, no. 1-2, pp. 89-98, 1998

Authors: Rimer, Barbara K. | Sugarman, Jeremy | Winer, Eric | Bluman, Leslie G. | Lerman, Caryn

Article Type: Research Article

Abstract: While the cloning of BRCA1 and BRCA2 in 1994 and 1995 engendered great enthusiasm from cancer patients, their families and physicians, concerns about potential problems faced by those undergoing genetic testing were also evident. Although much can be learned from previous research on informed consent for testing and research for predictive genetic testing in diseases other than cancer, there are some specific issues related to cancer that make the questions more pressing, more difficult, and of larger social concern. Organizations such as the National Advisory Council for Human Genome Research, the American Society for Human Genetics, the American Society of …Clinical Oncology and the Task Force for Genetic Testing have presented recommendations about informed consent for cancer susceptibility testing. However, many unanswered questions remain concerning the informed consent process. This review provides background on informed consent, summarizes studies that have been conducted in the area of genetic testing, with a focus on testing for BRCA1 and BRCA2, and details recommendations for achieving informed consent for genetic testing for cancer susceptibility and research on cancer genetics. Show more

DOI: 10.3233/BD-1998-101-212

Citation: Breast Disease, vol. 10, no. 1-2, pp. 99-114, 1998

Authors: Berry, Donald A. | Parmigiani, Giovanni

Article Type: Research Article

Abstract: Tests for the presence of mutations of genes BRCA1 and BRCA2 are increasingly available. Genetic testing creates dilemmas for women and men who regard themselves to be at high risk for breast cancer. Who will benefit from genetic testing? What is the benefit? Does testing improve quality of life? An important consideration in addressing these questions is the woman's chance of carrying a mutation at BRCA1 or BRCA2. Also important are the effectiveness and cost of the testing procedure, the availability of prophylactic interventions, the effectiveness and negative aspects of interventions, the impact of testing on other family members, and …the impact of testing on the woman's ability to obtain insurance coverage. In this article we review the development of a statistical model for predicting whether a woman is a carrier of a BRCA1 or a BRCA2 mutation. We also show how this calculation can be used to assess the benefit of testing, and we quantify the size of the benefit in terms of its improvement on quality-adjusted life years (QALYs). Show more

DOI: 10.3233/BD-1998-101-213

Citation: Breast Disease, vol. 10, no. 1-2, pp. 115-125, 1998

Authors: Dressler, Lynn

Article Type: Research Article

Abstract: Genetic testing for the BRCA1 gene is available commercially and clinically. The information gained from this test impacts not only on the individual tested, but on family members as well. The test can offer an individual and their family the opportunity to gain valuable information about their risks of developing certain forms of inherited breast cancer and other inherited cancers. In addition to its emotional and psychological impact, this information is associated with significant social and economic issues. This includes the potential for denial, loss, or increased rates for health insurance as well as denial and loss of employment based …on genetic test information. The risk for such discrimination can lead to fear of seeking testing and can discourage participation in and potential benefit from prevention, screening, and treatment programs. Therefore, misuse of this information carries significant risk for the individual being tested and for their family members. It is imperative that the potential benefits of genetic testing and genetic information be afforded to all without this risk and fear. In addition to protecting all individuals from genetic discrimination, there is a need to protect the confidentiality of genetic information and an individual's right to privacy. This article discusses protection currently available through legislation at the federal and state level, focusing on the experience in North Carolina in developing and passing a genetic antidiscrimination bill. Although progress has been made, troublesome issues still remain. Show more

DOI: 10.3233/BD-1998-101-214

Citation: Breast Disease, vol. 10, no. 1-2, pp. 127-135, 1998

Authors: Barr, Patricia | Reese-Coulbourne, Jane

Article Type: Research Article

DOI: 10.3233/BD-1998-101-215

Citation: Breast Disease, vol. 10, no. 1-2, pp. 137-140, 1998