Comparisons of two breast cancer risk estimates in women with a family history of breast cancer.

There is an increasing need for accurate prediction methods of assessing individual risk for breast cancer for both clinical and research purposes. The purpose of this study is to compare the Gail and Claus model risk estimates of breast cancer among women with a family history of breast cancer. This study presents risk estimates from two models of breast cancer risk in 491 women 18 to 74 years of age with a family history of breast cancer who were recruited to risk counseling clinical trials in Seattle, Washington between 1996 and 1997. These trials included women from the general population and additional samples of Ashkenazi Jewish, African-American, and lesbian women. We estimated and compared lifetime (to age 79) and 5-year risk for developing breast cancer using the National Surgical Adjuvant Breast and Bowel Project adaptation of the Gail model and the Claus model. About one-quarter of participants fell into the Gail "high" risk category (> or =1.7% risk of developing breast cancer in the next 5 years). The average lifetime risk was estimated at 13.2% by the Gail model and 11.2% by the Claus model. Estimates from the two models were moderately and positively correlated (r = 0.55) with the Gail model yielding a higher estimate than the Claus model for most participants. If women with a family history of breast cancer are being counseled regarding decisions on genetic testing, tamoxifen use, or other preventive measures, presenting both Claus and Gail estimates may be the best option.

Women's interest in genetic testing for breast cancer susceptibility may be based on unrealistic expectations.

We report on results of an interview study assessing women's attitudes toward and hypothetical interest in genetic susceptibility testing for breast cancer. Data are from 246 interviews with women of varying ethnicity (African American, European American, Native American, and Ashkenazi Jewish), family history of breast cancer (negative, positive, and borderline), and educational level. Semistructured interviews included questions on general health beliefs; attitudes, experiences, and concerns about breast cancer; and hypothetical interest in genetic testing. Influence of specific test characteristics was assessed with 14 Likert scales varying negative and positive predictive value, timing of disease, possible medical interventions following a positive result. Results reported include both statistical and qualitative analysis. We found that women had a high level of interest in testing which, in general, did not vary by ethnicity, level of education, or family history. Interest in testing appeared to be shaped by an exaggerated sense of vulnerability to breast cancer, limited knowledge about genetic susceptibility testing, and generally positive views about information provided through medical screening. However, study participants were most interested in a test that didn't exist (high positive predictive value followed by effective, noninvasive, preventive therapy) and least interested in the test that does exist (less than certain positive predictive value, low negative predictive value, and limited, invasive, and objectionable therapeutic options). Our data suggest that without a careful counseling process, women could easily be motivated toward interest in a test which will not lead to the disease prevention they are seeking.

Opportunities for public health genetics trainees: results of an employer/workplace survey.

OBJECTIVE: To conduct the first employer/workplace survey identifying employment opportunities for graduates of programs with training in public health genetics in the USA, and to determine whether employment opportunities will increase in coming years. METHODS: Six public health genetics training competencies were developed. A survey about workplace and employment opportunities was then conducted with mailings to (1) departments in schools of public health and departments of preventive medicine, (2) local and regional public health officials, (3) insurance companies and health management organizations (HMOs), and (4) biotechnology and pharmaceutical companies. RESULTS: A total of 196 surveys were returned among 1,464 that were mailed. Response rates varied from 5.8 to 46.5% among the target groups. The percent of responding organizations currently employing individuals with skills in genetics ranged from 20 to 62%. The percent currently employing individuals with skills in public health ranged from 39 to 96%. Training opportunities such as internships or practicum experiences are reported for one-third of respondents. For all of the competencies, approximately half of survey respondents who rated the competency important or very important already employ individuals with public health genetics skills. Similarly, at least a quarter of survey respondents who rated the competency important or very important plan to hire individuals with that skill in the next 5 years. Overall, approximately 40% of those surveyed are planning to hire individuals with competencies in public health genetics in the next 5 years. CONCLUSION: Employment opportunities already exist and new positions are becoming available in schools of public health and departments of preventive medicine, departments of public health, insurance companies and HMOs for professionals with public health genetics training. Based on our survey findings, skills and training in public health genetics are important in the workplace.

Genetic counseling for women with an intermediate family history of breast cancer.

Women with a family history of breast cancer often over-estimate their personal risk for cancer and may view themselves as candidates for genetic testing even when the likelihood of an informative test result is low. We report here on genetic counseling of women with an intermediate family history of breast cancer, defined as women who have one or more biological relatives with breast cancer but whose pedigree suggests a low likelihood of autosomal dominant transmission. A genetic counseling protocol based on traditional genetic counseling strategies was developed with additional components added to address the needs of women with moderately increased breast cancer risk. These additional components included information about non-genetic risk factors, comparisons of high and moderate risk pedigrees, and evaluation of personal risk based on both genetic and nongenetic risk factors. Most participants liked the genetic counseling and found it useful. At baseline, participants over-estimated both their personal risk of breast cancer and that of the average woman. After counseling, estimates of personal and average risk of breast cancer were lower, although both remained higher than actual risk. Most participants reported that they felt less worried about breast cancer after receiving their personal-risk estimate. At baseline, most women judged themselves to be candidates for genetic testing and expressed interest in testing. The number who considered themselves candidates for testing was reduced after counseling (60% versus 82%) but still constituted a majority. Similarly, interest in testing was partially reduced by counseling (60% versus 91%). We conclude that genetic counseling can help women with an intermediate family history of breast cancer to develop more accurate views of their risk, reduce their breast cancer worry, and aid some of them in developing a more realistic view of genetic testing.

Participation in breast cancer risk counseling among women with a family history.

Recent scientific breakthroughs in the genetics of breast cancer may have had effects on women's perceptions of risk and subsequent worry about breast cancer. Here, we present the rates of interest in counseling among women identified from diverse sources, their levels of cancer worry and perceived risk, and predictors of their agreement to participate in breast cancer risk counseling. Women were identified through breast cancer cases and through media offers. They completed a telephone survey and were ultimately either entered or not entered into a counseling trial. Overall, almost half (46%) of cases who were approached responded to the contact letter asking for information about potentially interested relatives. A total of 588 women responded to the brief media solicitations over a 15-week period. Participants recruited from media contacts reported slightly but significantly higher levels of worry about getting cancer, compared to case-recruited participants. Cancer worry negatively and significantly predicted entry into the counseling project. The results presented here may have implications for recruiting women in the general population with a family history of breast cancer for counseling about their risk for the disease.

Attitudes and interest in genetic testing for breast and ovarian cancer susceptibility in diverse groups of women in western Washington.

OBJECTIVES: This paper examines the knowledge, opinions, and predictors of interest in genetic testing for breast cancer risk in a demographically diverse group of women in western Washington who participated in a randomized controlled trial (RCT) of breast cancer risk counseling methods. MATERIALS AND METHODS: Four groups of women were surveyed, all with some family history of breast cancer: (a) 307 white women; (b) 36 African-American women; (c) 87 lesbian/bisexual women; and (d) 113 Ashkenazi Jewish women. As part of the baseline questionnaire for the RCT, participants were asked about their familiarity with genetic testing for breast cancer risk, their interest in such testing and opinions of it, and actions they anticipated based on test results. RESULTS: Women in all four groups favored ready access to testing, believed the decision to be tested should be a personal choice, believed that genetic test results should stay confidential, and were not greatly concerned that this might not be possible. Women anticipated using such genetic test results to increase the frequency of various breast cancer screening methods (in all four groups, > 69% would increase mammogram frequency, > 85% would increase clinician exam, and > 92% would increase breast self exam). Women overwhelmingly rejected prophylactic surgery as a preventive measure (in all > 80% probably or definitely would not consider it). Significant predictors of interest in genetic testing for cancer risk included perceived risk, cancer worry, and beliefs about access to testing. CONCLUSIONS: These data will be of interest to health care providers, payers, public health professionals, legislators, and others as they consider issues associated with population testing for susceptibility to common diseases such as breast cancer.

Testing for inherited susceptibility to breast cancer: a survey of informed consent forms for BRCA1 and BRCA2 mutation testing.

The identification of genetic mutations linked to breast cancer has made it possible to test for the genetic predisposition to this disease. However, though this test may provide certain benefits, there are also potential risks involved with the testing process, including social and economic considerations. In light of these potential risks, we sought to determine what information individuals are receiving in the informed decision making process. To learn the minimal amount of information the actual testees receive, we obtained 10 informed consent forms from seven different testing facilities. These testing centers include the major sources of BRCA1 and BRCA2 mutation testing in the United States at this time. We analyzed the content of these forms by developing content categories and scoring them appropriately. We found all ten forms discussed in varying ways and to varying degrees the purpose of genetic testing, limitations of the test, implications of both positive and negative results, and confidentiality procedures; most, but not all, addressed various psychological and insurance risks. Overall, the forms demonstrated substantial variation in content and organization, underlining the need for more discussion and research on the purpose, nature, and effectiveness of informed consent forms for this type of genetic test.

The advent of the "unpatients'.

Predictive diagnosis by molecular methods will change the scientific basis of prognostics. At the same time, it will change the ethical dimensions of the relation among patients, their doctors and other providers of care.

Ethics and the Human Genome Project.

This article provides an overview of ethical issues in genetic testing and screening as they are currently considered in relationship to the Human Genome Project. Previous landmark reports and policy recommendations on genetic testing and screening are briefly described. The goals and research interests of the joint National Institutes of Health/Department of Energy Ethical, Legal, and Social Working Group of the Human Genome Project are outlined. To provide an example of one method by which ethical issues in genetics may be addressed, the ethical framework and practical aspects of a clinical ethics research project at the University of Washington, Seattle, are described. Finally, future directions for the study of ethical and social issues related to genetic testing and screening programs are suggested.

Concerted evolution of primate alpha satellite DNA. Evidence for an ancestral sequence shared by gorilla and human X chromosome alpha satellite.

To understand evolutionary events in the formation of higher-order repeat units in alpha satellite DNA, we have examined gorilla sequences homologous to human X chromosome alpha satellite. In humans, alpha satellite on the X chromosome is organized as a tandemly repeated, 2.0 x 10(3) base-pairs (bp) higher-order repeat unit, operationally defined by the restriction enzyme BamHI. Each higher-order repeat unit is composed of 12 tandem approximately 171 base-pair monomer units that have been classified into five distinct sequence homology groups. BamHI-digested gorilla genomic DNA hybridized with the cloned human 2 x 10(3) bp X alpha satellite repeat reveals three bands of sizes approximately 3.2 x 10(3), 2.7 x 10(3) and 2 x 10(3) bp. Multiple copies of all three repeat lengths have been isolated and mapped to the centromeric region of the gorilla X chromosome by fluorescence in situ hybridization. Long-range restriction mapping using pulsed-field gel electrophoresis shows that the 2.7 x 10(3) and 3.2 x 10(3) bp repeat arrays exist as separate but likely neighboring arrays on the gorilla X, each ranging in size from approximately 200 x 10(3) to 500 x 10(3) bp, considerably smaller than the approximately 2000 x 10(3) to 4000 x 10(3) bp array found on human X chromosomes. Nucleotide sequence analysis has revealed that monomers within all three gorilla repeat units can be classified into the same five sequence homology groups as monomers located within the higher-order repeat unit on the human X chromosome, suggesting that the formation of the five distinct monomer types predates the divergence of the lineages of contemporary humans and gorillas. The order of 12 monomers within the 2 x 10(3) and 2.7 x 10(3) bp repeat units from the gorilla X chromosome is identical with that of the 2 x 10(3) bp repeat unit from the human X chromosome, suggesting an ancestral linear arrangement and supporting hypotheses about events largely restricted to single chromosome types in the formation of alpha satellite higher-order repeat units.

Patterns of intra- and interarray sequence variation in alpha satellite from the human X chromosome: evidence for short-range homogenization of tandemly repeated DNA sequences.

A number of processes, such as sequence conversion, unequal crossingover, and molecular drive, have been postulated to explain the homogenization of tandemly repeated DNA families. To investigate the nature and extent of such processes in the alpha satellite family of centromeric DNA, we determined the nucleotide sequence of approximately 700 bp from each of 40 representative alpha satellite repeats from six sources of human X chromosomes, obtaining a total of approximately 28 kb of sequence data. Sequence divergence among the repeats examined was low, with an average pairwise difference of approximately 1%. Pairwise comparisons of all repeats indicate that the degree of similarity for those repeats in physical proximity (within approximately 15 kb) of each other is significantly greater than that for randomly located repeats, from either the same or different X chromosomes, suggesting that the mechanisms predicted to homogenize these arrays are effectively short-range in action. Analysis of individual patterns of sequence variation allows the assignment of haplotypes for five high-copy-number diagnostic positions and reveals distinct positions of equilibrium and disequilibrium within the repeat. These analyses address hypotheses about the origin of the observed patterns of variation throughout alpha satellite evolution.

Regional localization of the TIMP gene on the human X chromosome. Extension of a conserved synteny and linkage group on proximal Xp.

The gene encoding a tissue inhibitor of metallo-proteinases, TIMP, has previously been shown to be X-linked in both the human and mouse genomes. We have used a series of somatic cell hybrids segregating translocation and deletion X chromosomes to map the TIMP gene on the human X chromosome. In combination with previous data, the gene can be assigned to Xp11.23----Xp11.4. Genetic linkage analyses demonstrate that TIMP is linked to the more distal ornithine transcarbamylase (OTC) locus at a distance of about 22 centimorgans. The data are consistent with the conclusion that TIMP maps to a conserved synteny and linkage group on the proximal short arm of the human X chromosome and on the pericentric region of the mouse X chromosome, including loci for synapsin-1, a member of the raf oncogene family, OTC, and TIMP.

Molecular analysis of a polymorphic domain of alpha satellite from the human X chromosome.

Alpha satellite DNA, a diverse family of tandemly repeated DNA sequences located at the centromeric region of each human chromosome, is organized in a highly chromosome-specific manner and is characterized by a high frequency of restriction-fragment-length polymorphism. To examine events underlying the formation and spread of these polymorphisms within a tandem array, we have cloned and sequenced a representative copy of a polymorphic array from the X chromosome and compared this polymorphic copy with the predominant higher-order repeat form of X-linked alpha satellite. Sequence data indicate that the polymorphism arose by a single base mutation that created a new restriction site (for HindIII) in the sequence of the predominant repeat unit. This variant repeat unit, marked by the new HindIII site, was subsequently amplified in copy number to create a polymorphic domain consisting of approximately 500 copies of the variant repeat unit within the X-linked array of alpha satellite. We propose that a series of intrachromosomal recombination events between misaligned tandem arrays, involving multiple rounds of either unequal crossing-over or sequence conversion, facilitated the spread and fixation of this variant HindIII repeat unit.