The emerging role of the physician in genetic counselling and testing for heritable breast,ovarian and colon cancer.

As a genetic testing for susceptibility to breast, ovarian and colon cancer becomes more readily available, physicians are faced with an increasing demand for information about inherited cancer risk. Because advances in treatment have not kept pace with advances in predictive testing, the provision of genetic counselling and testing marks a departure from the traditional role of the physician. A systematic framework is needed within which the physician''s emerging role in predictive testing for heritable cancer can be delineated. The development of such a framework will require collaboration among professionals in a range of scientific disciplines, as well as the suspension of traditional assumptions about the physicians role.     

A current perspective on genetic testing for breast and ovarian cancer: the oral contraceptive decision

A clinician faces a problem in how best to counsel the woman with a family history of breast or ovarian cancer about her options for pregnancy prevention. The physician must guide her as she makes new and complex decisions. Recent data strongly support an amplified effect of the estrogens in oral contraceptives for the woman with a genetic risk for breast cancer. Nonetheless, a woman's immediate need to prevent pregnancy may be much more important to her than worrying about the long-term risk of breast cancer. Another factor is that oral contraceptives prevent ovarian cancer, so the physician may wish to prescribe them to protect her from ovarian cancer. In some genetic backgrounds, however, oral contraceptives not only do not prevent ovarian cancer, but they may raise the risk of breast cancer so significantly that they should not be taken. With other genetic backgrounds, oral contraceptives will protect the woman from ovarian cancer without much effect on her breast cancer risk. When does each of these cancer risks or benefits become significant? The clinician can provide an important benefit to a woman who must prevent pregnancy yet worries about her cancer risk. The physician can help her evaluate the evidence, with its gaps and uncertainties, in the context of her own preferences. To assist in this evaluation, this decision aid provides base-line estimates of the cancer risk that accompanies each of a woman's options. In some cases, genetic testing is likely to provide valuable information as she makes choices about contraception and the risks vs. benefits of different alternatives available to her.     

Women's need for information before attending genetic counselling for familial breast or ovarian cancer: a questionnaire,interview, and observational study.

OBJECTIVES: To describe women''s information needs prior to genetic counselling for familial breast or ovarian cancer. DESIGN: Prospective study including semistructured telephone interviews before genetic counselling, observations of consultations, completion of postal questionnaires, and face-to face interviews within two months of counselling. SUBJECTS: 46 women attending genetic counselling for familial breast or ovarian cancer. MAIN OUTCOME MEASURES: Subjects'' understanding of process and content of genetic counselling before attending and attitudes about their preparation for the counselling session. RESULTS: Although all women interviewed before the clinic expected to discuss their risk of developing cancer and risk management options, there was evidence of a lack of knowledge about the process and content of genetic counselling, 17 (37%) women said they did not know what else would happen. Most women interviewed after counselling viewed it positively, but 26 (65%) felt they had been inadequately prepared and 11 (28%) felt that their lack of preparation meant that they could not be given an accurate estimation of their risk of cancer. CONCLUSIONS: Some women felt that they did not obtain optimum benefit from genetic counselling because they were inadequately prepared for it. We suggest that cancer family history clinics should provide women with written information about the process and content of genetic counselling before their clinic attendance.     

Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship

The possibility of a genetic relationship between ovarian, breast, and endometrial cancer was investigated in data from a large multicenter, population-based, case-control study, the Cancer and Steroid Hormone Study conducted by the Centers for Disease Control (CDC). Age-adjusted relative risks (RRs) for mothers and sisters of 493 ovarian cancer cases, 895 breast cancer cases, and 143 endometrial cancer cases versus 4,754 controls were calculated. Significantly elevated age-adjusted RRs were found for ovarian cancer (RR = 2.8; 95% confidence interval [CI] = 1.6-4.9) and breast cancer (RR = 1.6; 95% CI = 1.1-2.1) among relatives of ovarian cancer probands and for breast cancer (RR = 2.1; 95% CI = 1.7-2.5) and ovarian cancer (RR = 1.7; 95% CI = 1.0-2.0) among relatives of breast cancer probands. Relatives of endometrial cancer probands had an elevated RR for endometrial cancer only (RR = 2.7; 95% CI = 1.6-4.8). The genetic relationship between ovarian, breast, and endometrial cancer was tested using a multivariate polygenic threshold model developed by Smith (1976), which was modified to accommodate three classes of probands. Estimates of heritability for ovarian, breast, and endometrial cancer were 40%, 56%, and 52%, respectively. There was a significant genetic correlation between ovarian and breast cancer (R12 = .484). Evidence for significant genetic overlap between endometrial cancer and either ovarian or breast cancer was not found. These results suggest the existence of a familial breast/ovarian cancer syndrome. Endometrial cancer, while heritable, appears to be genetically unrelated.     

Diagnostic genetic testing for hereditary breast and ovarian cancer in cancer patients: women's looking back on the pre-test period and a psychological evaluation

The aim of this retrospective, exploratory study was to gain insight into how cancer patients who had a diagnostic genetic test for hereditary breast and/or ovarian cancer looked back on the pre-test period and to gain insight into the psychological impact of the genetic test result. Data were collected by semistructured interviews and self-report questionnaires in 19 BRCA1 or BRCA2 mutation carriers, 7 noncarriers, and 36 patients with an inconclusive genetic test result. Cancer patients had a genetic test mainly for other persons, especially relatives in the descendant line. Mutation carriers felt more in control, but they also reported negative effects of genetic testing such as negative emotional impact and being concerned about their children. Non-carriers were relieved. The group of women where no BRCA1 or BRCA2 mutation was found in the family was heterogeneous. Some misinterpreted the genetic test result as revealing the absence of a genetic predisposition. Others were relieved but also still aware of an increased risk, whereas a last group experienced continuing uncertainty and felt less in control. Self-report questionnaires did not reveal differences in general and cancer-specific distress as a function of the genetic test result. Furthermore, no differences among the three groups were found regarding perceived seriousness of breast and ovarian cancer and perceived control of breast cancer. Perceived control of ovarian cancer was highest in the inconclusive group.     

Factors associated with an individual's decision to withdraw from genetic testing for breast and ovarian cancer susceptibility: implications for counseling

Our study aimed to examine why individuals withdraw from genetic testing for breast and ovarian cancer susceptibility. We explored the characteristics of 334 individuals from high-risk breast and ovarian cancer families who declined genetic testing for BRCA1/2 mutations, when, and why they did so. Individuals who declined genetic testing were older, and a greater proportion had never developed breast or ovarian cancer. Fifty one per cent (51.1%) of individuals withdrew after the first genetic counseling session. Most of those who declined were afraid of the psychological effects of genetic testing (36.3%). The next most-cited explanations concerned logistic problems such as a limited ability to travel, lack of time, personal issues, advanced age, or health problems (21.7%). The third category included individuals who did not see any advantage in being tested (14.5%). Insurability was a concern (5.9%), mainly for men. Surprisingly, confidentiality was not a frequently reported issue (1.3%). Sixty eight per cent (68%) of individuals belonging to a family in which at least one individual has been tested withdrew after the presence of a deleterious BRCA1/2 mutation in a relative was disclosed, compared to 42% after the disclosure of a nonconclusive test result in at least one relative. Concern about the psychological effects of the result was still one of the major reasons. Several factors may influence an individual's decision to decline genetic testing; a greater understanding of these issues may help health professionals to better meet the needs and concerns of individuals from high-risk families, thus possibly improving their health outcomes.     

The genetics of breast cancer. A genetic dispersion analysis and the genetic heterogeneity of breast cancer

The multifactorial nature of breast cancer was established based on population and family study, the contribution of genetic factors being 52% (premenopausal--62 and postmenopausal--39%). Genetic heterogeneity of different coefficients of inheritance of breast cancer with the portion of common genes was shown to be 53%. The analysis of breast cancer interaction with other malignant neoplasms revealed that the development of other malignant neoplasms was the result of the influence of partially common genes. On the basis of data obtained in this study, the tables of repeated risk for the relatives have been worked out which may be used for medico-genetic consultations.     

Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic.

OBJECTIVE--To introduce and monitor a screening programme for first degree relatives of patients with colorectal cancer based on their calculated lifetime risk. DESIGN--Lifetime risks were calculated for first degree relatives of patients with colorectal cancer and used to offer screening based on estimated risk. SETTING--A family cancer clinic was set up as part of the North East Thames Regional Genetic Service for relatives of patients who had developed colorectal cancer before the age of 45 and members of families in which multiple cancer had occurred. PATIENTS--Self referrals as well as patients referred by general and hospital practitioners. INTERVENTION--Relatives with a lifetime risk of 1 in 10 or greater (high risk group) were offered screening five yearly by colonoscopy, and those whose risk was between 1 in 10 and 1 in 17 were offered yearly screening for faecal occult blood. Women with family histories compatible with Lynch type II cancer family syndrome were offered screening for breast and pelvic tumours. RESULTS--In four years 715 patients were seen. Acceptance of screening was 90% (644 patients). Of 151 patients screened for faecal occult blood, two were found to have polyps. This screening test was unsatisfactory for the high risk group, having a negative predictive value of 78% in 59 patients tested. Regular screening by colonoscopy was offered to 382 high risk patients; 62 patients with polyps and five with colonic cancer were found. One hundred and ten pedigrees were identified with the Lynch type II cancer family syndrome, and four of 35 women screened were found to have breast cancer. Of 14 relatives aged over 65 with a 1 in 2 risk of site specific colonic cancer or Lynch type II cancer family syndrome, seven were found to have polyps, one of whom had carcinoma in situ. CONCLUSIONS--Family history can be used to identify those at risk of colonic cancer and to target appropriate screening. Colonoscopy detected a high number of premalignant colonic polyps, but faecal occult blood testing was unsatisfactory for those at high risk of colorectal cancer.     

Simultaneous interdisciplinary counseling in German breast/ovarian cancer families: first experiences with patient perceptions, surveillance behavior and acceptance of genetic testing

As part of a multicenter study supported by the German Mildred Scheel foundation we have established an interdisciplinary counseling setting for members of breast and/or ovarian cancer families. We offer simultaneous counseling by a team consisting of a geneticist, a gynecologist and a psycho-oncologist. Here we describe our counseling protocol and our first short-term experience with this interdisciplinary approach. Preliminary data on patient perceptions and behaviors in the context of DNA testing are reported. Overall, our counseling approach was perceived as beneficial both by the counselors and the consultants. A marked overestimation of the risk to develop breast and/or ovarian cancer was noted in the group of unaffected individuals from medium to low risk breast cancer families in contrast to an appropriate risk perception in members from high risk families. All participants shared many of the same expectations about genetic testing and counseling and appeared to base their decision-making about testing on the risk classification given by the genetic counselor. The reported participation in gynecological cancer prevention programs was high in all families at risk, but was less sufficient in unaffected as compared to affected persons. Although current data on BRCA1/BRCA2 mutation analyses render testing in medium to low risk individuals questionable, our findings emphasize the importance of genetic counseling and education in all risk categories of breast and/or ovarian cancer families.     

A novel protease homolog differentially expressed in breast and ovarian cancer.

BACKGROUND: Using differential display (DD), we discovered a new member of the serine protease family of protein-cleaving enzymes, named protease M. The gene is most closely related by sequence to the kallikreins, to prostate-specific antigen (PSA), and to trypsin. The diagnostic use of PSA in prostate cancer suggested that a related molecule might be a predictor for breast or ovarian cancer. This, in turn, led to studies designed to characterize the protein and to screen for its expression in cancer. MATERIALS AND METHODS: The isolation of protease M by DD, the cloning and sequencing of the cDNA, and the comparison of the predicted protein structure with related proteins are described, as are methods to produce recombinant proteins and polyclonal antibody preparations. Protease M expression was examined in mammary, prostate, and ovarian cancer, as well as normal, cells and tissues. Stable transfectants expressing the protease M gene were produced in mammary carcinoma cells. RESULTS: Protease M was localized by fluorescent in situ hybridization analysis to chromosome 19q13.3, in a region to which other kallikreins and PSA also map. The gene is expressed in the primary mammary carcinoma lines tested but not in the corresponding cell lines of metastatic origin. It is strongly expressed in ovarian cancer tissues and cell lines. The enzyme activity could not be established, because of difficulties in producing sufficient recombinant protein, a common problem with proteases. Transfectants were selected that overexpress the mRNA, but the protein levels remained very low. CONCLUSIONS: Protease M expression (mRNA) may be a useful marker in the detection of primary mammary carcinomas, as well as primary ovarian cancers. Other medical applications are also likely, based on sequence relatedness to trypsin and PSA.     

The supply of breast/ovarian cancer genetic susceptibility tests in France

One example of the recent advances of scientific research on the human genome is the identification of two susceptibility genes to breast/ovarian cancer, BRCA1 and BRCA2, making possible the introduction in medical practices of genetic testing to detect patients with an increased risk of developing such cancers. In this context of diffusion, two surveys were carried out to appraise the activity profiles in 1998 and in 2001 of all the different participants in those new medical practices in France, physicians in charge of genetic counselling, medical centres where consultations take place and laboratories. Results show that over the period 1998-2001, few changes occurred, mainly the reduction of the average waiting time to get the result of a genetic test, the increase in the annual number of BRCA2 families identified to a level similar to the one of BRCA1 and the automation of the biological analyses without noting a considerable increase in the annual output of laboratories till 2001 however. This surprising moderate evolution must be connected to the existence of some particular external factors making the framework of the development of these new medical and biological practices and their future really uncertain. The diffusion of BRCA1/2 genetic testing has been carried out facing the traditional difficulties of any innovating activities, but also the uncertainties related to intellectual property rights on genes and the reimbursement of genetic counselling and biological testing. These uncertainties have certainly restrained the pace of change as many actors in this field have opted for a wait and see strategy bearing in mind the possible future constraints imposed to their future activity, especially if European patents on the BRCA1/2 genes are finally granted by the European patent office (EPO).     

Referral and experience with genetic testing among women with early onset breast cancer

The purpose of this study was to determine whether physicians refer women with early onset breast cancer for genetic testing for BRCA1 and BRCA2, and how women respond to being offered testing and use the results. A web-based survey was distributed to 1221 women with early onset breast cancer. The survey included 158 questions divided into the following sections: demographics, family history of cancer, medical history, treatment history, and experience with genetic testing. Of 551 women diagnosed since 1993 who responded to the survey (45.1%), less than half (45%, n = 246) had ever discussed genetic testing with their physician and/or been referred to see a genetic counselor. Women with a family history of cancer (53%) and Ashkenazi Jewish women (81%) were more likely to have been referred. Of those who had discussed testing, 60% had undergone or were interested in testing. Overall 92 women were tested and 19 (20.6%) of these tested positive for a deleterious BRCA1 or BRCA2 mutation. Fourteen (74%) who tested positive subsequently underwent prophylactic surgery. Satisfaction with counseling and the decision to be tested was high. Among women who were not offered testing, the fact that the test had not been offered by their physician (89%), and fear of discrimination (83%) were the two most frequently cited factors for lack of interest in testing. A substantial number of women are not being referred to genetic counseling and/or testing after a diagnosis of early onset breast cancer. Among those who were tested, there was high interest in prophylactic surgery after confirmation of a BRCA1/2 mutation.     

Neuronal guidance. A genetic perspective

Remarkable advances have been made recently to identify the molecules required for the development of neural connections within the brain. A range of ligands and receptors have been uncovered that guide extending neurons to appropriate targets and away from inappropriate areas. These molecules point to the signalling mechanisms that guide the neurons and provide entry points for the further dissection of this process. Here I highlight the part genetic screens and analyses have played in revealing some of the key players in neuronal guidance.