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PubMed2005

BRCA1 and BRCA2: the genetic testing and the current management options for mutation carriers.

Approximately 5-10% of breast carcinomas and 10% of ovarian carcinomas are ascribable to a genetic susceptibility. Of these, about 40% are related to genetic mutations in the genes BRCA1 and BRCA2. Despite the increasing demand for genetic testing arising from the patients and their relatives, the genetic testing can be offered yet only to individuals belonging to high-risk families in which the probability that there is a germline mutation in a BRCA gene is high and thus cancer occurrence is likely the expression of a highly penetrant genetic predisposition. In this article, we review how the current knowledge on the biological mechanisms underlying BRCA1 and BRCA2 dysfunction may contribute to the understanding of breast and ovarian cancer predisposition. The most currently employed methods for genetic testing are critically overviewed, together with some indications for the interpretation of the test outcome and the clinical management of mutation carriers.

BRCA1 Protein↗

PubMed1999

Screening for hereditary cancer and genetic testing, epitomized by breast cancer.

The new genetics is having an impact on many areas of healthcare. Diversity in the genetic code accounts for differences in phenotypes between populations and it is becoming apparent that genetic differences may have a role in predisposition to and behaviour of disease. Genetic models suggest that there are two types of genetic predisposition to disease: the so-called high and low penetrance genes. At present, most of the impact on medicine has been from highly penetrant genes, and genetic testing for disease predisposition, particularly for diseases of late onset (e.g. certain cancers) is in its infancy. As a general statement, approximately 5-10% of common cancers are due to such highly penetrant genes. The category of genes that will become of increasing interest is that of the low penetrance genes. Often these are normal variations in genes that result in a slightly increased risk of disease. These are analogous to high blood pressure carrying an increased risk of cardiovascular disease. Once rapid genetic analysis is available for these types of genes, such analysis would be analogous to taking someone's blood pressure in a general practitioner's (GP's) surgery to identify individuals at increased risk of cardiovascular disease. This will produce a revolutionary change in the way we practise medicine. Genetic analysis will become faster and may therefore be more commonplace. It is possible to envisage an era when genetic analysis will become a routine part of primary care to identify changes in low penetrance genes that will confer a 'risk profile' for patients. This will then enable their primary care physicians to advise about primary prevention and even prescribe certain preventive drugs to decrease the risk of certain diseases occurring. This proactive rather than reactive style of practising medicine is potentially exciting, however it carries with it ethical, legal and social implications for how we deal with this new knowledge.

Adult↗

PubMed2001

Motivations and psychosocial impact of genetic testing for HNPCC.

A type of hereditary colorectal cancer (CRC) known as hereditary nonpolyposis colorectal cancer (HNPCC) is associated with MLHI and MSH2 gene mutations. This study consists of a pilot, cross-sectional study of 50 individuals who were engaged in the genetic testing process for HNPCC. The study investigated the motivations and attitudes around genetic testing and current psychosocial functioning through the use of standardized measures, as well as obtained information on disclosure patterns associated with test results. The mean age of the sample was 44.3 years. (SD = 15.0). Twenty-three individuals were identified as "carriers" (13 had a previous history of CRC), seven were "non-carriers" and 20 individuals were still awaiting test results. The primary motivations for participating in genetic testing were similar to previous reports and included: wanting to know if more screening tests were needed, obtaining information about the risk for offspring and increasing certainty around their own risk. The psychosocial scores demonstrated that a subgroup of individuals exhibited distress, with greater distress for those individuals awaiting results or testing positive. There was a high level of satisfaction associated with the experience of testing. Individuals in this study tended to disclose their test results to a variety of family and non-family members. Disclosure was primarily associated with positive experiences however, some individuals reported regret around disclosure of their results. These preliminary findings should be further explored in a larger prospective study design over multiple time points.

Adult↗

PubMed1998

The question not asked: the challenge of pleiotropic genetic tests.

Nearly all of the literature on the ethical, legal, or social issues surrounding genetic tests has proceeded on the assumption that any particular test for a gene mutation yields information about only one disease condition. Even though the phenomenon of pleiotropy, where a single gene has multiple, apparently unrelated phenotypic effects, is widely recognized in genetics, it has not had much significance for genetic testing until recently. In this article, I examine a moral dilemma created by one sort of pleiotropic testing, APOE genotyping, which can yield information about the risk of two different conditions -- coronary heart disease and Alzheimer's disease. A physician administering APOE testing for the beneficial purpose of assessing the risk of heart disease may discover medically useless and socially harmful information about the patient's risk of Alzheimer's disease. I explore how much providers should disclose to patients about pleiotropic test results and whether patients are obligated to know as much about their genetic condition as possible.

Dementia↗

PubMed2001

Testing genetic susceptibility loci for alcoholic heart muscle disease.

BACKGROUND: Although many heavy alcohol users have subclinical alcoholic heart muscle disease, only a very few develop severe dilated cardiomyopathy. Therefore, and because cardiac abnormalities correlate only weakly with the duration or quantity of drinking, individual susceptibility differences may exist. In this work we examined whether common gene variants previously associated with cardiac hypertrophy or altered alcohol metabolism could modify the effects of alcohol on the heart. METHODS: We studied 700 middle-aged male victims of sudden death who underwent a medicolegal autopsy. In addition to routine postmortem examination, the weights and the cavity and wall dimensions of the left and right ventricle were measured. Coronary artery stenoses were determined from a silicone rubber cast of the arteries. Alcohol consumption and cardiovascular risk factors were assessed by a structured interview of the spouse. The following gene polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism and solid-phase minisequencing techniques: angiotensin converting enzyme I/D, angiotensin II type 1 receptor 1166A/C, aldosterone synthase -344C/T, alcohol dehydrogenases 2 and 3, acetaldehyde dehydrogenase 2, and cytochrome P-450 2E1 DraI, PstI, RsaI, and MspI. RESULTS: The most consistent effects of alcohol (p < 0.05) were a higher total heart weight and a larger right ventricle size with increasing daily drinking. However, these and other effects of alcohol were statistically fully independent of the studied genotypes. CONCLUSIONS: The gene polymorphisms selected for and analyzed in our study are unlikely to modify the effects of alcohol on the heart. Other unknown factors determine the individual susceptibility to alcoholic heart muscle disease.

Adult↗

PubMed2003

The effect of disease penetrance, family size, and age of onset on family history with application to setting eligibility criteria for genetic testing.

The concept of family history of disease has been used as a surrogate for genetic susceptibility in many epidemiological studies and has also been important as a criterion for selecting individuals for genetic testing. However, little is known about the precise interplay between the true genetic model (genotype-specific penetrances, age of onset distribution), life expectancy, and reproductive patterns in determining the level of family history. In order to address these questions, we performed a simulation study to address these relationships. Factors examined were the age-, sex-, and genotype-specific penetrance of the disease and the distribution of the number of offspring per family. When considering the average number of affected individuals among first-degree relatives of mutation positive probands, penetrance-related factors accounted for 64% of the variance in the average number of affected first-degree relatives, and 58% of the variance in the number of affected first- or second-degree relatives. In general, the average proportion of mutation-positive probands with at least one affected first-degree relative was low, especially for a sex-limited disease, ranging between 20% and 46%, depending on the lifetime penetrance in mutation carriers. Lack of family history among first-degree relatives of mutation positive probands is not necessarily unexpected even for loci conferring relatively high lifetime risk. In selecting probands for genetic testing, we found that under a wide variety of conditions, criteria based on the number of affected among first- and second-degree relatives were superior to those based on first-degree family history alone.

Adolescent↗

PubMed1996

Genetic testing for cancer in children. Short-term psychological effect.

OBJECTIVE: To study the psychological effect of genetic testing in children. DESIGN: We evaluated the psychological effect of predictive genetic testing through surveys of children at risk for familial adenomatous polyposis. Their psychological state was assessed before testing and 3 months later. SETTING: A research clinic. PARTICIPANTS: A volunteer sample of 41 children, aged 6 to 16 years, and their parents. MAIN OUTCOME MEASURES: Self-report inventories of depression, anxiety, behavior problems, and competence. RESULTS: Nineteen children were found to have a gene mutation (mutation-positive) and 22 did not (mutation-negative). Their depression, anxiety, and behavior problem and competence scores remained in the normal range after testing. Also, parents' depression scores remained within normal limits at follow-up. There were subclinical changes, however. Mutation-positive children with affected mothers had significantly higher depression scores at follow-up. Also, regardless of test results, children with affected mothers had significantly increased anxiety scores after testing. In families with mutation-positive and mutation-negative children, familial adenomatous polyposis-unaffected parents experienced significantly increased depressive symptoms at follow-up. CONCLUSIONS: Predictive testing of children at risk for familial adenomatous polyposis did not lead to clinically significant psychological symptoms in tested children or their parents. However, it is premature to conclude that long-term follow-up will be equally favorable. Additional study will be needed to determine the families' understanding of the genetic information and the effect of the information on familial relationships.

Adenomatous Polyposis Coli↗

PubMed2006

Presymptomatic and predictive genetic testing in minors: a systematic review of guidelines and position papers.

The objective of this study is to review ethical and clinical guidelines and position papers concerning the presymptomatic and predictive genetic testing of minors. The databases Medline, Philosopher's Index, Biological Abstracts, Web of Science and Google Scholar were searched using keywords relating to the presymptomatic and predictive testing of children. We also searched the websites of the national bioethics committees indexed on the websites of World Health Organization (WHO) and the German Reference Centre for Ethics in the Life Sciences, the websites of the Human Genetics Societies of various nations indexed on the website of the International Federation of Human Genetics Societies and related links and the national medical associations indexed on the website of the World Medical Association. We retrieved 27 different papers dealing with guidelines or position papers that fulfilled our search criteria. They encompassed the period 1991-2005 and originated from 31 different organizations. The main justification for presymptomatic and predictive genetic testing was the direct benefit to the minor through either medical intervention or preventive measures. If there were no urgent medical reasons, all guidelines recommend postponing testing until the child could consent to testing as a competent adolescent or as an adult. Ambiguity existed for childhood-onset disorders for which preventive or therapeutic measures are not available and for the timing of testing for childhood-onset disorders. Although the guidelines covering presymptomatic and predictive genetic testing of minors agree strongly that medical benefit is the main justification for testing, a lack of consensus remains in the case of childhood-onset disorders for which preventive or therapeutic measures are not available.

Age Factors↗

PubMed2006

Economic evaluation of the familial cancer programme in Western Australia: predictive genetic testing for familial adenomatous polyposis and hereditary non-polyposis colorectal carcinoma.

AIM: To evaluate costs and outcomes of genetic testing for familial colorectal cancer through services provided by Genetic Services of Western Australia (GSWA). METHODS: Costs and outcomes of predictive DNA-based testing for inherited colorectal cancers (CRC) were assessed, specifically for familial adenomatous polyposis (FAP) and hereditary non-polyposis CRC (HNPCC) using a decision-analysis model. Costs were assigned according to standards of care in Western Australia (WA). Cancer risks and the efficacy of surveillance on long-term outcomes were derived from the published literature. RESULTS: The cost-effectiveness of genetic testing was compared in first-degree relatives of known mutation carriers who have a 50% risk of carrying the mutated gene (intervention group) to individuals with the same risk but who do not undergo a genetic test (control subjects). Compared with control subjects undergoing the same high-level surveillance and surgery, the FAP and HNPCC intervention groups provided total savings of 13,390 US dollars and 14,783-15,460 per person (males-females), respectively. HPNCC mutation carriers also gained 1 CRC-free year. Compared to control subjects having only population surveillance, individuals in the FAP intervention group delayed the onset of CRC by 40 years for a net cost of 9,042 US dollars. Individuals in the HNPCC intervention group delayed the onset of CRC by 8 years at a net cost of 12,141 US dollars for males and 12,596 US dollars for females. CONCLUSIONS: Genetic testing for familial CRC in WA allows targeted surveillance for mutation carriers, which ensures the efficient use of resources and reduces cancer-related morbidity, if clinical recommendations for intervention are adopted.

Adenomatous Polyposis Coli↗

PubMed2004

Psychological impact of genetic testing for hereditary non-polyposis colorectal cancer.

The psychological impact of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC) was assessed in 114 individuals (32 carriers and 82 non-carriers) attending familial cancer clinics, using mailed self-administered questionnaires prior to, 2 weeks, 4 months and 12 months after carrier status disclosure. Compared to baseline, carriers showed a significant increase in mean scores for intrusive and avoidant thoughts about colorectal cancer 2 weeks (t = 2.49; p = 0.014) and a significant decrease in mean depression scores 2 weeks post-notification of result (t = -3.98; p < 0.001) and 4 months post-notification of result (t = -3.22; p = 0.002). For non-carriers, significant decreases in mean scores for intrusive and avoidant thoughts about colorectal cancer were observed at all follow-up assessment time points relative to baseline. Non-carriers also showed significant decreases from baseline in mean depression scores 2 weeks, 4 months and 12 months post-notification. Significant decreases from baseline for mean state anxiety scores were also observed for non-carriers 2 weeks post-notification (t = -3.99; p < 0.001). These data indicate that predictive genetic testing for HNPCC leads to psychological benefits amongst non-carriers, and no adverse psychological outcomes were observed amongst carriers.

Adult↗

PubMed2002

[Genetic test and prophylactic treatment in breast cancer families].

Fifteen (13.3%) and 21 (18.6%) deleterious germline mutations were identified in BRCA1, and BRCA2 genes among 113 Japanese breast cancer families. We found a BRCA1 codon 63 (nucleotide 307) nonsense mutation and a 4-bp deletion at codon 1858 (nucleotide 5802) of BRCA2 in 4 and 7 independent families, respectively. Haplotype analysis has revealed that these two mutations were founder mutations. Lifetime risk of breast cancer in BRCA1 or BRCA2 mutation carriers was estimated at nearly 80%, and that of ovarian cancer in BRCA1 mutation carriers was about 40%. A questionnaire survey as to the genetic testing (BRCA1 and BRCA2) and prevention was carried out with 146 healthy women (hospital workers or medical students) and 84 breast cancer patients. About 80% of healthy women as well as breast cancer patients responded positively to the genetic testing, based on the assumption their's was a breast cancer family, and about 20% of each group answered that they would opt for prophylactic mastectomy and oophorectomy if they were found to be germline mutation carriers. These results indicate that genetic testing and prophylactic surgery would be acceptable among a considerable number of Japanese women, and seem to support the establishment an infrastructure for genetic testing in Japan.

Adult↗

PubMed1999

Mexican geneticists' views of ethical issues in genetics testing and screening. Are eugenic principles involved?

Herein we discuss Mexican geneticists' views of ethical issues in genetic testing and screening, analyzing whether eugenic principles are involved in this activity. The information was obtained from a comprehensive survey on genetics, ethics, and society organized by Wertz and Fletcher in 1993, in which 37 nations participated. The responses to 21 questions from 64 out of 89 (72%) geneticists invited to participate are analyzed in this paper. The questions were practically the same as those answered recently by a group of Chinese geneticists (Mao X. Chinese geneticists' views of ethical issues in genetic testing and screening: evidence for eugenics in China. Am J Hum Genet 1998: 63: 688-695), who work in a country where the furtherance of eugenic principles is considered to be the goal of human genetics. We concluded that although there are many similarities in the answers from both countries, this is not indicative of Mexican geneticists pursuing eugenic goals because: a) there is no coercion involved; and b) there is no intention of improving the gene pool.

China↗

PubMed2001

The family covenant and genetic testing.

The physician-patient relationship has changed over the last several decades, requiring a systematic reevaluation of the competing demands of patients, physicians, and families. In the era of genetic testing, using a model of patient care known as the family covenant may prove effective in accounting for these demands. The family covenant articulates the roles of the physician, patient, and the family prior to genetic testing, as the participants consensually define them. The initial argument defines the boundaries of autonomy and benefit for all participating family members. The physician may then serve as a facilitator in the relationship, working with all parties in resolving potential conflicts regarding genetic information. The family covenant promotes a fuller discussion of the competing ethical claims that may come to bear after genetic test results are received.

Advance Directives↗

PubMed2006

The quest for the perfect baby: why do Israeli women seek prenatal genetic testing?

Since the mid-1990s, the Israeli medical scene has witnessed a real boom in elective prenatal testing for inherited diseases that has spread beyond risk groups to the general Jewish population, especially of Ashkenazi (European) origin. This study tried to identify key social influences involved in the growing range and prevalence of prenatal genetic tests as they emerged from women's own perspective. Twenty-seven women having blood tests for genetic mutations were interviewed at two types of genetic clinics, and re-interviewed after getting test results. The names of 23 women who chose not to have elective tests were obtained from testers, and these non-testers were interviewed for comparison. Women's accounts suggest that elective genetic testing is more acceptable, if not normative, among educated middle class Ashkenazi women, and is more often questioned and refused by lower class Mizrahi women, as well as religious women of any ethnic origin. The key forces that drive women's choice of prenatal genetic diagnosis include the fear of having a sick and/or socially unfit child in an unsupportive environment; strong endorsement of testing by gynaecologists; popular and professional discourse on the common Ashkenazi mutations causing genetic anxiety in this ethnic group (i.e. apprehension of multiple known and unknown dangers hidden in its genetic makeup); and the emerging social pressure for comprehensive prenatal screening as an indispensable part of good motherhood. Many women described the experience of testing as frustrating because of the long wait for results and difficulty of their interpretation and subsequent decision-making. Women who rejected elective tests explained their decision by moral/religious objections to abortion and/or eugenic aspects of prenatal screening, as well as by prohibitive costs and poor understanding of the tests' meaning and implications. Yet, few informants voiced objections to the excessive medicalisation of pregnancy as such; ethno-national motives of reproductive decisions were also uncommon in this group. More critical reflection is clearly needed from both providers and users of elective genetic screening before the more widespread uptake of this practice.

Adult↗

PubMed2006

Genetic testing for hereditary breast and ovarian cancer: responsibility and choice.

Genetic testing for hereditary breast-ovarian cancer has become an important part of clinical genetics practice. Although considerable work has focused on the psychological impact of this technology, there has been little research into the moral implications of genetic information on hereditary cancer families. In this article, the author examines moral issues related to individuals' decisions to seek or decline testing. In-depth interviews with 53 participants make up the core of the research. Analysis of participants' accounts illustrates how the decision to be tested (or not) interconnects with moral agency and aspects of self (embodied, familial-relational, and civic self). The findings form the foundation for inquiry into conceptualization of moral responsibility, autonomy, and choice. They also provide insight that might assist clinicians to understand more fully the needs and responses of those who seek genetic testing for hereditary breast-ovarian cancer.

Adult↗

PubMed2006

Genetic testing for hereditary cancers: the impact of gender on interest, uptake and ethical considerations.

Genetic testing promises earlier intervention and more successful outcomes for individuals at risk for hereditary breast/ovarian and colorectal cancer. Research shows that gender influences health and access to health care services. In this paper, we review theoretical issues of gender, and research outcomes, in relation to genetic testing for hereditary cancers. We argue that integrating a gender analysis into assessment of new technologies and health programs is necessary to improve appropriateness, accessibility and effectiveness. Attention to gender is also critical to developing a deeper understanding of the ethical issues (both benefits and harms) raised by new genetic technologies.

Bioethical Issues↗

PubMed1997

[Genetic testing for cancer susceptibility: the present situation in Japan].

Genetic diagnosis of hereditary tumors has progressed extensively and contributed to the presymptomatic testing for mutation carriers. This evolution of genetic testing for cancer susceptibility leads to improved prevention and early detection of cancers. However, the benefits and limits of testing, and the range of prevention and treatment are different in each hereditary tumor. The American Society of Clinical Oncology (ASCO) made the statement on genetic testing for cancer susceptibility and showed three categories for consideration of cancer predisposition testing. They recommend that genetic testing should be offered only for the categories including well-defined tumors. We described the characteristics of hereditary tumors in the three categories and discussed the significance of genetic testing for each tumor. In conclusion, genetic testing for cancer susceptibility should be applied only for subsets of hereditary syndromes, and it is important to continue the analysis of the significance (frequency or penetrance) of mutations of cancer predisposition genes and to make clear the genotype-phenotype and other correlations.

Breast Neoplasms↗

PubMed2001

Predictive genetic testing in maturity-onset diabetes of the young (MODY).

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance of young-onset non-insulin-dependent diabetes. It accounts for approximately 1% of Type 2 diabetes (approximately 20 000 people in the UK). Diagnostic and predictive genetic tests are now possible for 80% of MODY families. Diagnostic tests can be helpful as the diagnosis can be confirmed and the subtype defined which has implications for treatment and prognosis. However predictive genetic testing, particularly in children, raises many scientific, ethical and practical questions. METHODS: This is a case report of a family with diabetes resulting from an hepatic nuclear factor (HNF)1alpha mutation, who request a predictive test in their 5-year-old daughter. The scientific issues arising from molecular genetic testing in MODY are discussed, along with the process of genetic counselling. The views of the family and the clinical genetics team involved are presented. RESULTS: The implications of positive and negative predictive test results and the possibility of postponing the test were among many issues discussed during genetic counselling. The family remained convinced the test was appropriate for their daughter and the clinical genetics team fully supported this decision. The family, motivated by their family history of diabetes and personal experiences of the disease, wished to reduce uncertainty about their daughter's future irrespective of the result. CONCLUSIONS: This case emphasizes that decisions on predictive testing are very personal and require appropriate counselling.

Adolescent↗