Factors determining dissemination of results and uptake of genetic testing in families with known BRCA1/2 mutations

BACKGROUND: Uptake of genetic testing remains low, even in families with known BRCA1 and BRCA2 (BRCA1/2) mutations, despite effective interventions to reduce risk. We report disclosure and uptake patterns by BRCA1/2-positive individuals to at-risk relatives, in the setting of no-cost genetic counseling and testing. METHODS: Relatives of BRCA1/2-positive individuals were offered cost-free and confidential genetic counseling and testing. If positive for a BRCA1/2 mutation, participants were eligible to complete a survey about their disclosure of mutation status and the subsequent uptake of genetic testing by at-risk family members. RESULTS: One hundred and fifteen of 142 eligible individuals responded to the survey (81%). Eighty-eight (77%) of those surveyed disclosed results to all at-risk relatives. Disclosure to first-degree relatives (FDRs) was higher than to second-degree relatives (SDRs) and third-degree relatives (TDR) (95% vs. 78%; p < 0.01). Disclosure rates to male versus female relatives were similar, but reported completion of genetic testing was higher among female versus male FDRs (73% vs. 49%; p < 0.01) and SDRs (68% vs. 43%; p < 0.01), and among members of maternal versus paternal lineages (63% vs. 0%; p < 0.01). Men were more likely than women to express general difficulty discussing positive BCRA1/2 results with at-risk family members (90% vs. 70%; p = 0.03), while women reported more emotional distress associated with disclosure than men (48% vs. 13%; p < 0.01). DISCUSSION: We report a very high rate of disclosure of genetic testing information to at-risk relatives. However, uptake of genetic testing among at-risk individuals was low despite cost-free testing services, particularly in men, SDRs, and members of paternal lineages. The complete lack of testing among paternally related at-risk individuals and the lower testing uptake among men signify a significant barrier to testing and a challenge for genetic counselors and physicians working with high-risk groups. Further research is necessary to ensure that family members understand their risk and the potential benefits of genetic counseling.     

Knowledge, attitudes, and utilization of BRCA1/2 testing among women with early-onset breast cancer

A total of 2,400 questionnaires were mailed to members of two mid-Atlantic breast cancer awareness/support groups to investigate the association between attitudes, knowledge, and use of BRCA1/2 testing among women with early-onset breast cancer. Of the 493 (21%) questionnaires returned, 406 respondents had a diagnosis of breast cancer, of whom 248 were diagnosed prior to age 50 and included in the analyses. Eighty-three percent (206/248) of these women had heard of BRCA1/2 testing and 12.5% (31/248) had undergone BRCA1/2 testing. Among women who had heard of BRCA1/2 testing, women who had been tested were younger (p = 0.03), more likely to have a college education (p = 0.03), more likely to have a family member who had undergone BRCA1/2 testing (p = 0.005), and had greater knowledge, more positive attitudes, and fewer negative attitudes about BRCA1/2 testing (p = 0.02, p = 0.004, and p = 0.004, respectively). In this sample, knowledge regarding BRCA1/2 testing is high, but uptake of genetic testing is low. Lack of information regarding how genetic testing might alter health-care decisions and fear about the genetic testing procedure, its costs, and possible false-positive results are associated with low uptake of genetic testing. Further education regarding these specific points may enhance the use of genetic testing.     

Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial

Genetic counseling and testing, particularly for adult onset conditions, has become increasingly available over the last decade, and it is expected that this trend will continue as additional genes are identified and as such testing diffuses into mainstream clinical care. To meet the increased demand for services, it will become necessary to explore alternative avenues to traditional face-to-face genetic counseling. One such modality is the use of telephone genetic counseling (TGC), which is easy to implement and still allows for comprehensive service delivery. Although TGC has been used with increased frequency, there is a paucity of data about its effectiveness and impact on important patient outcomes. This paper provides an overview of the evolution of telephone counseling in nongenetics and genetics settings. The rationale and aims of the largest randomized clinical trial to be performed with this mode of counseling in the context of cancer susceptibility testing for mutations in the BRCA1 and BRCA2 genes are also explained. In addition, procedural aspects of the genetic counseling intervention and the novel tools developed to facilitate this process and to ensure adequate counselor training and quality assurance are described.     

Variants of uncertain clinical significance as a result of BRCA1/2 testing: impact of an ambiguous breast cancer risk message

The identification of an increasing number of variants of uncertain clinical significance (VUCS) in genetic testing for hereditary breast cancer poses serious problems for genetic counseling, because no data are available about the psychosocial impact of discussing such an unclear risk message. The current study is the first to present data on how test applicants actually understand and cope with such a result if communicated by a geneticist. We compared 10 women who received a VUCS result with 34 women who carried the deleterious mutation, 37 women who did not carry the deleterious mutation or 'true negatives,' and 160 women who received a so-called inconclusive result before and after test disclosure. Women, with whom a VUCS result was discussed, reported quite a high level of comprehension of the result. In addition, compared with the pretest measures, they did not report a higher level of perceived risk (p = 0.58) and even reported a decrease in breast cancer distress (p = 0.03). They were very comparable to women who received an inconclusive result on all post-disclosure measures. Our results suggest that discussing a VUCS result in genetic counseling does not give rise for concern.     

Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching

This study sought to investigate the impact of BRCA1 and BRCA2 mutation searching on women previously diagnosed with breast or ovarian cancer. In-depth interviews were undertaken with 30 women who had undergone a BRCA1 and BRCA2 mutation search within the clinical setting. The main reasons reported for undergoing mutation searching were: to provide genetic information for other family members, general altruism, curiosity about the aetiology of cancer, and to provide information to facilitate risk management decisions. In the main, the process of undergoing genetic testing was not experienced as anxiety provoking. The benefit of receiving a result confirming the presence of a genetic mutation was seen as an end to uncertainty, whereas the costs included difficulties in disclosing information to kin and potentially increased anxiety about one's own or others' cancer risks. Women receiving an inconclusive test result reported a range of emotional reactions. There was evidence that some women misunderstood the meaning of this result, interpreting it as definitive confirmation that a cancer-predisposing mutation was not present within the family. It is concluded that women with cancer who participate in BRCA1 and BRCA2 testing need to receive clear information about the meaning and implications of the different types of test results. Some recommendations for clinical practice are discussed.     

Information needs of mothers regarding communicating BRCA1/2 cancer genetic test results to their children

Mothers who participate in genetic testing for hereditary breast/ovarian cancer risk must decide if, when, and how to ultimately share their BRCA1 and BRCA2 (BRCA1/2) test results with their minor-age children. One of the primary aides for mothers in making this decision is cancer genetic counseling. However, counseling is limited in how well it can educate mothers about such decisions without the availability of resources that are specific to family communication and genetic testing per se. In an effort to fill this gap and identify mothers most likely to benefit from such resources, surveys were conducted with 187 mothers undergoing BRCA1/2 testing who had children 8-21 years old. Data were collected weeks after genetic testing but prior to mothers' learning of their test results; quantitative assessments of informational resource needs (i.e., speaking with previous BRCA1/2 testing participants who are parents regarding their experiences, reading educational literature about options and what to expect, speaking with a family counselor, attending a family support group, and self-nominated other resources), testing motivations, decision making vigilance, and decisional conflict regarding communicating test results to children were included. Mothers' most-to-least frequently cited information resource needs were: literature (93.4%), family counseling (85.8%), prior participants (79.0%), support groups (53.9%), and other (28.9%; e.g., pediatricians and psychologists). Seventy-eight percent of mothers were interested in accessing three or more resources. In multivariate regression analyses, testing motivations (beta = 0.35, p = 0.03), decision-making vigilance (beta = 0.16, p = 0.00), and decisional conflict (beta = 0.10, p = 0.00) were associated with mothers' need level; mothers with a greater interest in testing to learn about their children's risks, those with more vigilant decision-making styles, and those with higher decisional conflict had the greatest need. In conjunction with enhanced genetic counseling focusing on family disclosure, educational literature, and psychosocial support may promote improved outcomes.     

A computer model to simulate family history of breast/ovarian cancer in BRCA1 mutation carriers

The BRCA1 gene and its relationship to family history of breast/ovarian cancer are difficult to study in a population because of practical and ethical issues. The paucity of information on BRCA1 in the general population was a major theme in a recent review of genetic testing in Canada. We develop a simulation model to mimic genetic inheritance and cancer incidence in the family of someone with a germline BRCA1 mutation. Given someone's age and family structure, our model simulates his or her family history in three steps: (1) determine which family members have the mutation, (2) determine the ages of family members and (3) determine which family members have breast/ovarian cancer. Each step involves random variation. Some parameters in our model are estimated using local (British Columbia, Canada) population data. The breast/ovarian cancer risk associated with BRCA1 mutations is estimated using values published in the literature. An example is provided to illustrate the model's application. The model incorporates results from genetics, demography and epidemiology, but requires several additional assumptions. Research to address these assumptions is recommended.     

Impact of BRCA1 testing on women with cancer: a pilot study

We sought to understand better the impact of genetic testing and counseling in a group of women who had early breast cancer (age <50) or ovarian cancer and a family history of cancer. Thirty-five women underwent genetic counseling and genetic testing for BRCA1/2 at the University of Colorado Cancer Center, Hereditary Cancer Clinic. Psychological assessment (IES and Hopkins Symptom Checklist) was made before counseling, and 1 month after genetic test results were reported to women. A statistically significant decrease in anxiety was evidenced 1 month after results were given (p = 0.024). Decreased intrusive thoughts related to genetic testing were seen only for those testing negative (p = 0.0003). Women diagnosed with cancer less than 1 year prior to genetic testing experienced the greatest cancer-specific distress (p = 0.01) and distress related to genetic testing (p = not significant). Satisfaction with the counseling and testing process was high. In conclusion, genetic testing and counseling can occur with little anxiety and stress. However, women less than 1 year from a cancer diagnosis will experience the greatest distress associated with genetic testing and counseling. Women who are considering genetic testing and counseling close to a diagnosis of cancer may require greater psychological support.     

Attitudes toward genetic testing among the general population and relatives of patients with a severe genetic disease: a survey from Finland.

In the present study we explore the attitudes of the Finnish population toward genetic testing by conducting a questionnaire study of a stratified sample of the population as well as of family members of patients with a severe hereditary disease, aspartylglucosaminuria (AGU). The questionnaire evaluated attitudes toward gene tests in general and also respondents' preparedness to undergo gene tests for predictive testing, carrier detection, prenatal diagnosis, and selective abortion, in theoretical situations. The results of the study indicate that both the Finnish population in general and family members of AGU patients have a favorable attitude toward genetic testing. However, a commonly expressed reason against testing was that test results might lead to discrimination in employment or insurance policies. Based on the responses, we predict that future genetic testing programs will most probably be met with a high acceptance rate by the Finnish population.     

Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan

The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.     

Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.     

RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies

RAD51 is an important component of double-stranded DNA–repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5′ untranslated region (UTR) of RAD51, 135G→C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G→C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25–2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83–1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91–1.51) among heterozygotes and 3.18 (95% CI 1.39–7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G→C variant affects RAD51 splicing within the 5′ UTR. Thus, 135G→C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.     

Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2.

The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer.     

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.     

Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2

Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.     

Carbamoyl phosphate synthetase 1 deficiency in Italy: clinical and genetic findings in a heterogeneous cohort

Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder, potentially leading to lethal hyperammonemia. Based on the age of onset, there are two distinct phenotypes: neonatal and late form. The CPS1 enzyme, located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa, is encoded by the CPS1 gene. At present more than 220 clear-cut genetic lesions leading to CPS1D have been reported. As most of them are private mutations diagnosis is complicated.Here we report an overview of the main clinical findings and biochemical and molecular data of 13 CPS1D Italian patients. In two of them, one with the neonatal form and one with the late form, cadaveric auxiliary liver transplant was performed. Mutation analysis in these patients identified 17 genetic lesions, 9 of which were new confirming their “private” nature. Seven of the newly identified mutations were missense/nonsense changes. In order to study their protein level effects, we performed an in silico analysis whose results indicate that the amino acid substitutions occur at evolutionary conserved positions and affect residues necessary for enzyme stability or function.