Jill Stopfer

BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer

BACKGROUND To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families. METHODS Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer. Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations. RESULTS BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation. No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family. CONCLUSIONS Among women with breast cancer and a family history of the disease, the percentage with BRCA1 coding-region mutations is less than the 45 percent predicted by genetic-linkage analysis. These results suggest that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative.

Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care providers professional judgment based on the clinical circumstances of a client.

Application of Breast Cancer Risk Prediction Models in Clinical Practice

Breast cancer risk assessment provides an estimation of disease risk that can be used to guide management for women at all levels of risk. In addition, the likelihood that breast cancer risk is due to specific genetic susceptibility (such as BRCA1 or BRCA2 mutations) can be determined. Recent developments have reinforced the clinical importance of breast cancer risk assessment. Tamoxifen chemoprevention as well as prevention studies such as the Study of Tamoxifen and Raloxifene are available to women at increased risk of developing breast cancer. In addition, specific management strategies are now defined for BRCA1 and BRCA2 mutation carriers. Risk may be assessed as the likelihood of developing breast cancer (using risk assessment models) or as the likelihood of detecting a BRCA1 or BRCA2 mutation (using prior probability models). Each of the models has advantages and disadvantages, and all need to be interpreted in context. We review available risk assessment tools and discuss their application. As illustrated by clinical examples, optimal counseling may require the use of several models, as well as clinical judgment, to provide the most accurate and useful information to women and their families.

Anticipated Versus Actual Emotional Reactions to Disclosure of Results of Genetic Tests for Cancer Susceptibility: Findings From p53 and BRCA1 Testing Programs

PURPOSE We examined the ability of individuals undergoing genetic testing for cancer susceptibility in two structured research protocols to accurately anticipate emotional reactions to disclosure of their test result. We explored whether accuracy of emotional anticipation was associated with postdisclosure psychologic adjustment. METHODS Data from 65 individuals were analyzed; 24 members of Li-Fraumeni cancer syndrome families were tested for p53 mutations (all 24 were unaffected), and 41 subjects with hereditary breast-ovarian cancer susceptibility were tested for BRCA1 mutations (34 were unaffected and seven were affected). Subjects were from families in which a germline mutation had been previously identified. At the pretest session, subjects rated the extent to which they anticipated feeling each of six emotional states (relief, happiness, sadness, guilt, anger, and worry) after disclosure that they did or did not carry the familial mutation. After receiving their test result, they rated their feelings on the same scale of emotions for the appropriate condition. Extent of accuracy and association with psychologic distress at 6 months, as assessed with standardized measures, were evaluated. RESULTS Overall, mean levels of emotional reactions after receiving test results were not different from those anticipated before result disclosure. However, affected BRCA1 carriers experienced higher levels of anger and worry than they had anticipated. Underestimation of subsequent distress emotions related to test result was associated with a significant increase in general psychologic distress at 6 months. CONCLUSION Unaffected individuals in cancer-predisposition testing programs are generally accurate in anticipating emotional reactions to test results. However, cancer patients may underestimate their distress after disclosure of positive results and could benefit from intervention strategies.

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.

The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

The demand for BRCA1 and BRCA2 mutation screening is increasing as their identification will affect medical management. However, both the contribution of different mutation types in BRCA1 and BRCA2 and whom should be offered testing for large genomic rearrangements have not been well established in the U.S. high-risk population. We define the prevalence and spectrum of point mutations and genomic rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi Jewish descent, using a sample set representative of the U.S. genetic testing population. Two hundred fifty-one probands ascertained through the University of Pennsylvania high-risk clinic, all with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation >or=10% using the Myriad II model and a DNA sample available, were studied. Individuals without deleterious point mutations were screened for genomic rearrangements in BRCA1 and BRCA2. In the 136 non-Ashkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1 and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands had point mutations; no genomic rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic rearrangements constituted 18% of all identified BRCA mutations; estimated mutation prevalence (Myriad II model) was not predictive of their presence. Whereas these findings should be confirmed in larger sample sets, our data suggest that genomic rearrangement testing be considered in all non-Ashkenazi Jewish women with an estimated mutation prevalence >or=10%.

BRCA1 and BRCA2 Mutation Frequency in Women Evaluated in a Breast Cancer Risk Evaluation Clinic

PURPOSE To determine the prevalence of BRCA1 and BRCA2 mutations in families identified in a breast cancer risk evaluation clinic. PATIENTS AND METHODS One hundred sixty-four families seeking breast cancer risk evaluation were screened for coding region mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS Mutations were identified in 37 families (22.6%); 28 (17.1%) had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10 families (6.1%). However, 6174delT (BRCA2) was found in only one family (0.6%) despite estimates of equal frequency in the Ashkenazi population. In contrast to other series, the average age of breast cancer diagnosis was earlier in BRCA2 mutation carriers (32.1 years) than in women with BRCA1 mutations (37.6 years, P =.028). BRCA1 mutations were detected in 20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16 families with both breast and ovarian cancer in a single individual. Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in families with ovarian cancer (P =.01). Eight families had male breast cancer; one had a BRCA1 mutation and three had BRCA2 mutations. CONCLUSION BRCA1 mutations were three times more prevalent than BRCA2 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, breast and ovarian cancer in a single individual, and male breast cancer were all significantly more common in families with BRCA1 and BRCA2 mutations, but none of these factors distinguished between BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance associated with the BRCA2 mutation 6174delT was noted.

Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer

UNLABELLED BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results. SIGNIFICANCE Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2 negative patients with early onset breast cancer

Purpose:Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.Methods:We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).Results:Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.Conclusion:These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med 17 8, 630–638.

Low rates of acceptance of BRCA1 and BRCA2 test results among African American women at increased risk for hereditary breast-ovarian cancer

Purpose: This study evaluated rates of BRCA1 and BRCA2 (BRCA1/2) test result acceptance among African American women and identified determinants of test result acceptance.Methods: Acceptance of BRCA1/2 test results was evaluated among 157 African American women at high and moderate risk for having a BRCA1/2 mutation who were offered genetic testing as part of a clinical genetic counseling research program.Results: Twenty-two percent of women received BRCA1/2 test results. Test result acceptance differed between women with ≥10% prior probability of having a BRCA1/2 mutation (34%) and those who had a 5% prior probability (8%). Among women with ≥10% prior probability, test result acceptors were most likely to be married (OR = 5.29, 95% CI = 1.82, 15.38, P = 0.002) and be less certain about their risk of developing cancer (OR = 3.18, 95% CI = 1.04, 9.80, P = 0.04).Conclusion: These results demonstrate that acceptance of BRCA1/2 test results may be limited among African American women. Being married and having less certainty about ones cancer risk may motivate acceptance of BRCA1/2 test results among African American women. It may be important to emphasize the possibility that BRCA1/2 test results may not clarify cancer risks during pre-test counseling with African American women to ensure informed decision-making about testing.