Hereditary breast/ovarian cancer – pitfalls in genetic counseling

Genetic counseling and risk assessment, given to women with a family history of breast/ovarian cancer, are regularly based on pedigree analysis. In the Ashkenazi Jewish population, hereditary breast/ovarian cancer is mainly attributed to three founder mutations, namely, 185delAG, 5382insC, and 6174delT, in BRCA1/2 genes. The overall frequency of these mutations, in the Jewish Ashkenazi population, is as high as 2.5%. Based on clinical and family history data, the results of BRCA molecular testing, in Ashkenazi individuals at risk, are appropriately anticipated in most cases. Here we report on five families, in which the segregation of BRCA1/2 mutations, in affected and unaffected family members, was unexpected, emphasizing the need to test, for founder mutations, every Ashkenazi individual at risk, irrespective of the genotype of affected family members. Ultimately, risk assessments and recommendations, in Ashkenazi women, should be invariably based on the results of genetic testing.     

Active approach for breast cancer genetic counseling during radiotherapy: long‐term psychosocial and medical impact

Genetic counseling and DNA testing (GCT) for breast cancer is increasingly being actively offered to newly diagnosed patients. Little is known about the consequences of such an approach. Therefore, the long‐term psychosocial and medical impact of referring breast cancer patients for GCT during an early phase of treatment was studied. A group of 112 breast cancer patients who had been actively offered GCT during adjuvant radiotherapy 7–14 years earlier, returned a self‐report questionnaire. We compared their experiences with a group of 127 breast cancer patients who had not met the criteria for GCT. In total, 239 women participated in this long‐term follow‐up study (72% response rate). Nearly 75% of them had received regular mammography surveillance in the past 3 years. Preventive surgery was reported more often in the counseling group (specifically in the BRCA1/2 mutation carriers). Like the comparative group, only a minority of patients who had received GCT were experiencing high levels of depression (5%) or psychological distress (14%). Breast cancer patients can be actively approached and referred for GCT at the beginning of their radiotherapy without a threat to psychological functioning in the long term.     

Factors influencing intrafamilial communication of hereditary breast and ovarian cancer genetic information

What factors influence intrafamilial communication of hereditary breast and ovarian cancer (HBOC) genetic risk information? Such information can have health implications for individuals who undergo genetic testing, but it can also have implications for their blood relatives. This literature review adopts an ecological model to summarize factors at the individual, familial, and community levels, as well as cross cutting factors relating to the complexity of HBOC genetic information and responsibilities that this information can give rise to. These factors are complex and may result in conflicting senses of responsibility. Faced with the task of communicating HBOC genetic information, the response may be to attempt to balance the potential negative impact of the information on the well-being of the informee (eg, can s/he handle this information?) against the potential health benefit that the knowledge could result in. This balancing represents an effort to reconcile conflicting approaches to protecting family members, and is a moral dilemma. This review sheds light on the factors that contribute to resolve this dilemma.     

Disclosure to the family of breast/ovarian cancer genetic test results: Patient's willingness and associated factors

Informed probands are key actors for disclosing genetic information to their relatives when a mutation has been identified in the family. The objectives were to study women's attitudes towards the family disclosure of positive breast cancer genetic testing results and to determine the predictive factors of the diffusion patterns observed. A national multi‐center cross‐sectional survey was carried out at five French cancer genetic clinics during a 1‐year period. Self‐administered questionnaires were completed after the consultation by 84.5% (398/471) of women attending breast cancer genetic clinics for the first time. Among the 383 respondents who had at least one living first‐degree relative to inform, 8.6% would inform none, 33.2% would inform at least one of them, and 58.2% would inform all of them. The sibship would be the most frequently informed blood relatives, sisters in 86.9% and brothers in 79% compared with mother in 71.4%, children in 70.4%, and father in 64.9%. Women of the family would be more frequently informed than men (P < 0.05). After multivariate adjustment, age, the fact to be affected by cancer, the number of daughters, and the emotional disturbance due to cancer in a close relationship were the main determinants (P < 0.05) of the diffusion patterns observed. The first step of the relatives' attendance to genetic counseling and the proband's willingness to disclose breast cancer genetic tests results was high in this study and was clearly dependent on the women's personal and emotional characteristics. Am. J. Med. Genet. 94:13–18, 2000. © 2000 Wiley‐Liss, Inc.     

'Indirect' BRCA1/2 testing: a useful approach in hereditary breast and ovarian cancer families without a living affected relative

We report an approach for BRCA1/2 testing whereby genetic testing can be offered to families at high risk of hereditary breast and ovarian cancer but where no DNA from affected relatives is available. By testing two or more unaffected relatives at 50% risk of being heterozygous for a potential BRCA1/2 mutation, there is a chance of up to 99% of finding a mutation that would have been detectable in an affected individual from the same family. The overall likelihood of identifying a mutation is dependent on the family history, and therefore 'indirect' testing would be most applicable for families with a very high risk of carrying a BRCA1/2 mutation. Using this approach also requires balancing issues of testing resource limitations, family dynamics and adequate preparation of unaffected persons for a positive test, with the advantages of targeting screening and prophylactic surgery.     

Communication and technology in genetic counseling for familial cancer

When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at‐risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or ‘reach’ of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet‐based processes for communication between investigators and relatives.     

Comparing family members' motivations and attitudes towards genetic testing for hereditary breast and ovarian cancer: a qualitative analysis

Genetic testing for hereditary breast and ovarian cancer reveals significant risk information regarding one''s chances of developing cancer that has potential implications for patients and their families. This study reports on the motivations and attitudes of index patients and their relatives towards genetic testing for hereditary breast and ovarian cancer. In total, 10 female index patients and 20 of their relatives were interviewed regarding their experiences of communicating genetic information within their families, and their motivations and attitudes towards genetic testing. The analysis found two types of ‘family groups'': groups strongly committed to genetic testing and groups uncertain about testing. Within committed family groups, index patients and their relatives felt obliged to be tested for others, leading some relatives to be tested without having fully thought through their decision or the implications of knowing their mutation status. These family groups also described considerations in relation to the value of testing for themselves. In family groups uncertain about testing, relatives had not attended for predictive testing, had postponed decision making until some point in the future or had expressed ambivalence about the value of testing for themselves. Results suggest the value of explicitly acknowledging motivations for genetic testing within the context of family obligations, relationships and communication, and the possible value of involving family members in genetic counselling and decision making from a family''s first contact with genetic services.     

遗传性乳腺癌-卵巢癌综合征中BRCA1/2的表达

目的检测BRCA1/2在遗传性乳腺癌-卵巢癌综合征(HBOC)患者所患卵巢癌和散发性卵巢癌组织中蛋白表达的差异,探讨其在HBOC患者卵巢癌发病中的意义。方法收集我院妇科2001年1月至2010年10月HBOC患者卵巢癌40例和散发性卵巢癌20例(对照组)的石蜡组织标本,行免疫组化检测BRCA蛋白的表达;收集2011年1月-2013年12月HBOC卵巢癌11例和同期散发性卵巢癌10例(对照组)的新鲜标本,行Western Blot检测BRCA蛋白的表达。结果免疫组化结果显示HBOC组BRCA2蛋白阳性产物OD值(0.64±0.013)明显高于对照组(0.24±0.002,0.05)。Western blot结果显示HBOC组BRCA2蛋白OD值(0.68±0.02)明显高于对照组(0.26±0.01,0.05)。但是,对于BRCA1没有明显区别。结论 BRCA2蛋白在HBOC患者卵巢癌组织过表达提示BRCA2可能与HBOC的发病相关。     

Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families

To meet the increasing demand for BRCA1 and BRCA2 mutation analysis, a robust system for selecting families who have a higher chance of a mutation has become important. Several models have been developed to help predict which samples are more likely to be mutation positive than others. We have undertaken a complete BRCA1 and BRCA2 mutation analysis in 267 Danish families with high-risk family history. We found deleterious mutations in 28% (76) of the families, 68% (52) of those in BRCA1 and 32% (24) in BRCA2. We compared our results with two popular manual models developed to estimate the chance of a positive result. One is the recently published Manchester model and the other is the Frank 2 model updated by Myriad Genetic Laboratories, Inc. Neither of the models would have suggested screening all mutation-positive samples. The Manchester model would have suggested screening 124 of the families in the cohort, thereby detecting 54 of 76 mutations (sensitivity 71%; specificity 63%), whereas the Frank 2/Myriad model would have found 60 of 76 mutations by screening 169 samples if a 10% likelihood was adapted (sensitivity 79%; specificity 43%). The updated Manchester model suggested screening 172 families whereby 64 mutations would have been detected (sensitivity 84%; specificity 44%). We conclude that although both models would have reduced the number of samples screened significantly, up to 28% of the mutations would not have been found by applying these models to this Danish cohort of families. This raises the question whether models designed for specific populations can be used in a wider setting.     

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute-Comprehensive Cancer Center

Germline mutations (eg, BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.     

Frequency of three BRCA1 gene founder mutations in breast/ovarian cancer families from the Pomerania-Kujawy region of Poland

A group of 63 families from the Pomerania-Kujawy region were analyzed for three BRCA1 gene Polish founder mutations, 5382insC, 300T>G, and 4153delA, because of breast (BrCa) and/or ovarian cancer (OvCa) history. The analysis was carried out by multiplex polymerase chain reaction method. BRCA1 mutation was revealed in nine (14%) families: in three (33%) of hereditary BrCa and OvCa families, in three (8%) of hereditary BrCa families, and in three (21%) of hereditary OvCa families. According to risk criteria, it was revealed in 45% of high-risk families with more than three cancers, 13% of moderate-risk families with two cancers, and 8% of families with sporadic OvCa. In six families, the mutation was found in a proband with BrCa or OvCa and in three families, the mutation was found in a healthy proband, first-degree relative of a patient deceased of BrCa or OvCa. 5382insC frameshift mutation accounted for 67% and 300T>G missense mutation for 33% of all identified familial mutations. 4153delA frameshift mutation was not found in analyzed sample of families. 5382insC mutation was found in 9% and 300T>G in 5% of all investigated families, and in 27 and 18%, respectively, of high-risk families. This underlines the importance of applying strict inclusion criteria to analyze mutation frequency in hereditary BrCa/OvCa families.     

High frequency and allele‐specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus

Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T. High frequency and allele‐specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Breast cancer and ovarian cancer are common malignancies in Belarus accounting for about 3500 and 800 new cases per year, respectively. For breast cancer, the rates and age of onset appear to vary significantly in regions differentially affected by the Chernobyl accident. We assessed the frequency and distribution of three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two hospital‐based series of 1945 unselected breast cancer patients and of 201 unselected ovarian cancer patients from Belarus as well as in 1019 healthy control females from the same population. Any of these mutations were identified in 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and 0.5% of the controls. In the breast cancer patients, BRCA1 mutations were strongly associated with earlier age at diagnosis, with oestrogen receptor (ER) negative tumours and with a first‐degree family history of breast cancer, although only 35% of the identified BRCA1 mutation carriers had such a family history. There were no marked differences in the regional distribution of BRCA1 mutations, so that the significant differences in age at diagnosis and family history of breast cancer patients from areas afflicted by the Chernobyl accident could not be explained by BRCA1. We next observed a higher impact and a shifted mutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer patients where the three founder mutations accounted for 26.4% (53/201). While the Cys61Gly mutation appeared underrepresented in ovarian cancer as compared with breast cancer cases from the same population (p = 0.01), the 4153delA mutation made a higher contribution to ovarian cancer than to breast cancer (p < 0.01). BRCA1 mutations were significantly enriched among ovarian cancer cases with a first‐degree family history of breast or ovarian cancer, whereas the median age at ovarian cancer diagnosis was not different between mutation carriers and non‐carriers. Taken together, these results identify three BRCA1 founder mutations as key components of inherited breast and ovarian cancer susceptibility in Belarus and might have implications for cancer prevention, treatment and genetic counselling in this population.     

Psychological and social determinants of women's decisions to undergo genetic counseling and testing for breast cancer

This study examined the demand for breast cancer genetic testing and counseling among Canadian women diagnosed with breast cancer under the age of 50, together with some of the factors predicting both their intentions to be tested and the degree to which they act on their intentions. Participants were 110 women under the age of 50 and comprised of two groups: 1) women diagnosed with breast cancer (BC, n = 60): and 2) an index group of unaffected women from the general population (GP, n = 50). All participants completed a survey that addressed family history of breast and other cancers, demographic variables, knowledge and attitudes about breast cancer, and genetic testing. Members of the BC group were offered genetic counseling and testing for BRCA1 and BRCA2 free of charge. Overall, 60% of participants indicated they would like the test, and 40% either did not want it or were uncertain. Seventy-two percent of women in the BC group wanted to be tested. Of these, only 49% had actually contacted the genetic counselor about testing at follow-up 3-15 months later. Intention to be tested was associated with presence of breast cancer, greater perceived benefits of testing, fewer perceived 'costs' of testing, and higher levels of concern about the risk of relatives developing breast cancer. Actual arranging to meet with the genetic counselor among women in the BC group was associated with fewer perceived costs of having the test. Results suggest a moderate level of interest in gene testing, though intention to be tested may not translate into actual uptake. Women who do choose to have the test may believe the potential 'costs' of using this new genetic technology to be relatively few. This has implications for genetic counselors in terms of providing balanced and complete information to women considering genetic testing for breast cancer susceptibility.     

A population‐based study of hereditary non‐polyposis colorectal cancer: evidence of pathologic and genetic heterogeneity

Hereditary non‐polyposis colorectal cancer (HNPCC) may be the result of Lynch syndrome (LS) caused by mutations in mismatch repair (MMR) genes, a syndrome of unknown etiology called familial colorectal cancer type‐X (FCCTX), or familial serrated neoplasia associated with the colorectal cancer (CRC) somatic BRAF mutation. To determine the cause of HNPCC in the founder population of the island of Newfoundland, we studied 37 families with LS and 29 families without LS who fulfilled the Amsterdam I criteria. In non‐LS, four index CRCs were BRAF mutation positive, one of which was microsatellite instable. Geographic clustering of LS families caused by three different founder mutations in MSH2 was observed. Nine unique MMR mutations in four MMR genes were identified in single families distributed in different geographic isolates. The geographic distribution of non‐LS was similar to LS. The coefficient of relatedness using genotype data was significantly higher for non‐LS than for all CRC. Extensive genealogic investigation failed to connect non‐LS families and in some clusters pathologic CRC heterogeneity was observed. We conclude that non‐LS HNPCC may be a heterogeneous disorder with different pathogenic pathways, and that the geographic distribution is consistent with multiple different mutations in unknown CRC susceptibility gene(s).     

Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe

Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS). Young onset breast cancer (BC), triple negative phenotype, or bilateral BC are considered as criteria for genetic testing in all, with differences in age limits. Testing of invasive epithelial non-mucinous ovarian cancer is also universally accepted. While breast magnetic resonance imaging (MRI) is consistently recommended in high-risk individuals, age of onset for mammograms differ between 30 and 40 years. Risk-reducing mastectomy is commonly offered as an option, while risk-reducing salpingo-oophorectomy is universally recommended. The largest differences are observed with respect to ovarian surveillance prior to risk-reducing salpingo-oophorectomy and in breast surveillance for carriers of non-BRCA1/2 genes. These differences in national guidelines reflect the variations in clinical consensus that may be reached in the absence of consistent evidence for some recommendations.     

Genetic testing for breast cancer susceptibility: Awareness and interest among women in the general population

Previous research has suggested that demand for genetic testing for breast cancer susceptibility may be quite high, even among those at relatively low risk of carrying a mutation. This study examined the extent to which a group of female HMO enrollees were aware of the discovery of the BRCA1 gene and, without having received detailed information about the test, whether they would be interested in being tested to find out if they have the gene. Factors associated with awareness of and interest in testing were also examined. Four hundred seventy-three women age 50 and over, almost all of whom did not have an increased risk of breast cancer based on family history, were surveyed by telephone. Fifty-one percent of respondents had heard about the discovery of a breast cancer gene. In logistic regression analysis, women who described themselves as comfortable financially, had at least some college education, and were premenopausal were more likely to have heard of the gene discovery than women who were not comfortable financially, had no more than a high school education, and were postmenopausal. Sixty-nine percent of the respondents said that they would be interested in being tested to find out if they had a breast cancer gene. Women who were younger than 60, white, believed their family would benefit if they had a mammogram, and believed that regular mammograms give them a feeling of control over their health, were more likely to be interested in testing than those who were 60 or older, African-American or other, and did not believe that their family would benefit if they had a mammogram or that mammograms give them a feeling of control over their health. These findings have implications for education and counseling. Women who express an interest in being tested must be made fully aware of the limitations and possible consequences of testing. Special efforts may be needed to make information about testing available to women who have low levels of education. Am. J. Med. Genet. 68:43–49, 1997 © 1997 Wiley-Liss, Inc.     

BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin

Infante M, Durán M, Acedo A, Pérez-Cabornero L, Sanz DJ, García-González M, Beristain E, Esteban-Cardeñosa E, de la Hoya M, Teulé A, Vega A, Tejada M-I, Lastra E, Miner C, Velasco EA. BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin.
The distribution of BRCA1 and BRCA2 germ line mutations in breast/ovarian cancer families varies among different populations, which typically present a wide spectrum of unique mutations. Splicing mutation 5272-1G>A of BRCA1 and frameshift mutation 5374delTATG of BRCA2 are highly prevalent mutations in Castilla-León (Spain), accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively. To test the presence of founder effects, 9 Spanish 5272-1G>A and 13 5374delTATG families were genotyped with polymorphic markers linked to BRCA1 or BRCA2 . All the 5272-1G>A families shared a common haplotype in eight markers (1.1 Mb region) and the mutation age was estimated in 15 generations (∼380 years). A conserved haplotype associated to 5374delTATG was observed in four markers (0.82 Mb). The mutation occurred approximately 48 generations ago (∼1200 years). Each mutation likely arose from a common ancestor that could be traced to a small area of Castilla-León and expanded to other Spanish regions. They can have a significant impact on the clinical management of asymptomatic carriers as well as on the genetic screening strategy to be followed in populations with Spanish ancestries.     

Perceptions of genetic counseling services in direct‐to‐consumer personal genomic testing

To describe consumers' perceptions of genetic counseling services in the context of direct‐to‐consumer personal genomic testing is the purpose of this research. Utilizing data from the Scripps Genomic Health Initiative, we assessed direct‐to‐consumer genomic test consumers' utilization and perceptions of genetic counseling services. At long‐term follow‐up, approximately 14 months post‐testing, participants were asked to respond to several items gauging their interactions, if any, with a Navigenics genetic counselor, and their perceptions of those interactions. Out of 1325 individuals who completed long‐term follow‐up, 187 (14.1%) indicated that they had spoken with a genetic counselor. The most commonly given reason for not utilizing the counseling service was a lack of need due to the perception of already understanding one's results (55.6%). The most common reasons for utilizing the service included wanting to take advantage of a free service (43.9%) and wanting more information on risk calculations (42.2%). Among those who utilized the service, a large fraction reported that counseling improved their understanding of their results (54.5%) and genetics in general (43.9%). A relatively small proportion of participants utilized genetic counseling after direct‐to‐consumer personal genomic testing. Among those individuals who did utilize the service, however, a large fraction perceived it to be informative, and thus presumably beneficial.     

Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent

The BRCAPRO, Couch, Myriad I and II, Ontario Family History Assessment Tool (FHAT), and Manchester models have been used to predict BRCA1 or BRCA2 mutation carrier status of women at high risk for developing the heritable form of breast and ovarian cancers. We have evaluated these models for their accuracy in classifying 224 French Canadian families with at least three cases of breast cancer (diagnosed before the age of 65 years), ovarian cancer, or male breast cancer where mutation status was known for an index affected case used to assess the model. This series includes 44 BRCA1 and 52 BRCA2 mutation-positive families. Using receiver operator characteristics analyses, the C-statistics were found to be 0.81, 0.80, 0.79, and 0.74 for the BRCAPRO, FHAT, Manchester, and Myriad II models, respectively, when incorporating both BRCA1 and BRCA2 mutation carrier predictions. For the BRCAPRO model, 75% scored greater than a 0.43 probability in the mutation-positive group and 75% scored less than 0.50 in the mutation-negative group. Only 38 of 128 (30%) mutation-negative group had a probability greater than 0.43 with the BRCAPRO model. While all models were highly predictive of carrier status, the BRCAPRO model was the most accurate where a cut-off of 10% would have eliminated 60 of 128 (47%) mutation-negative families for genetic testing and only miss 10 of 96 (10%) mutation-positive families. A review of the cancer phenotypes with high BRCAPRO probabilities showed that significantly more metachronous bilateral breast cancer cases occurred in BRCA1/2 mutation carrier families in comparison to mutation-negative families, a feature which is not discriminated in the BRCAPRO model.