Predictive testing for BRCA1 and 2 mutations: a male contribution

P. A. Daly1,+, C. Nolan1, A. Green2, W. Ormiston1, N. Cody2, T. McDevitt2, B. O’hIci2, D. Byrne1, E. McDermott3, D. N. Carney4, N. O’Higgins3 and D. E. Barton2

1 Department of Haematology and Oncology, St James’s Hospital and Trinity College, Dublin; 2 National Centre for Medical Genetics and University College, Dublin; 3 St Vincent’s University Hospital and University College, Dublin; 4 Mater Misericordiae University Hospital and University College, Dublin, Ireland

Received 8 July 2002; revised 6 November 2002; accepted 28 November 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently.

Patients and methods:

Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures.

Results:

Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56.

Conclusions:

Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process.

Key words: BRCA1, BRCA2, cancer genetics, predictive testing in men


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
With the cloning of the BRCA1 and 2 genes in 1994 and 1995 [1, 2] widespread interest in genetic testing developed among women at risk of harbouring a disease-associated mutation. On detection of such a mutation in an affected family member, others within the family can opt for predictive testing. There remains, however, a large measure of uncertainty as to how this information is best used to guide decision making and many scientific and psychosocial issues remain unclear [3]. Cancer risks cannot be quantified with total precision and the efficacy of various interventions, screening, prophylactic surgery and chemoprevention remains somewhat unclear even when a deleterious mutation has been identified [46]. Some recent studies have improved our knowledge of the efficacy of prophylactic mastectomy [7] prophylactic oophorectomy [810], tamoxifen use [11] and screening [8] in this setting.

Women are usually motivated by personal considerations when opting for predictive testing for BRCA1 and 2 mutations and they can consider the treatment options with greater certainty if they are proven mutation carriers. Men can equally be mutation carriers but the implications for them are less clear. In a recent report of 10 000 individuals having gene sequence analysis of BRCA1 and 2 to detect germline mutations, 76 male participants with breast cancer were described [12]. Among the 76, eight had mutations in BRCA1 and 14 in BRCA2. This is a somewhat surprising finding, as hitherto male breast cancer had been mainly associated with BRCA2 and men harbouring a deleterious mutation were thought to have a life-time risk of 6% [13]. There is an increased risk of other cancers such as prostate cancer, laryngeal cancer, pancreatic cancer, ocular melanoma and adult leukaemia for those who carry BRCA1 and 2 mutations [1316]. The main emphasis, however, remains on breast and ovarian cancer in female family members. Because of this, predictive testing among males is less focused on personal health issues and is mainly undertaken towards clarifying matters for other family members, particularly daughters [17, 18]. The report on 10 000 individuals having gene sequence analysis [12] contained no unaffected males, although many unaffected females were tested. Liede et al. [19] have evaluated the needs and experiences of 59 male carriers of BRCA1 and 2 mutations and have highlighted the potential pressures which might influence men to request predictive testing, their difficulties in establishing appropriate surveillance programmes and a general lack of information regarding the particular experiences of men in this context. To date, within our research programme, 26 men from 10 families have undergone predictive testing for mutations in BRCA1 and 2. We report the process and outcome for this group.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study subjects
Between 1996 and 2002, 26 men from 10 families had predictive testing for mutations in BRCA1 or 2 in the context of research studies in the Irish setting. Deleterious mutations had previously been identified in female relatives of 25 men and a deleterious mutation was found in one man as part of the research study. These mutations were 1294 del 40, E143X and Q1414X in BRCA1 and S2984X, 5445 del 7 and 6503 del TT in BRCA2. The men had been informed of the finding of a mutation and of the potential implications for them and their family members. From information provided by other family members we know that the existence of a mutation and the availability of predictive testing was communicated to an additional 17 men who chose not to enter the process. Before predictive testing, the men were seen individually in all cases and collectively within families in some cases for pretest counselling by a consultant medical geneticist or medical oncologist and a cancer genetics nurse. They were all seen in person by the same personnel when hearing the test result and post-test counselling was provided according to need. All gave written, informed consent before testing was undertaken and the study had the approval of ethics committees at the participating institutions.

Analysis of BRCA1 and 2 mutations
Mutations were initially detected by the protein truncation test [20]. All six mutations were considered pathogenic as they result in premature truncation of the BRCA1 and 2 proteins and were associated with disease in affected relatives. Specific polymerase chain reaction-based tests were developed for each mutation for use in predictive testing.

Motivation for testing
During counselling sessions the motivation for predictive testing was explored with each man and the potential benefits as perceived by him were probed as well as potential adverse effects. Motivating factors were determined in terms of: (i) self-health; (ii) concern for children; (iii) pleasing their spouses; and (iv) just knowing.

An important part of the discussion was the prospect of communicating the result of predictive testing to ‘at risk’ individuals within the family.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Subjects and their motivation
The 26 men who had predictive testing represented 60% of those men within the families who had received information regarding this option. The general characteristics of the group are listed in Table 1. The age range was 28–82 years, median 55. Five men had developed cancer before entering the process. Three of these were from the same family; one had ureteric and prostate cancer, one had prostate cancer and the third invasive squamous cell skin cancer at two sites. The other men had prostate cancer and breast cancer. All expressed self-health concerns in seeking testing, but four of the five who had children were mainly concerned about their children’s welfare.


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Table 1. Characteristics of male participants
 
Three of the men did not have children and two of these were single and celibate. One of the latter had developed skin cancer but he and his brother mainly wished to know their carrier status towards fostering family solidarity and supporting others through the process. The third young man felt he needed to know his status towards assisting him in making decisions and especially one regarding having children.

The 23 men who had offspring all cited concern for their children as the main motivation. Apart from the four who had children and who had already developed cancer, they did not express significant self-health concerns. None of the 24 men with spouses felt that pleasing those spouses was their motivation. Nobody felt that just knowing their status was a sufficient motivation. The two older, childless men were intent on supporting other family members by seeking information regarding their own carrier status.

Family details
Twenty-four men had spouses and 23 had 89 offspring. Family size ranged from one child to 11, median three. Fifty of the offspring were female and 39 male (Table 1).

Test results
Eighteen of the 26 had positive tests and eight tested negative (Figure 1). The negative results meant that inheritance risk was removed from 33 offspring, 18 female and 15 male. Risk remained for the 32 female and 24 male offspring of the 18 mutation carriers. Two men with prostate cancer proved to be phenocopies, one had developed the disease at the age of 57 years and the other at age 60. In another family, despite dying of breast cancer with an age of onset of 53 years, the mother of two daughters with bilateral breast cancer and ovarian cancer was also a phenocopy and the 82-year-old father transmitted the mutation in BRCA1.



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Figure 1. Outcome of predictive testing (n = 26).

 
Imparting of information
Despite fully participating in the pretest process, three brothers steadfastly refused to impart knowledge of their positive results to their offspring, seven female and three male. One man who tested positive expressed regret at having gone through the process and refused further counselling. He allowed his wife to convey the result of his predictive test to their children, two female and one male. The spouse of one man had an adverse psychological reaction to the disclosure of his positive result. However, the information was conveyed to ‘at risk’ individuals within his family. All other outcomes were freely communicated within families.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The experience described with this cohort of males opting for predictive testing adds to the list of complex themes which arise in the context of this process. On a positive note, the study confirms that men recognise that they can carry BRCA1 and 2 mutations and transmit them to their offspring. They appear willing to enter the process of predictive testing even though the outcome may not be immediately relevant to their own health and well-being. Concerns about transmitting increased cancer risk to daughters appeared to be the major motivating factor and a desire to express solidarity with other family members was also present. This was the case for two single men, one a celibate priest, who participated. They appeared to understand basic genetic principles and were also concerned about transmission to and through their male children. These reasons for seeking predictive testing are in line with previous studies in women [2123] and in men [19].

The capacity to clarify the carrier status of multiple offspring by testing a relevant parent, male or female, is important for the health services as well as for individual family members. Those testing negative and their offspring can be reassured that they cannot transmit or inherit the mutation. Female children in particular can, therefore, be reassured that their risk of developing cancer is similar to that of the general population and there is no need for them to consider options such as more intensive screening, prophylactic surgery or chemoprevention. The effort to reduce cancer deaths can thereby be appropriately focused on the children of those with positive tests. Such children can opt for predictive testing at an appropriate age and base their decisions on the outcome or they can consider themselves at high risk of developing cancer and participate in relevant programmes to attempt to reduce their risk. In general it is best to base such major decisions on the outcome of predictive testing where this is possible and where no major contraindications exist. Legal and social issues are the dominant considerations in this regard with the potential for discrimination in areas such as insurance and employment.

It is a concern that four of the 26 men experienced difficulty having tested positive. This is reflected in their incapacity to proceed as agreed and to impart the result to their offspring. For three brothers this crisis appeared to relate to the death of their mother from cancer at a critical stage in their childhood and their experience of other cancer deaths within their family. They took the attitude, once informed of their positive results, that knowledge of this, if imparted to their female children, would only induce stress which would be likely to hasten the onset of cancer. They remain confirmed of this view and are now supported in it by their wives. This has clear, undesirable implications for their children. The three brothers were not accompanied by their wives during genetic counselling. In another family one man’s spouse had difficulty accepting his positive result. She was not present during pretest counselling and this is thought to have contributed to her adverse reaction. These findings highlight the importance of including partners in the counselling process.

The fourth man expressed regret at participating once he learned of his positive test result. His mother too had died when he was a teenager and he had seen two of his sisters die of breast cancer. None of his brothers reacted in this way, although three of them had already developed cancer. His wife felt that the trauma related to cancer within his family was the reason for his upset. He stated that he was concerned that the result might affect his business interests. He did allow his wife to communicate the results to his children but she expressed a fear that the upset surrounding his predictive test might be a barrier to their future participation in risk-reduction initiatives.

There is a suggestion that pressure from a wife or other family members may have led some men to enter the process, and others too [19] have expressed concern in this regard. This may have been the case more broadly but a negative test, in particular, may have hidden this once the test result was known. These findings confirm that subgroups can underestimate their distress at disclosure of a positive result, as has been shown for women with a positive personal history of breast cancer as well as men at risk of being mutation carriers [18, 24]. The findings also highlight the need for a highly structured protocol of care, which incorporates expert counselling and support towards improving the psychological well-being of those undergoing genetic testing [24, 25]. Men have particular needs in this regard and specific protocols need to be developed in the context of predictive testing, surveillance and general cancer care [19].

One man indicated that the test result would influence his decision regarding having children. He tested positive and said he intended not to have a family. Clearly this was a personal choice but one that is open to debate. He has seen many close relatives develop and die from cancer and this must have influenced his decision.

Determining the parental origin of an identified mutation is important and of value particularly to the extended family. Two revealing outcomes emerged from this study. One related to the subjects with prostate cancer at 57 and 60 years. Both were from families where a proven BRCA1 mutation exists. They proved to be phenocopies, a reassuring outcome for their seven offspring. In another case a BRCA1 mutation had been identified in a young woman aged 39 years, with bilateral breast cancer. Her sister, by age 45, had developed bilateral breast and ovarian cancers. Just before her death from breast cancer, diagnosed at 53, their mother had tested negative for the BRCA1 mutation. The father was then identified as the parent of origin. This had clear implications for the extended paternal lineage once the information was imparted.

Pretest and post-test counselling is a time-consuming exercise in the context of clinical genetics and a relatively new component of cancer care. Both clinical genetics and oncology services remain underdeveloped in many European countries. The needs of those with a possibly increased inherited risk of cancer must be considered in the development of services. The experience with this cohort of 26 men with 24 spouses and 89 children highlights the complexity of the process and the work involved. Men, as well as women must be participants in unravelling cancer genetics issues. This area now needs to be fully supported within the mainstream of medical care, while being the subject of on-going research and audit.


    Acknowledgements
 
This study was funded by the Health Research Board, Ireland.


    Footnotes
 
+ Correspondence to: Professor P. A. Daly, HOPE Directorate, St James’s Hospital, Dublin 8, Ireland. Tel: +353-1-4162164; Fax: +353-1-4103428; E-mail: pdaly{at}stjames.ie Back


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 Introduction
 Patients and methods
 Results
 Discussion
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