Introduction

As a result of rapid advances in molecular genetics, diagnostic capabilities in clinical genetics are rapidly increasing. One of the most significant characteristics of the emerging new genetics is the extension of options for predictive gene testing from ‘classic’, and relatively rare hereditary disorders to common diseases like cancer [1–3]. This development is generally seen as a major challenge to existing health care systems and to the organisation of clinical genetic services in particular [4, 5].

In this chapter we focus on cancer genetics as a field in which the extension of options for predictive genetic testing is already clearly visible and which thus allows us to study the implications of this development at an empirical level. The basis for this chapter is a more extensive study of the introduction of DNA diagnosis in the field of cancer genetics in three European countries — Denmark, France and The Netherlands. In the following we discuss two of the cancer genetic services examined in our study, one relating to familial adenomatous polyposis (FAP), the other to hereditary breast (and/or ovarian) cancer (HB(O)C). FAP is a rare, well-defined hereditary disease predisposing to colorectal cancer. HB(O)C is linked to a more widespread genetic susceptibility to breast and ovarian cancer.

Comparison of these two cases allows us to follow the extension of predictive genetic testing from rare hereditary disorders to more widespread genetic susceptibilities within the field of cancer genetics itself. To understand the implications of this development, our analysis relates the introduction of DNA diagnosis to a context of clinical practices already established in the field. In these practices we find particular configurations of skills, institutional and professional relations, definitions of demand and guidelines, to which the introduction of DNA diagnosis adds new elements. Depending on the situation the introduction of DNA diagnosis will imply a more or less radical reconfiguration and redefinition of the elements constituting current practices in the field [6, 7]. Seen from this perspective, the two cases are clearly different. In comparing them we will see a development from relative simplicity towards greater complexity, and identify a number of technical, organisational, ethical and political issues which deserve special attention in this context.

FAP

FAP is a rare dominantly inherited syndrome leading to colon cancer. Gene carriers have a lifetime risk of nearly 100%. The syndrome is primarily characterised by the appearance of hundreds to thousands of adenomatous polyps in the colon, with a high risk of developing cancer before the age of 45. In several countries, including Denmark and The Netherlands, registries have been created in which data are collected from FAP patients and family members at risk. On the basis of these registries, national screening programmes have been established in these countries [8–10], First-degree relatives have a 50% chance of developing the disease and are usually screened every 2 years through internal inspection of the rectum. Screening usually starts at the age of 10–12 years and may be continued to the age of 60. When adenomatous polyps develop, the colon is removed in patients in order to minimise the risk of cancer.

Among medical specialists involved in the diagnosis and treatment of FAP, there is a high level of consensus about diagnostic criteria for FAP and about guidelines for screening individuals at risk and treating patients [11]. Moreover, there is generally accepted evidence showing the effectiveness of screening and prophylactic treatment in terms of lower morbidity and mortality rates [8, 9]. The establishment in several countries of registries to promote screening not only reflects agreement on these matters. It has also created a structure which has reinforced consensus about and commitment to current screening practices.

Introduction of DNA Diagnosis

In 1987, the gene for FAP, the so-called APC gene, was localised, and then identified in 1991. Thus FAP was one of the first hereditary cancers for which presymptomatic DNA diagnosis was introduced [12–17]. In the context of established screening programmes for FAP, the introduction of DNA diagnosis in the early 1990s was generally seen as an opportunity to improve the organisation of screening [10, 18]. It opened the possibility to divide a known population at risk for FAP into a carrier group which could be followed with traditional clinical screening methods, and a non-carrier group which might be excluded from risk. Individuals in the non-carrier group thus could be reassured and relieved from participation in a burdensome and protracted screening programme.

For those found to be carriers, DNA diagnosis may have additional value in decisions about prophylactic interventions, and is available in the form of prenatal diagnosis, an option which, however, seems to be rarely used [18, 19]. In other words, in the case of FAP, established practices of screening have served as a ‘niche’ in which options for DNA diagnosis were readily accepted as an improved diagnostic tool. Given a well-defined and nearly completely registered risk population, and the availability of a well-organised and effective screening programme, neither the potential demand for DNA tests nor the ethical and social implications of presymptomatic testing were perceived as especially critical issues. The introduction of DNA diagnosis for FAP has not, however, remained completely without debate. One frequently mentioned issue is that, with the advent of DNA diagnosis, members of families at risk for (rare) hereditary tumours are confronted with more complex choices, which implies that in genetic counselling, ethical questions and psychosocial implications deserve particular attention [18, 20]. In this context, it is often emphasised that the introduction of DNA diagnosis requires close cooperation between medical specialists, clinical geneticists and, possibly, patient organisations. Indeed, with DNA diagnosis now being available for most family members at risk for FAP, the question of how to co-operate in offering this service has become a point of concern among medical specialists and clinical geneticists.

Hereditary Breast (and/or Ovarian) Cancer

HB(O)C is a dominantly inherited cancer which, in the early 1990s, began to attract a great deal of attention in the field of cancer genetics. It is primarily characterised by the development of breast cancer in premenopausal women. The lifetime risk for carriers in high-risk families is about 85%. On the basis of clinical examination, it is impossible to distinguish patients with HB(O)C from sporadic cases of breast (or ovarian) cancer. Recognition of HB(O)C depends on the observation of a particular family history of the disease. Although the importance of hereditary factors in the development of breast cancer has been pointed out by geneticists for a long time, this phenomenon has been mostly neglected by the general clinician [21].

The rapidly growing interest in HB(O)C in the early 1990s has largely been the result of activities in the field of DNA analysis. As a result of an intense gene-hunting effort, two breast cancer genes — BRCA 1 and 2 — were identified in the first half of the 1990s, and are thought to account for most cases of HB(O)C [22–26]. Since breast cancer is the most frequent cause of cancer deaths among women, and 5–10% is commonly attributed to inheritance, HB(O)C is considered as one of the most common genetic diseases in the industrialised world [27]. In this context, the isolated breast cancer genes have been welcomed as the first genes for which widespread presymptomatic testing might be appropriate [28].

In other words, in the case of HB(O)C, the introduction of DNA diagnosis has followed a pattern which is different from that seen with FAP. Whereas in countries like Denmark and The Netherlands, the introduction of DNA diagnosis of FAP took place in a situation in which practices of registration and screening had already been established on a national scale, the situation in the field of HB(O)C was rather the reverse. Initiatives to organise and co-ordinate registration and screening of HB(O)C families are being undertaken particularly in response to a growing interest in DNA analysis of HB(O)C. Because of this different pattern, the implications of the introduction of DNA diagnosis of HB(O)C appear to be far more complex and profound than in the case of FAP.

Questions to Be Resolved

One issue is the technical feasibility and reliability of large-scale testing. The two BRCA genes are very large and complex and a wide array of mutations have been identified. The development of highly sensitive and specific DNA diagnostic tests will thus be difficult and costly [29, 30]. However, it would be a serious mistake to imagine that the only barriers to DNA testing of BRCA mutations are technical ones [31]. As technical problems are being overcome, DNA diagnosis will become more and more a means enabling identification of BRCA mutations in individuals without a striking family history. Thus, the question arises as to who is to be offered a test. Should a test be offered for example to all women (below a certain age or not) with newly diagnosed breast cancer in order to track down relatives who are at risk? A point of serious concern in this context is that hardly any knowledge of the effectiveness of preventive strategies for women at risk is available at the moment [32–34]. Regular screening by mammography and physical examination is one option offered to these women, prophylactic mastectomy is another (but controversial) option. Neither of these options is considered a proven effective strategy. Indeed, although the technical feasibility to perform DNA tests may improve rapidly, options for screening and prevention can be offered only in the hope that, in the long run, these options will prove to be effective. Decisionmaking about these options is further complicated by the fact that about 15% of all women carrying a mutation may not develop breast cancer and this figure may be higher for those women who prove to be carriers without having a family history of breast cancer. Indeed, the individual risk of carriers, and thus the meaning of a test result, will depend on multiple and complex interactions involving both genes and the environment in a way which is currently largely unknown [35–37].

Strategies of Introduction

Given current estimates of the carrier rate of BRCA mutations, which range from 1:200 to 1:800, it is often expected that screening for BRCA mutations is likely to become the first widespread presymptomatic genetic test that finds its way into general medical practice [38]. Thus the introduction of a presymptomatic DNA test of HB(O)C holds the promise of a radical process of change in which early diagnosis and prevention, based on extensive DNA testing, may become a new standard in health care. However, many observers also agree that the introduction of BRCA testing should proceed with caution [31, 34]. For the time being, that is, tests should be provided only in a research context. At the same time, efforts should be focused on preparing for ‘a complex series of challenges’ to the health care system [38]. The establishment of multidisciplinary cancer family clinics offering specialist counselling and the establishment of registries of individuals at risk are generally perceived as necessary steps in this direction. Current models of future (cancer) genetic services also emphasise the role of general practitioners in identifying women with a family history of breast cancer and in educating and counselling them about their personal risk factors. General practitioners will act as ‘gatekeepers’ who may refer women to more specialised (cancer) genetic services on the basis of guidelines that may be used to assess breast cancer risk in relation to family history [34].

Thus, the introduction of DNA diagnosis of HB(O)C is linked to initiatives which will further enhance awareness of familial breast cancer risks and which are likely to generate increasing demand for a DNA diagnostic test. This strategy of introduction is primarily considered as a way to increase women’s options and choices, but it has other implications as well. With the introduction of BRCA testing, clinical genetic care is going to expand from a relatively small number of families who have already been identified as being at risk — as in the case of FAP — to large numbers of individuals with no prior knowledge of their risk status. In the first situation, the DNA test is primarily perceived as a means which made it possible to exclude individuals from risk. In the latter situation, the availability of a test implies that more and more individuals will be confronted with the possibility of being at risk. A large-scale introduction of presymptomatic testing of HB(O)C in medical practice thus will not only bring new options and choices for a large group of women, but will also generate anxiety and place women in dilemmas that will be especially difficult to cope with as long as the effectiveness of available options remains to be established. At the same time, as those involved in the introduction of BRCA testing emphasise, a careful approach which involves registration of carriers, retainment of testing in a controlled research setting for as long as possible and long-term follow-up of women making different treatment choices will create the opportunity to assess in the future the effectiveness of preventive strategies [32].

Conclusion and Discussion

In our account of recent developments in cancer genetics, we have emphasised the different patterns of introduction of DNA diagnosis which emerge from the cases we have studied in this field. Indeed, when comparing the two cases, we see a reversal taking place in the way in which DNA diagnosis has been introduced in clinical practice. In the case of FAP, an infrastructure of registries and screening programmes had been established to advance care of patients and relatives at risk, before the advent of DNA analysis. Within this infrastructure, the introduction of DNA diagnosis was a relatively straightforward development. Both the implications of and the demand for DNA tests could be relatively easily anticipated. What we see here is a process of incremental change taking place without major modifications of the existing infrastructure in which services are provided. In the case of HB(O)C, on the other hand, the advent of DNA analysis has preceded the emergence of a systematic organisation for the care of patients and relatives at risk. As a result, demand for DNA diagnosis of HB(O)C is taking shape in a highly undetermined situation. Implicated in this situation is a more complex and radical process of sociotechnical change including the establishment of registries, multidisciplinary clinics, counselling, guidelines and a new role for general practitioners.

In relation to the reversal noted above, we also see a shift taking place in the meaning given to DNA diagnosis. In the case of FAP, presymptomatic DNA diagnosis is generally perceived as an improved diagnostic tool which makes it possible to divide a well-defined and known population at risk into carriers and non-carriers. However, with the extension of options for genetic testing to more common cancers, presymptomatic DNA diagnosis is given another meaning as well. It is not only accepted as a means to divide a well-known risk population into carrier and non-carrier, but is also perceived as a means which makes it possible to identify individuals at risk beyond established risk groups.

The rising prospect of large-scale genetic testing for cancer susceptibilities in the population has generated extensive debate about conditions and standards that should apply to the introduction of new options for genetic testing in society [39–41]. What is emphasised most in this debate is the need for education and counselling which should allow individuals at risk to cope with the implications of genetic testing on a well-informed basis. In the debate on DNA diagnosis for HB(O)C, for example, both leading researchers and patient representatives make clear that tests should be made available, but not without thoroughly informing women about the many unresolved questions surrounding the test [32, 42–44]. In other words, debates on the introduction of genetic testing in society are dominated by a counselling response. In terms of this counselling response, the acceptability of practices of genetic testing depends primarily on the question of whether conditions have been created which allow individuals to make an autonomous and well-informed choice. Thus dilemmas and tensions relating to the introduction of new tests in society should be managed by informing potential users as fully as possible about options, limitations and implications of testing. This involves the need for pretest education, informed consent, posttest counselling, and long-term follow-up of individuals at risk. It also involves the need for education of health professionals and for counselling facilities.

However, with different patterns of introduction of DNA diagnosis and different meanings of DNA diagnosis involved in these patterns, the notion of individual autonomy underlying the counselling response cannot simply be taken for granted. On the one hand, DNA diagnosis is introduced in clinical practices which, as in the case of FAP, involve a relatively small number of families who have already knowledge of their risk status and for whom well-established options for screening and intervention are available. The introduction of DNA diagnosis in this situation adds an option which may help to exclude individuals from risk. Indeed, in this context, it will be relatively straightforward to make this option available in a way in which individuals can make informed choices about its use. On the other hand, DNA diagnosis may in the future more often be introduced according to the pattern observed in the case of HB(O)C. Thus it becomes a means to identify genetic susceptibilities to cancer (or other adult disorders) in individuals who have no prior knowledge of their risk status. Especially when there is, as in the case of HB(O)C, little or no experience with the options available for those identified as carriers, DNA diagnosis may become a source of uncertainty and anxiety rather than a source of help or relief [45–48]. In this context, the aim of ‘informed choice’ will be very difficult to achieve as both information and choice are becoming more complex. Thus, it is only to a limited extent that the complexities of the new genetics can be solved by ‘a high dose of education and counselling’ tailored to the autonomous individual [49].

The changing pattern of introduction of DNA diagnosis and the related prospect of more extensive practices of genetic testing also raise the issue of the broader social implications of the new genetics. Predictive genetic testing and screening obviously not only concerns the individual, but also has wider implications, involving the content and use of basic medical concepts such as ‘disease’ and ‘risk’. Indeed, in the context of cancer genetics, the concept of disease is being extended to genetic ‘susceptibilities’ which may never manifest clinically.

In the case of HB(O)C, as in other hereditary cancers, a substantial minority of gene carriers may never develop manifest disease. Nevertheless, gene carriers are diagnosed as having a health problem, which does not involve symptoms of disease, but a risk factor ‘opening up a space of future illness potential’. This may lead to new and wide-ranging practices of ‘surveillance medicine’, monitoring healthy populations in order to identify and prevent possible future abnormalities [50]. Such practices obviously also involve difficult ethical dilemmas. Should the genetic status of an individual be disclosed to family members potentially at risk, or should doctors act according to traditional medical ethical standards and exclusively treat the individual patient? A host of issues on which there is no basic agreement at the moment concerning consent, confidentiality, and handling and banking of genetic information need to be reconsidered in this light.

The current debate on BRCA testing clearly reflects concern about the various issues implicated in the emerging new genetics, as is apparent from pleas to proceed with caution, and to offer BRCA tests as yet only in a research context. For the time being, researchers involved in BRCA testing seek to maintain a protected space of academic centres and co-operative trials in which answers may be sought to various technical, organisational, educational and ethical questions before tests are moved into clinical practice on a larger scale [31, 42]. This raises the question of how in the near future the results of these learning processes are going to be evaluated. Currently, the debate on BRCA testing is mainly taking place in professional circles.

In this debate, the preservation of individual autonomy serves, as we have seen, as the gold standard in assessing the acceptability of the introduction of new options for genetic testing in society. But, as genetic tests for cancer susceptibilities begin to move into clinical practice on a larger scale, such tests will gradually enter into a grey zone between small-scale testing in high-risk families on the one hand and large-scale population screening on the other. Thus, there is a growing need for evaluation of these options, based on a broad set of standards, including those relating to population screening. Indeed, both internationally and nationally, general guidelines have been recently proposed with regard to population-based genetic screening [51, 52], but the implications of such guidelines in relation to a field like cancer genetics have yet to be discussed. In other words, what we need in reaction to the emerging new genetic in society is not only an adequate counselling response, based on a well-organised and high-quality system of genetics services. We also need an adequate regulatory response, based on a well-organised, high-quality system of assessment, evaluation and debate, involving the perspectives of a variety of actors, such as professionals, (potential) users, social scientists, ethicists and policy makers.