I am very pleased to have been asked to write the Foreword to this important and timely book. As Chair of the Human Genetics Commission I am only too aware of the impact of familial breast cancer, or indeed many other familial cancers, on our work.

The issues raised by an increased understanding of the genetics of breast cancer have formed part of our thinking on how to deal with issues of privacy and confidentiality, such as the provision of genetic information to family members. Moving beyond the clinical, we have also considered some of the issues concerning patenting of gene sequences, taking as one example the continuing debate about the BRCA1 and BRCA2 gene patents. In addition, we have considered familial breast cancer as one of several conditions on the radar of insurance companies before underwriting life or health insurance.

I am therefore pleased to see that a fellow member of the Human Genetics Commission, Professor Patrick Morrison, and his colleagues have so carefully and clearly set out many of these important issues in this book. I hope that it will be widely read by clinicians and those responsible for policy in all of these areas and that they will take note of the important messages herein.

There is a rapidly increasing appreciation of the importance of familial cancer susceptibility and the potential for the identification and surveillance of at-risk individuals with a strong family history of cancer to reduce morbidity and mortality from the disease.

The development of healthcare strategies for the identification of individuals with a risk of familial cancer susceptibility, for stratifying their risk and for developing agreed surveillance protocols is dependent on many factors, which will differ in different countries. This service development requires a partnership between clinicians, service providers and purchasers, and healthcare planners. Evaluation of the cost-effectiveness of such a service is vital. In many countries this service was initially funded by research charities. However, funding is now being transferred to the public sector as the research questions are answered.

There is a good deal of inequality in the sophistication of cancer genetics services in different countries, and those countries initiating service development should be enabled to benefit from the experience of others with established services.

This type of service has several levels; (1) there is a need for ascertainment and prioritization of referrals at the primary care level; (2) there should be an agreed management care pathway for the surveillance of individuals at different degrees of estimated moderate risk; and (3) there should be provision for genetic counselling and testing of individuals from families in which there is a high chance of an inherited susceptibility to specific cancers.

Most countries now have services for familial cancer genetics, but these vary considerably (Harris, 1998; Hodgson et al., 2000). There are, broadly, three potential approaches for developing a clinical service in response to the growing evidence of the links between inherited genetic factors and the risks of developing breast and ovarian cancers:

1. An ad hoc system of providing advice to patients, i.e. ‘demand led’

2. The development of a selective system of screening patients who are estimated to be at relatively high genetic risk of developing these cancers

3. The establishment of systems of population screening to identify patients at increased risk

Over the last few years, many clinics worldwide have been providing advice to patients with a family history of cancer through clinics in an ad hoc and uncoordinated manner, funded largely through ‘soft money’. The resources available have not kept pace with the rapid growth in demand, and this is reflected in the sharp increase in waiting times for appointments in recent years.

Only 5% of breast and ovarian cancers are thought to be due to a strong inherited susceptibility. A process of selection of individuals who are estimated to be at high risk on the basis of their family history for screening for cancer is a more pragmatic approach than screening the general population. However, it is important to demonstrate clearly the benefit of such surveillance programmes before this can be advocated on a large scale (Scottish Office Home and Health Department, 1998).

It is abundantly clear from the contents of this book that our understanding of the inherited aspects of cancer has increased enormously in the past decade. Epidemiological studies (Easton et al., 1995) demonstrate that familial clusters of common cancers could be due to: (1) germline mutations in rare, highly penetrant cancer susceptibility genes, (2) more common, less penetrant mutations, or (3) common environmental factors. It is likely that all of these mechanisms are important. Subsequent to the identification of BRCA1 and BRCA2 (Miki et al., 1994; Wooster et al., 1995), large collaborative studies of families with hereditary breast and ovarian cancer suggest that currently detectable germline mutations in these genes account for approximately 85% of families with six cases of breast cancer but only 41% of those with four to five cases, most families with two ovarian cancer (in addition to breast cancer) cases but 88% (69% due to BRCA1 mutations) with only one ovarian cancer case, while 77% of families with four female cases and one male case of breast cancer are due to BRCA2 and 19% of such families to BRCA1 mutations (Easton et al., 1995; Ford et al., 1998; Thorlacius et al., 1998). Thus a significant proportion of smaller families, particularly those with no cases of ovarian cancer, are likely to be due to polymorphic variants in other genes.

It has long been recognized that some very rare forms of cancer, such as retinoblastoma and neurofibromatosis, are caused by inherited genes. It is only within the last few years, however, that rapid progress has been made in understanding the role that inherited genes also play in determining a proportion of the more common cancers, including breast, colorectal and ovarian cancer. Although there is still uncertainty about the precise contribution of inherited predisposition genes to the incidence of these cancers, the available evidence suggests that breast, colorectal and ovarian cancer have a number of common genetic features.

• A small proportion of these cancers (about 5%) are caused by inherited genes which, though comparatively rare, confer very high lifetime risks of developing cancer. In some cases these lifetime risks may be as high as 80%.

• Cancers caused by these high penetrance genes are more likely to occur at an early age than sporadic cancers, and 15–20% of the cancers diagnosed in people under the age of 50 years may be accounted for by these genetic mutations.

• Carriers of known genetic mutations, which confer high lifetime risks of developing breast or ovarian cancer, are also at significantly increased risk of developing certain other forms of cancer.

• A further 10–20% of breast, ovarian and colorectal cancers are likely to be caused by inherited polymorphisms in predisposition genes, which are commoner but less penetrant but which confer some increased risk (more than three times the general population risk).

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