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Gene Watch: The New Genetics - Consequences for Clinical Practice

The rapid progress now being made in molecular genetics will have far reaching consequences for clinical practice. It will be crowned by the completion of the largest co-operative international biomedical project ever undertaken: the mapping and sequencing of the human genome. This will not only radically increase our understanding of normal development and disease processes but it will also open up possibilities for new methods of preventing, diagnosing and treating currently intractable diseases. Not surprisingly this new and powerful knowledge will bring with it, indeed, it has already posed new and difficult ethical, social and economic problems.

The R&D Directorate has commissioned two reports on the likely implications for the NHS of this rapid progress in genetics and the associated technology. They are due to be published soon.

Bandolier will discuss some of these new areas of genetics in simple terms in an occasional Gene Watch series, highlighting the progress and opportunities provided but also posing some of the questions that the NHS and society at large must face. We would welcome readers' comments on what they would find most useful and interesting.

This issue starts with a brief consideration of breast cancer genetics and the significance of the recent identification of the inherited susceptibility gene BRCA1.

Genetics of breast cancer

The present management of breast cancer in the UK provides a classic case of the opportunities and dilemmas presented by the new genetics. Up to 10% of the 25,000 new breast cancer patients each year have an inherited basis. Young age at onset and strong family history are the most obvious indicators. The implication is that more than 1,000 women per year will join the ranks of those at very high risk of getting breast cancer (a lifetime risk of over 80%).

Susceptibility genes BRCA1& BRCA2

Paul Broca in 1866 is reputed to be the first person to report the importance of family history in breast cancer. Warthin in 1913 reported the results of the first comprehensive study of family histories in cancer. But it was not until 1990 that Marie-Clare King reported mapping, by segregation analysis, the first breast cancer susceptibility gene (BRCA1) to chromosome 17q21. The recent identification and sequencing of the gene by Mark Scolnick and colleagues in the USA has ended the race by at least 8 major scientific groups around the world to be the first team to isolate the gene - the fact that there are 46 authors is itself a comment on modern research.

The BRCA1 gene confers an 83% risk of breast and 63% risk of ovarian cancer by age 70 and a modestly elevated risk of colon and prostate cancer.

A second breast cancer susceptibility gene, BRCA2, has recently been mapped to chromosome 13q12. This gene probably confers about the same risk of early onset (female) breast cancer as BRCA1 but it also appears to increase the risk for male breast cancer and be less involved in ovarian cancer. A third, as yet unmapped, locus is thought to confer up to 1/5 of the total inherited risk.

Other 'breast cancer' genes

Breast cancer also occurs as a part of the rare Li-Fraumeni syndrome which is usually associated with germline mutations of the p53 gene located on chromosome 17p12. The AT (Ataxia Telangectasia) gene on chromosome 11q22 is also thought to play an important role in breast cancer, claims being made that it may be responsible for up to 13% of cases.

Several oncogenes and tumour supressor genes have been implicated in sporadic (i.e. non- inherited) cases of breast cancer. Those most commonly implicated in such sporadic breast cancers are p 53 on chromosome 17p12; rb on 13q14; AT on 11q22; cmyc on 8q24; cerbB2 on 17q; and int2, hst1, prad1 and ems1 all on 11q13. Mutations in these genes in somatic cells underlie the malignant transformations leading to these tumours.

Tests and screening

Any investigations or screening tests based on these genes will be fundamentally different from genetic tests for the susceptibility genes BRCA 1 and 2. Although they may be valuable in establishing an accurate diagnosis, helping to clarify the prognosis and suggesting the most appropriate therapy they will have consequences only for the patient in which they are found and not in any of the patient's relatives. Professor Bruce Ponder has offered guidelines to GPs on which relatives of breast cancer patients should be referred to specialist clinics for counselling and screening.

The recent isolation and sequencing of the BRCA1 gene provides the basis for a DNA test of susceptibility for high risk women but there is almost universal agreement that this would be premature outside a strictly controlled research programme. It does, however, emphasise the urgency of the situation and the need to agree a coherent screening policy perhaps involving regulation or licensing of testing. If this is not done market forces will predominate and it will then be very difficult to introduce a rational, controlled and cost-effective programme.

Unfortunately the situation regarding the gene test is more complex than might have been hoped. At least 100 different mutations have already been identified in the BRAC1 gene and it is likely that many more will found. Information on the frequency and severity of effect of these different mutations will be needed and the sensitivity and specificity of any proposed diagnostic test must be established before it is adopted as a routine procedure.

Questions to be answered

When an acceptable test becomes available a number of difficult questions will need to be answered:-
  • Who will decide whom to test?
  • How many of the female relatives of existing breast cancer patients should be offered the gene test and counselling?
  • Who else should be eligible for testing?
  • What advice should be offered to individuals found to have BRCA1 mutations?

Options after a positive test

  • Bilateral mastectomy, but if this option is chosen then logically removal the ovaries should also be considered? When should surgery be done?
  • Prophylactic tamoxifen, or other anti-oestrogen treatment (trials of effectiveness are currently in progress but results not yet known). From what age and for how long should prophylaxis be continued?
  • Intensive surveillance including mammography, but the effectiveness of this in patients below 50 is still disputed and it may be positively harmful in a subset of patients who are more sensitive than normal to the effects of radiation.
  • What advice should be offered to individuals found not to have BRCA1 mutations? Should their surveillance be different from the normal population with its 1 in 12 lifetime chance of breast cancer?
All this highlights the urgent need for carefully planned programmes to evaluate these options. Bandolier will try to highlight evidence-based information as it becomes available.

Dr Eric Sidebottom, Oxford

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