At the time of writing, the Human Fertilisation and Embryology Authority (HFEA) of the UK is about to launch a consultation exercise to discover the attitude of the public towards preimplantation genetic diagnosis (PGD) for disorders that are not immediately apparent in early childhood, but may manifest themselves later in life. The HFEA exercises tight control over which clinics may offer PGD and over the conditions for which treatment may be offered, a situation that is in stark contrast to that pertaining to termination of an established pregnancy following an adverse test for a genetic condition, where the decision is left to the individual clinician. PGD involves the genetic testing of one or two single cells removed from a 3-day-old embryo consisting of approximately eight cells, and barely visible to the naked eye. To avail themselves of this option, the parents must go through the procedure of in vitro fertilization (IVF) to allow access to the embryos at a sufficiently early stage, even if the parents are fertile. An increasing number of couples are willing to take this route to enable them to start a pregnancy, knowing that it is unaffected with the genetic disorder that is present in their family. They see this as an altogether more acceptable option than the standard method of becoming pregnant naturally, undergoing prenatal testing 2–3 months into the pregnancy and then having to make the agonizing decision about whether to terminate the pregnancy if the test is positive. PGD allows the couple to make a private decision about the matter without other family members being involved and before bonding with the fetus has occurred. The arguments in favor of PGD become even more persuasive when conditions of variable penetrance and expressivity are considered. Many couples are faced with the dilemma of having to decide whether to allow a pregnancy to continue when a positive gene test cannot itself predict the severity of a disease, or even whether the child in question will ever develop the disease state. In such a situation, how much more preferable would the PGD option be, if available?
To be able to put the PGD option in context, it is important to understand the basic biologic facts that pertain to embryos created by IVF and also to those conceived naturally. The fertilization of human eggs in a laboratory allows us to follow subsequent events closely and to observe that most of the embryos created are destined to die; on average, only one out of five human IVF embryos has the potential to implant in the womb and grow to form a baby. Similarly, with natural conceptions, for couples with no known fertility problems, on average, their chances of conceiving in any one monthly cycle are approximately one in five. The normal procedure during IVF is to fertilize several eggs simultaneously and, after 2 or 3 days, for the embryologist to select the two embryos with the best development for transfer to the mother. Any others that are of good quality may be frozen for later use, but the majority will be discarded. In the case of a couple undergoing PGD to avoid passing on a serious genetic disorder, an additional selection criterion will be applied, namely to select embryos that are also free of that disorder.
The HFEA has, over the years, issued licenses for certain late-onset disorders, including Huntington’s Disease and cancer-prone conditions such as familial adenomatous polyposis (which predisposes to colorectal cancer), neurofibromatosis Type 2 and Li Fraumeni syndrome. It is therefore something of a mystery as to why the HFEA now finds it necessary to hold a public consultation exercise to consider the question of PGD for late-onset disorders. Manifestation of disease requires additional somatic genetic changes in all cases of hereditary cancer predisposition, hence none will show 100% penetrance, although some, such as retinoblastoma, do approach this level of penetrance. It would appear that it is the question of whether to allow PGD for the breast/ovarian cancer genes, BRCA1 and 2, that has prompted this exercise. After all, it has been said that a woman with a mutation in the BRCA1 gene has ‘only an 80% chance of developing breast cancer’!
In the UK population as a whole, approximately one in 400 people carry a mutation in BRCA1 or 2. The presence of an autosomal dominant mutation is a predisposing factor in approximately 10% of the 41,000 cases of breast cancer diagnosed each year; most of these mutations will be in BRCA1 or BRCA2. These genes also predispose to ovarian cancer; approximately 8% of cases are due to mutation in one of these two genes. In the general population, a woman’s lifetime risk of developing breast cancer is approximately one in nine (11%); most of these cancers will occur in postmenopausal women. Women with a mutation in either of the BRCA1 or 2 genes have a lifetime risk of 60–80% for breast cancer and 20–50% for ovarian cancer. It is important to recognize that, in those women who have already inherited the first mutation, the cancers will occur at a much earlier age, affecting women in their thirties who may well have young children. In genetic terms, these are very highly penetrant genes. In multicase families, those whose members are likely to seek prenatal or preimplantation diagnosis, the risk for gene carriers of breast cancer is 80% and that for ovarian cancer is 50%.
Recent headlines rightly proclaim the advances made in the treatment of breast cancer. Two-thirds of women diagnosed with breast cancer can now expect to survive for at least 20 years. However, for ovarian cancer, the outlook is far less optimistic; two-thirds of the 6600 cases diagnosed each year will not survive. Even for breast cancer, survival comes at a price: mastectomy, oophorectomy, chemotherapy and radiotherapy. Young women carrying a mutation in BRCA1 or 2 will be advised to undergo the first two of these (removal of both breasts and ovaries) as prophylactic measures. Women who have been diagnosed as gene carriers but have so far been lucky enough to escape cancer will still face discrimination when seeking life insurance. Spare a thought also for the younger generation growing up in a family where there is a well-known history of breast or other cancers. International guidelines have been agreed such that, unless there is an opportunity for treatment, genetic testing is deferred until the young person is able to make their own decision regarding testing, usually at 18 years of age. The young person thus grows up knowing that he or she has a 50% chance of being a gene carrier, with all the implications for future health problems that have been so evident in members of his or her family. Research shows that these youngsters have varied means of coping with this threat, but there is no doubt that it adversely affects their lives.
One basic tenet of medicine is that one should do no harm. It could be argued that selecting the sex of an embryo for reasons of ‘family balancing’ could do harm to modern society by upsetting the balance of the sexes, although this is unlikely to be the case for the UK population. In 2002–2003, the HFEA carried out a consultation on the question of sex selection. In total, only 641 responses were received, 575 from individuals; 83% were against the use of PGD for sex selection for non-medical reasons. It will be interesting to see how many responses are received to the current consultation exercise on PGD for late-onset disorders; if the numbers are as small as for the sex selection exercise, then it is to be hoped that the HFEA will not consider the results to be binding. As for most other situations concerning genetic testing, the decision regarding whether to opt for PGD to avoid passing on a deleterious gene should be left to the families to decide. They are the ones who have to suffer from the curse of a cancer-predisposing gene, and should be given the chance to eliminate it from their family forever.