Most cancers arise due to sporadic events (mainly environmental risks) and few individuals have more than one primary tumour in their lifetime. However, individuals with an inherited susceptibility are prone to developing more than one cancer in multiple organs, a risk that remains throughout their lives. In spite of clinical surveillance, surgery and other treatments, morbidity and mortality due the inherited mutation can be high.
For example, patients with inherited mutations in the APC gene can develop cancers of the colon, small intestine, thyroid, skin and brain. Therefore, even after prophylactic removal of the large bowel these patients require life long clinical surveillance for the detection of cancers in other parts of the body. One of the primary causes of death in individuals with inherited APC mutations following colorectal surgery is the occurrence of benign tumours known as desmoids because the anatomical location of these tumours can make surgical removal difficult.
The age of onset for inherited cancer is generally much earlier than in sporadic cases, but the penetrance of these disorders can be variable as not all individuals with an inherited mutation in a cancer predisposing gene develop cancer. Mutations in the APC gene result in an almost 100 per cent risk of developing colorectal cancer if prophylactic surgery is not carried out, however inherited BRCA1 mutations confer a 60-65 per cent risk of breast cancer in women.
By following up families with inherited cancer, better knowledge of the spectrum of tumours and the clinical complications that can arise has led to the creation of a number of guidelines for the clinical management of these patients. Once the causative germline mutation is identified in a family member with inherited cancer, other family members need genetic counselling to prepare for the stress of genetic testing. Even if cancer treatment is not required, asymptomatic mutation carriers undergo regular and often invasive clinical screening as well as prophylactic surgery in some cases. It is surprising that in spite of almost all types of inherited cancer showing autosomal dominant inheritance (where 50 per cent of offspring will have high genetic susceptibility to developing cancer), counselling on reproduction is rarely included in guidelines on clinical management.
Reproductive decision making for cancer predisposition is complex. This is because the extent of clinical manifestation due to a germline mutation is largely unpredictable and in some cases the availability of clinical surveillance for the early detection of tumours results in a favourable prognosis following treatment. For some couples termination of an established pregnancy because of cancer susceptibility is inappropriate yet passing on this genetic burden equally is not an acceptable option. PGD gives individuals with known germline mutations an opportunity to avoid passing on the inherited cancer risk to their children without the need to consider the termination of pregnancies.
In PGD genetic testing is carried out on embryos from the couple created by IVF. Only embryos that do not carry the inherited mutation are transferred back to the mother with the aim of establishing a pregnancy. In practical terms, children born following PGD for cancer predisposition avoid the need to prepare for a genetic test, where a positive result would have a significant impact throughout their lives whether or not they were to ever develop cancer.
In our experience, couples requesting PGD for cancer predisposition want to remove the burden of having an inherited mutation in these genes even if they themselves have not had clinical screening or cancer treatment, for example male carriers of BRCA1 mutations. We have carried out a total of 11 cycles of PGD for eight couples with inherited mutations in four different cancer predisposing genes. Three of these couples have had the birth of a healthy child following PGD to avoid retinoblastoma, neurofibromatosis type 1 and familial adenomatous polyposis and two others have ongoing pregnancies (retinoblastoma and inherited breast/ovarian cancer due to BRCA1).
PGD is therefore a highly successful option for couples with cancer predisposition as the live birth /pregnancy per cycle of PGD is 45.5 per cent (5/11) and per couple it is 62.5 per cent (5/8). The HFEA has licensed PGD for other cancer predispositions including von Hippel Lindau syndrome, multiple endocrine neoplasia type I and neurofibromatosis type 2. Worldwide, PGD has been carried out for inherited mutations in a number of different genes including MSH2, MLH1, RET, BRCA2, TSC2, and CDH1.(1) We are working towards developing PGD for inherited mutations in these genes so that more couples in the UK can be offered PGD as a reproductive option.