Rare cancer gene found in sperm donor sparks European regulatory concerns

A case in which a sperm donor was later found to be carrying a cancer-causing pathogenic variant in his gametes has highlighted the problems of regulating gamete donation at European and international level, the annual conference of the European Society of Human Genetics will hear today (Saturday). Dr Edwige Kasper, a specialist in genetic predisposition to cancer at the Rouen University Hospital, Rouen, France, will say that the lack of cross-border regulation in Europe can result in the multiple use of gametes in families and risks inbreeding and the abnormal dissemination of inherited diseases.

Towards the end of 2023, Dr Kasper's laboratory was contacted by a French clinician who said that one of his patients had received a letter from a private sperm bank located in Europe, alerting her to the identification of a 'variant of unknown significance' in the TP53 (tumour protein 53) gene in less than 50% of the donor's gametes. TP53 provides instructions for making a tumour suppressor protein, keeping cells from growing and dividing too fast or in an uncontrolled way. The letter said that the donor was in good health, but that his biological children could be at risk of Li-Fraumeni syndrome, a rare inherited disorder that predisposes to the development of cancers. Some of these children had already developed leukaemia and non-Hodgkin's lymphoma, and this led to any use of the donor's gametes being definitively blocked.

I analyzed the variant using population and patient databases, computer prediction tools, and the results of functional trials, and came to the conclusion that the variant was probably cancer-causing and that children born from this donor should receive genetic counselling."

Dr. Edwige Kasper, a specialist in genetic predisposition to cancer, Rouen University Hospital, Rouen, France

After discussion with French networks, the researchers presented these cases at a meeting of the European Reference Network on genetic tumour risk syndromes (GENTURIS) in 2024. Simultaneously, a number of Genetics and Paediatric Departments across Europe were investigating their own cases, leading to 67 children from 46 families in eight European countries being tested, with the variant being found in 23 of them and cancer found in ten to date.

Alterations in the TP53 gene cause Li-Fraumeni syndrome, one of the most severe inherited predispositions to cancer that is characterised by a broad spectrum of tumours at an early age. The affected children, born between 2008 and 2015, are being closely monitored to detect the first signs of cancers. "The follow-up protocol involves whole-body MRI scans, MRI scans of the brain and, for adults, of the breast, ultrasound examination of the abdomen, and a clinical examination by a specialist. This is heavy and stressful for carriers, but we have seen its effectiveness in that it has enabled early detection of tumours and thus improved patients' chances of survival," says Dr Kasper. "Because animal models of Li-Fraumeni syndrome have shown that exposure to genotoxic chemotherapy or X-rays accelerated tumour development, these children should avoid radiation-based imaging techniques such as mammography and PET scans, if possible."

The researchers are continuing to identify cases of European children born from the same donor. "Although the variant would have been practically undetectable in 2008 when the individual started to donate sperm, there are many things that could have been and still need to be improved," says Dr Kasper. "Some fertility clinics have refused to provide information to the families concerning the variant because they wanted the children to be tested in their own laboratories. There is a major issue here concerning a lack of harmonised regulation across Europe."

Currently, laws on sperm donation differ from one European country to another. Private sperm banks usually limit donation from one donor to 75 countries worldwide. The law in France sets a limit of ten births per donor. However, in addition, there can be up to 15 births in Germany and in Denmark, and in the UK the same donor may be used for 12 and 10 families, respectively. At a European or international level this can represent a large number of births.

"My advice to French parents would be to favour a medically assisted procreation procedure in France, where donation is voluntary, anonymous, and free. The latter may explain the difference between parents' needs and the lack of resources," says Dr. Kasper, "but it is very much safer. While donor examinations are routinely conducted in many countries, in France, gamete donation is medically supervised for both donors and recipients. Importantly, any suspicion of a genetic disorder must be promptly reported and investigated. Above all, each donor is limited to a maximum of ten births across the country, and the import or export of gametes may only be requested by an approved centre and is subject to authorisation from the Agence de la Biomédecine. "The fact that the case in point is very rare does not mean that it will not reoccur, and gonadal mosaicism – where one or more groups of cells possess a different genetic makeup – has previously been reported in a sperm donor with reference to neurofibromatosis type 1. We need proper regulation at European level to try to prevent it happening again, and to implement measures to ensure a worldwide limit on the number of offspring conceived from the same donor."

Chair of the conference Professor Alexandre Reymond said: "While current legislation on assisted reproduction usually does not cross borders, this is a good example of why wider oversight is needed. But for now, what we learn in genetics in one country can help future parents everywhere."