Li-Fraumeni syndrome (TP53): inherited cancer risk from childhood

The TP53 gene makes a protein that acts as a guardian of the cell: it controls when a cell divides and can halt it when DNA is damaged. Cancer Research UK describes TP53 as a tumour suppressor gene. In Li-Fraumeni syndrome a person is born with a harmful change in one copy in every cell, so one line of defence is missing from the start.

Cancer Research UK says the most common cancer in the syndrome is breast cancer, and other possible cancers include bone cancer, acute myeloid leukaemia, soft tissue sarcoma, brain tumours and cancer of the adrenal gland. The NHS Genomics Education Programme adds that breast cancers in this setting are often diagnosed before 30 and are more commonly HER2-positive, that the sarcomas are mainly rhabdomyosarcoma and osteosarcoma, and that a wide variety of other cancers have been reported at ages younger than expected.

The programme has also introduced a broader description, heritable TP53-related cancer syndromes, because some families with a TP53 variant do not meet the classic clinical criteria.

Li-Fraumeni syndrome is autosomal dominant. A parent who carries the variant has a 50% chance of passing it to each child, and the same applies to each brother and sister of an affected person, regardless of sex. A child who does not inherit the variant is not at risk of passing it on.

Not every case comes from a visible family history. The NHS Genomics Education Programme says that 7% to 20% of TP53 variants arise de novo, meaning for the first time in the person, and that germline mosaicism is not infrequent, so a child may be affected even when neither parent has had cancer. Conversely a family history of cancer is not always caused by TP53. In the programme's figures, 60% to 80% of people who meet the classic criteria and about 30% who meet the Chompret criteria turn out to carry a constitutional TP53 variant.

The risk figures themselves are averages. The programme says exact risks depend on the specific variant and may be modified by lifestyle, other genetic factors and the family history. Some carriers reach later life without cancer.

Testing for TP53 is available through the NHS National Genomic Test Directory. Certain cancers prompt testing whatever the family history: adrenocortical cancer at any age, choroid plexus cancer, rhabdomyosarcoma at five years or under, breast cancer at 30 or under, HER2-positive breast cancer at 35 or under, and some childhood leukaemias, medulloblastomas and jaw osteosarcomas.

Testing is also offered when two or more related cancers occur at young ages in the same person, or across close relatives, following clinical criteria known as the classic and Chompret criteria. Once a variant is found in a family, relatives can be offered a predictive test.

The NHS says genetic testing is free when a hospital specialist refers you and that a genetic counsellor can talk through what the result means for you and your relatives. Counselling matters particularly here because the surveillance programme begins in early childhood.

The UK Cancer Genetics Group published consensus guidance, summarised by the NHS Genomics Education Programme. Because risk begins in early childhood, cancer risk management starts from birth. The programme notes that funding for the recommended screening is not uniformly provided across the NHS at present.

• Adrenal glands: abdominal ultrasound every three to four months from birth to 18 years.

• Brain: annual dedicated brain MRI from birth.

• Soft tissue and bone: annual whole-body MRI from birth.

• Breast: annual dedicated MRI from age 20 to 70, with risk-reducing mastectomy considered from 20.

• Skin: annual dermatology review from 18.

• Children: a full physical examination every three to four months. In adults, routine examination is not recommended; instead there is detailed discussion of warning symptoms and a low threshold for fast-track referral.

• Blood cancers and stomach: routine screening is not indicated for lack of evidence, although Helicobacter pylori testing and treatment are recommended.

Evidence suggests that radiation increases the risk of second primary cancers in TP53 carriers. The NHS Genomics Education Programme therefore advises avoiding radiation where an equally good alternative exists. For a woman with breast cancer, for example, mastectomy is usually recommended instead of wide local excision plus radiotherapy. Screening that uses ionising radiation is avoided where possible, which is why MRI and ultrasound feature in the surveillance programme.

This is not an absolute ban. Where radiotherapy offers the best treatment and no alternative is as good, TP53 status is not considered a complete contraindication. Treatment decisions are made by the cancer team together with clinical genetics.

The Human Fertilisation and Embryology Authority has approved pre-implantation genetic testing (PGT-M) for couples where a parent carries a TP53 variant. A genetic counsellor can also discuss prenatal testing, donor gametes and adoption.

Patient groups named by the NHS Genomics Education Programme are the George Pantziarka TP53 Trust and the Li-Fraumeni Syndrome Association. Living with a high-risk diagnosis in a family often includes parents managing surveillance on behalf of children, and these groups offer experience that clinic appointments cannot.