Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline variants in the TP53 gene. It is characterised by a high risk of developing a broad range of malignancies with an associated lifetime risk of cancer of ≥70 per cent for men and ≥90 per cent for women. The commonest cancers in affected individuals are adrenocortical carcinomas, breast cancer, central nervous system tumours, osteosarcomas and soft-tissue sarcomas.
Cancers associated with Li-Fraumeni syndrome typically affect younger individuals than the general population, with up to 50 per cent of all carriers developing a tumour before the age of 30 years. Affected individuals are more likely to have multiple cancers. The prevalence of pathogenic germline TP53 variants is estimated between 1:5,000–1:20,000 individuals worldwide; the exact Irish prevalence is unknown at present. There is currently no Irish registry of individuals affected by Li-Fraumeni syndrome.
Diagnosis of classical Li-Fraumeni syndrome is made through identification of a heterozygous pathogenic mutation within the TP53 gene, in the context of an appropriate history meeting all three classic clinical criteria (see Table 1).
A diagnosis should be suspected in those who meet the Chompret criteria (see Table 2), or have early-onset hypodiploid acute lymphoblastic leukaemia, or suggestive findings on somatic tumour tissue testing. It is, however, possible that neither of these scenarios occur. There are some patients in whom a pathogenic mutation is not identified despite meeting clinical criteria, or the opposite may also occur, a pathogenic mutation is identified in a patient without a family history, ie, a spontaneous mutation. With increasing numbers of patients undergoing ‘panel testing’, evaluating a range of target genes, including TP53, pathogenic mutations have been identified in patients not meeting these criteria. It is felt that such patients represent an atypical phenotype and our knowledge of such patients is expanding continuously.
Diagnosis requires extensive pre-testing genetic counselling given the complexity of the diagnosis and implications for the individual and his/her family.
Patients with Li-Fraumeni syndrome appear to have an increased risk of radiation-induced malignancy. This has implications for individuals undergoing regular imaging and for those diagnosed with cancer.
In general once an individual with Li-Fraumeni syndrome is diagnosed with cancer he/he should receive routine oncologic management of their malignancy. In women with breast cancer however, mastectomy is usually recommended in lieu of lumpectomy and radiotherapy to reduce the risks of a second radiation-induced cancer. Patients should have routine follow up care following their treatment but with a modification in screening modalities used.
Risk-reduction programmes have been in place for other cancer predisposition syndromes such as BRCA1/2 and Lynch syndrome for some time. It has been more difficult to implement the same for Li-Fraumeni syndrome given the wide variety of malignancies and lack of evidence demonstrating a mortality or morbidity benefit. However, in recent years, several groups have proposed surveillance programmes in an effort to increase early diagnosis and reduce morbidity.
Whole body MRI is a mainstay of any Li-Fraumeni syndrome surveillance programme that has been instituted worldwide. One of the earliest protocols is known as the ‘Toronto’ protocol, published first in 2011, which combined clinical, radiological and biochemical surveillance, along with colonoscopy. The Toronto protocol included those under 18 years.
Several groups have published modified versions of this protocol, including the UK SIGNIFY study which included adult patients only. In this study, asymptomatic carriers (those without a diagnosis of malignancy) were enrolled in a pilot study assessing the incidence of malignancies using a once-off, non-contrast whole body MRI when compared to the general population. In this study, just over 13 per cent of asymptomatic carriers were diagnosed with a malignancy, all of which had the potential to be life-threatening if untreated.
A 2017 meta-analysis of 13 cohorts (578 participants) estimated the overall detection rate for previously unrecognised new, localised malignant neoplasms by a single baseline scan in those with Li-Fraumeni syndrome was 7 per cent. A high false-positive rate of 42.5 per cent was also noted. This high false-positive rate is of concern, but it is worth noting that evidence shows improved psychosocial wellbeing associated with inclusion within a surveillance programme, independent of the impact of cancer-related morbidity and mortality.
Internationally, the National Cancer Control Network (NCCN) in the US recommends annual breast MRI, whole body MRI, brain MRI, dermatologic examination, and comprehensive physical examination. They also recommend endoscopic evaluation based upon the family history.
The guidelines in the UK NHS are similar, recommending annual whole brain and body MRI from birth, and MRI breast from the age of 20 (among other imaging recommendations).
Until recently, Irish patients affected by Li-Fraumeni syndrome did not have an available surveillance programme. They underwent site-specific examinations such as bilateral breast MRI, colonoscopy, etc, but a formal service did not exist. This year, the Department of Cancer Genetics at St James’s Hospital, Dublin, has secured funding from the Bobbie Bastow Cancer Genetics Foundation for surveillance of affected individuals. This includes whole body, brain and, where appropriate, breast MRI.
Individuals known to the service have been contacted directly and informed about the availability of screening. If you have a patient whom you believe should be offered this programme, please contact us at firstname.lastname@example.org or write to the Cancer Genetics Department at St James’s Hospital.
References on request
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