Li‐Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition

Abstract

Li-Fraumeni syndrome (LFS) is a rare cancer predisposing condition caused by germline mutations in TP53, the gene encoding the TP53 transcription factor. LFS is typified by the development of a wide spectrum of childhood and adult-onset malignancies, which includes, among others, the lymphoid and myeloid leukaemias, myelodysplastic syndrome and, to a lesser extent, lymphoma. Accordingly, it is important that haematologists/oncologists be familiar with this pleiotropic hereditary cancer syndrome. The high cancer risk and variability in type and age of cancer onset have raised questions about the underlying biology and optimal treatment approaches for individuals with LFS. Since its description almost 50 years ago, many clinical and basic research investigations have provided insights into the pathogenesis, manifestations, genetic testing and management strategies for individuals with LFS. Here we provide an update on the current state of knowledge regarding LFS with an emphasis, where possible, on information relevant to practicing haematologists.

Parent–child communication surrounding genetic testing for Li–Fraumeni syndrome: Living under the cloud of cancer

“…This uncertainty is well exemplified for families with Li–Fraumeni syndrome (LFS), a cancer‐predisposing condition caused by germline pathogenic variants in the TP53 tumor suppressor gene. Over the course of their lives, most individuals with LFS will develop cancer, with 20% presenting with a malignancy before age 20 . Individuals with LFS are prone to develop a variety of cancers, including soft tissue and bone sarcomas, early‐onset breast cancers, adrenocortical carcinomas, acute leukemias and brain tumors, and many develop multiple primary tumors .…”

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits

“…The TP53 mutations found in LFS are rare in the general population 44 . However, here we show relatively frequent SNPs related to p53 affect cancer risk and anthropometric traits.…”

Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions

“…The relative risk of leukemia in individuals with LFS is estimated to be 6-fold higher than the general population, developing predominantly in TP53 mutation carriers less than 45 years old (14). The leukemias occurring in affected children tend to be low-hypodiploid acute lymphoblastic leukemia (ALL), most commonly of B-cell origin, although other leukemia subtypes and therapy-associated leukemias have also been reported (15). Low-hypodiploid ALL is defined by leukemia cells containing 32 to 39 chromosomes; remarkably, up to 40% of children with low-hypodiploid B-ALL harbor germline TP53 mutations (16).…”