Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li–Fraumeni syndrome

Abstract

Approximately 10% of cases of childhood cancer arise in the context of a cancer predisposition syndrome (CPS) [1]. Among the rare CPS, Li-Fraumeni syndrome (LFS, MIM#151623) is relatively common and estimated to account for >1% of cases of childhood cancer [2]. LFS is a dominantly inherited condition caused by pathogenic germline variants in the TP53 tumor suppressor gene [3, 4]. Children with LFS are predisposed to a range of neoplasms such as osteosarcoma, adrenocortical carcinoma, medulloblastoma, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, and (frequently hypodiploid) acute lymphoblastic leukemia (LFS-ALL) [5, 6]. Notably,

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges

“…49 Germline TP53 mutations are found in ˜50% of paediatric patients with hypodiploid ALL and are associated with inferior outcomes. Hypodiploid ALL in children and adolescents is now included in germline TP53 screening guidelines, [50][51][52] although leukaemia is a relatively rare manifestation in Li Fraumeni kindreds, with ˜4% of cases presenting with low hypodiploid ALL, therapy related or de novo MDS/AML. 53…”

Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

“…Therefore, it is highly recommended that all patients with low-hypodiploidy B-ALL are tested for germline TP53 mutations [ 24 , 69 ]. Strikingly, the germline TP53 mutations in these cases have been associated with increased mortality due to second neoplastic malignancies following hematopoietic stem cell transplantation (HSCT), highlighting the importance of the germline study in low-hypodiploid B-ALL to assess HSCT versus less toxic alternative therapies [ 26 , 67 , 70 ]. The presence of other recurrent mutations in near-haploid and low-hypodiploid B-ALL cases, such as alterations in the RAS-pathway, IKZF or RB1 , has not shown a clear association with patient prognosis [ 23 ].…”

B‐cell acute lymphoblastic leukaemia: recent discoveries in molecular pathology, their prognostic significance, and a review of the current classification

“…TP53 mutations are reported in ~3% of children, up to ~15% in adults with ALL and are enriched in relapsed disease. They are also reported in up to 90% of low‐hypodiploid cases, and are germline in ~50%, implying these ALL cases may be a manifestation of Li‐Fraumeni syndrome 5,9,84,94–96 . The majority of TP53 mutations are missense mutations, although frameshift, splice‐site and nonsense mutations are also observed.…”

“…They are also reported in up to 90% of low-hypodiploid cases, and are germline in ~50%, implying these ALL cases may be a manifestation of Li-Fraumeni syndrome. 5,9,84,[94][95][96] The majority of TP53 mutations are missense mutations, although frameshift, splice-site and nonsense mutations are also observed. Point mutations frequently involve 'hotspots' at p.R175, p.G245, p.R248, p.R249, p.R273 and p.R282.…”