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, somatic mutations and germline variants of TP53 are enriched at relapse and are associated with poor prognosis in relapsed childhood ALL [7]. A recent study involving 3801 children with ALL showed that LFS-ALL accounts for less than 1% of ALL cases [8] and was associated with inferior event-free survival as well as overall survival, and higher risk of second malignant neoplasms (SMN) [8]. Nevertheless, the clinical and genetic characteristics of LFS-ALL are poorly studied. Therefore, we conducted a retrospective cohort study on 18 children with LFS-ALL to further delineate the characteristics of this rare association. All 18 ALL patients were identified as having LFS based on the presence of a (likely) pathogenic TP53 germline variant (see also Supplementary Table 1). Six patients were identified in a cohort of patients with relapsed ALL among 564 analyzed patients with relapsed ALL registered in the multicentre randomized trial ALL-REZ BFM 2002. At the time of initial ALL diagnosis, all six patients were enrolled