Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome

Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germlinemutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellularprocesses including cell-cycle arrest and apoptosis to prevent aberrant cell proliferation. Currentcancer therapies involve agents that damage DNA, which also affect non-cancerous hematopoieticstem/progenitor cells. Here, we report on a child with LFS who developed genomic instability duringcraniospinal irradiation for metastatic choroid plexus carcinoma (CPC).Case presentation: This previously healthy 4-year-old boy presented with parieto-temporal brain tumor,diagnosed as CPC grade-3. Screening for cancer-predisposing syndrome revealed heterozygous p53 germlinemutation, leading to LFS diagnosis. After tumour resection and systemic chemotherapy, entire craniospinalaxis was irradiated due to leptomeningeal seeding, resulting in disease stabilization for nearly12 months. Blood lymphocytes of LFS patient (p53-deficient) and age-matched tumor-children (p53-proficient) were collected before, during and after craniospinal irradiation and compared with asymptomaticcarriers for identical p53 mutation, not exposed to DNA-damaging treatment. In p53-deficientlymphocytes of LFS patient radiation-induced DNA damage failed to induce cell-cycle arrest or apoptosis.Although DNA repair capacity was not impaired, p53-deficient blood lymphocytes of LFS patient showedsignificant accumulation of 53BP1-foci during and even several months after irradiation, reflecting persistentDNA damage. Electron microscopy revealed DNA abnormalities ranging from simple unrepairedlesions to chromosomal abnormalities. Metaphase spreads of p53-deficient lymphocytes explored bymFISH revealed high amounts of complex chromosomal aberrations after craniospinal irradiation.Conclusions: Tumor suppressor p53 plays a central role in maintaining genomic stability by promotingcell-cycle checkpoints and apoptosis. Here, we demonstrate that a patient with LFS ...