Shwachman-Diamond Syndrome (SDS) due to SBDS mutations is associated with a high rate of leukemic transformation. Mutational somatic profile was evaluated on a cohort of patients from the french SCN registry
Hematological data were correlated with targeted NGS performed in SDS cohort of 57 patients.
We detect the presence of an acquired TP 53 mutation in 32/57 SDS patients (56%) with VAF (Variant Allele Frequency) ranging from 0.5% to 82.6%. Five patients had more than one mutation either concomitantly or at different times of evolution. The other mutations detected affect the DNMT3A (2 patients), IDH1, SF3B1, PHF6, SMC1A, ASXL2, FLT3 and KRAS genes. The longitudinal follow-up of 13 patients shows that the VAFs of TP53 mutations can grow or decrease and that clones can become detectable or undetectable over time in the same patient. In 11 patients we detected TP53 mutations with VAFs greater than 10% (affecting more than 20% of the cells analyzed). Of these, 5 patients were in fatal leukemic transformation with complex karyotype, 1 were at the SMD stage with excess blasts, 2 were in severe cytopenia without SMD, and 3 had no severe cytopenia with stable or decreased VAF over time. In the rest of the cohort, we observe that patients who do not have mutated TP53 clone clones or clones with low VAF (<10%) have few severe hematologic complications.
Mutations of TP53 are detected in half of the SDS and constitute a somatic event essential in the evolution in SMD or LAM, detectable early.