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An international team of researchers has recently clarified the impact of TP53 mutations in myelodysplastic syndrome patients with isolated del5q, a condition found in 20% of the cases. Main results show that multiple mutations in TP53, or single mutations with allele frequency over 20%, classify as worst overall survival and higher risk of AML transformation, while single mutations in TP53 with allele frequency lower than 20% behaves just as non-mutated, being associated with good prognosis.
Myelodysplastic Syndromes (MDS) are a group of haematological malignancies diagnosed in adults, usually over 60 years of age. The underlaying causes of MDS are not known, but the patient’s blood cells do not develop properly and accumulate at the bone marrow. Over time, MDS may progress towards an aggressive form of acute myeloid leukaemia (AML), a much worse disease. In 20% of the cases, MDS cells bear the del5q genetic alteration, a rather benevolent feature conferring higher sensitivity to lenalidomide and better overall survival.
On the other hand, the World Health Organisation has described mutations in the TP53 gene as a specific kind of myeloid neoplasm, characterized by poor overall survival and higher risk of AML transformation. While alterations in TP53 are found in 5 to 10% MDS cases, they are present in 20% of MDS del5q patients and current knowledge is inconsistent to whether the co-occurrence of both anomalies poses an additional thread for patients.
To understand the effect of harbouring both del5q and TP53 mutations, the research team screened a cohort of 682 MDS patients with del5q (and no other chromosomal rearrangements), the largest ever assembled. The team, led by researchers from the Vall d’Hebron Hospital in Barcelona, counted also with the collaboration of Dr. Francesc Solé, head of the Myelodysplastic Syndromes lab at the Josep Carreras Leukaemia Research Institute, and Dr. Pamela Acha, former lab member, currently at Vall d’Hebron Institute of Oncology.
In the studied cohort, almost 20% of the patients had mutations on TP53, of which 76% were monoallelic (single mutation) and 24% multihit, the worst-case scenario. Among the monoallelic, almost half the cases had a Variant Allele Frequency (VAF) lower than 20%, meaning that of one in five cancer cells, or less, carried the mutation.
Using this cohort, where the only alterations were the del5q and TP53 mutations, the research team was able to see the real effects of each genetic condition on the clinical outcome of the patients in terms of overall survival, progression to AML and treatment success rate, among other. Their results, published at Blood, the highest-level academic journal in the field of haematology, showed that VAF was actually a very useful metric, and that the 20% threshold was key.
Results showed that multihit TP53 mutations and monoallelic TP53 mutations with VAF over 20% were associated with very poor outcomes, regardless of the del5q status. Patients under those circumstances should be included at the WHO TP53 myeloid neoplasm class and are at a higher risk of AML transformation and lower survival rates. On the contrary, monoallelic TP53 mutations with VAF below 20% behaved as if they had no TP53 mutations whatsoever and showed the typical good prognosis of the del5q MDS population.
Altogether, these results encourage for a thorough TP53 mutational status determination during diagnosis, with special emphasis on VAF (with cut-off set at 20%), as a means to anticipate whether a patient would benefit from the standard lenalidomide treatment or might need a more intense therapeutic intervention.
The research showcased here has been partly funded by the European Union, the Instituto de Salud Carlos III, Generalitat de Catalunya CERCA program and the International Josep Carreras Foundation against Leukaemia. No generative AI tools have been used in the production of this manuscript.
