Incidence of 17p deletions and TP53 mutation in myelodysplastic syndrome and acute myeloid leukemia with 5q deletion

Abstract

TP53 mutations are frequent in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex karyotype that include del(5q) and are often associated with deletion of 17p. They have also recently been observed in MDS with isolated del(5q). We assessed the incidence of 17p deletion detected by fluorescence in situ hybridization (FISH) and of TP53 mutations detected by direct sequencing and their correlation and prognostic value in 26 MDS and 17 AML with del(5q). In the 20 cases with isolated del(5q) or one additional abnormality, no 17p deletion was found and 3 of the 18 cases analyzed (17%) had TP53 mutation. In the 23 patients with complex karyotype, 17p deletion was suspected by conventional cytogenetics in 15 cases and confirmed by FISH in 10 of them, while TP53 mutation was found in 8 of the 15 patients tested (53%), only five of whom had 17p deletion. In the whole patient series, TP53 mutations were associated with shorter survival (P = 0.07). We confirm the existence of TP53 mutations in 17% of MDS with isolated del(5q). In patients with del(5q) and complex karyotype, FISH and direct sequencing are complementary techniques to analyze TP53 abnormalities. Our findings also suggest that sequencing of the TP53 gene should be included in the study of patients with del(5q) as a single abnormality or in complex karyotype before lenalidomide treatment.

Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

“…Gene mutation screening in del(5q) MDS has been performed in previous studies, but most of these studies focused on a limited number of genes, and mainly employed traditional sequencing methods. 9,[34][35][36][37][38][39][40] Other studies have investigated a larger number of genes [41][42][43] but did not specifically focus on MDS cases with del(5q). To our knowledge, the present work is the first attempt to screen a large number of genes using a targeted next-generation sequencing approach in both early and advanced del(5q) MDS.…”

Clinical and genetic predictors of prognosis in myelodysplastic syndromes

“…However, highly adverse TP53 mutations often co-exist in patients with del(5q), including those with del(5q) as their sole karyotype abnormality. 41,43 Isolated del(5q) patients with TP53 mutations appear to have a poorer prognosis and an earlier relapse after lenalidomide treatment than expected, even in cases where the initial TP53 mutant subclone is very small. 47 This finding justifies TP53 screening of all patients prior to treatment with lenalidomide, as suggested by the ELN guidelines.…”

“…But even there, prognostic variability exists as some patients may have larger 5q deletions or TP53 mutations, both of which have been shown to be prognostically adverse. [41][42][43] The clinical heterogeneity associated with MDS is further reflected in the various patterns of mutation observed in patients. Most of the recurrently mutated genes can overlap with each other, although examples of mutual exclusivity or apparent cooperativity between mutations have been identified.…”

Myelodysplastic syndromes with a deletion 5q display a characteristic immunophenotypic profile suitable for diagnostics and response monitoring

“…TP53 mutations in MDS with isolated del(5q) have been reported in up to 20% of lower risk MDS. 15 A mutational screening is recommended in patients with isolated del(5q) because of their potential resistance to lenalidomide and higher rate of AML evolution in TP53 mutated cases. From our data, we hypothesize that especially patients with isolated del(5q) but a non-typical low del(5q)-score raise suspicion of harboring a TP53 mutation and should subsequently be referred to mutational screening.…”