Publication details

Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status

Title in English Low- burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status.
Authors

KUBEŠOVÁ Blanka PAVLOVÁ Šárka MALČÍKOVÁ Jitka KABÁTHOVÁ Jitka RADOVÁ Lenka TOM Nikola TICHÝ Boris PLEVOVÁ Karla KANTOROVÁ Barbara FIEDOROVÁ Kristýna SLAVIKOVA M. BYSTRÝ Vojtěch KISSOVÁ Jarmila GISSLINGER B. GISSLINGER H. PENKA Miroslav MAYER Jiří KRALOVICS R. POSPÍŠILOVÁ Šárka DOUBEK Michael

Type Article in Periodical
Magazine / Source Leukemia
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1038/leu.2017.230
Keywords TP53 mutations; myeloproliferative neoplasms
Description The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2-16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.
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