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

Abstract

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.

Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms

“…TET2 mutations are found in approximatively 12% of MPN and TP53 mutations in MPN phase correlates with age . TP53 mutations in MPN are often difficult to detect because of a very low VAF . If TP53 is well‐known for its pejorative impact, TET2 is not considered to have adverse prognostic mutations .…”

Characterization of tumor microenvironment and Immune infiltration in head and neck squamous cell carcinoma

“…Top 10 mutated genes that related to TMB were TP53, TTN, FAT1, MUC16, CDKN2A, CSMD3, SYNE1, LRP1B, NOTCH1 and PIK3CA. Kubesova et al 41 reported that TP53 mutations with low variant allele frequency irrespective of disease subtype, driver gene status and cytoreduction during myeloproliferative neoplasm. Mukhopadhyay et al 42 suggested that ESR2-mutant TP53 combination prognosticates survival in triple negative breast cancer.…”

MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

“…The tumour suppressor gene TP53 is located on chromosome 17, encoding a DNA binding protein that responds to DNA damage by inducing transcriptional programs that result in cell cycle arrest or cell death via apoptotic pathways [132]. The presence of TP53 mutations at low allelic frequency in chronic MPN with subsequent loss of heterozygosity is strongly associated with leukemic transformation [133]. This was confirmed by recent studies showing that TP53 is more significantly enriched in leukemic transformation, found in 16-17% of cases compared to approximately 2% of chronic phase MPNs [16,61,62,134].…”