Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status.
Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status.
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DOI：
10.1038/leu.2017.230
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Doubek M
中科院分区：
文献类型：
--
作者：
Kubesova B;Pavlova S;Malcikova J;Kabathova J;Radova L;Tom N;Tichy B;Plevova K;Kantorova B;Fiedorova K;Slavikova M;Bystry V;Kissova J;Gisslinger B;Gisslinger H;Penka M;Mayer J;Kralovics R;Pospisilova S;Doubek M
骨髓增生性肿瘤（MPN）转化为急性髓系白血病（AML）期间TP 53突变扩展的多步骤过程已被回顾性记录。目前尚不清楚具有低变异等位基因频率（VAF）的TP 53突变有多常见，它们是否与羟基脲（HU）细胞减少有关，以及它们携带的疾病进展风险。使用超深度下一代测序，我们检查了254名接受HU，干扰素α-2a或anagrelide治疗的MPN患者和85名未接受治疗的患者。我们发现TP 53突变50例（0.2-16.3% VAF），无论疾病亚型，驱动基因状态和细胞减少。治疗和TP 53突变都与年龄较大密切相关。随时间推移的分析表明，突变可能在诊断时无法检测到，并在疾病过程中缓慢增加。尽管3例TP 53突变患者进展为TP 53突变型或TP 53野生型AML，但我们在随访期间未观察到对总生存率的显著年龄无关影响。此外，我们表明，完全p53失活单独导致既不胚转化也不HU抗性。总之，我们揭示了患者的年龄是影响MPN低负荷TP 53突变发生率的最强因素，并发现TP 53突变与羟基脲之间无显著的年龄无关性。突变可能会持续多年处于低水平，而不会立即出现进展风险。
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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影响因子：
6.5
作者：
Jethwa, Alexander;Huellein, Jennifer;Zenz, Thorsten
通讯作者：
Zenz, Thorsten
影响因子：
11.2
作者：
Abdel-Wahab O;Manshouri T;Patel J;Harris K;Yao J;Hedvat C;Heguy A;Bueso-Ramos C;Kantarjian H;Levine RL;Verstovsek S
通讯作者：
Verstovsek S
影响因子：
20.3
作者：
Finazzi, G;Caruso, V;Barbui, T
通讯作者：
Barbui, T
DOI：
10.1073/pnas.021282898
发表时间：
2001-01-30
影响因子：
11.1
作者：
Gottifredi, V;Shieh, SY;Prives, C
通讯作者：
Prives, C
影响因子：
20.3
作者：
Beer, Philip A.;Delhommeau, Francois;Green, Anthony R.
通讯作者：
Green, Anthony R.