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

J 2018

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

KUBEŠOVÁ, Blanka, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Jitka KABÁTHOVÁ, Lenka RADOVÁ et. al.

Basic information

Original name

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

Authors

KUBEŠOVÁ, Blanka (203 Czech Republic, belonging to the institution), Šárka PAVLOVÁ (203 Czech Republic, guarantor, belonging to the institution), Jitka MALČÍKOVÁ (203 Czech Republic, belonging to the institution), Jitka KABÁTHOVÁ (203 Czech Republic, belonging to the institution), Lenka RADOVÁ (203 Czech Republic, belonging to the institution), Nikola TOM (203 Czech Republic, belonging to the institution), Boris TICHÝ (203 Czech Republic, belonging to the institution), Karla PLEVOVÁ (203 Czech Republic, belonging to the institution), Barbara KANTOROVÁ (203 Czech Republic, belonging to the institution), Kristýna FIEDOROVÁ (203 Czech Republic, belonging to the institution), M. SLAVIKOVA (203 Czech Republic), Vojtěch BYSTRÝ (203 Czech Republic, belonging to the institution), Jarmila KISSOVÁ (203 Czech Republic, belonging to the institution), B. GISSLINGER (40 Austria), H. GISSLINGER (40 Austria), Miroslav PENKA (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution), R. KRALOVICS (40 Austria), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution) and Michael DOUBEK (203 Czech Republic, belonging to the institution)

Edition

Leukemia, London, Nature Publishing Group, 2018, 0887-6924

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 9.944

RIV identification code

RIV/00216224:14110/18:00101843

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1038/leu.2017.230

UT WoS

000424517300022

Keywords in English

TP53 mutations; myeloproliferative neoplasms

Abstract

V originále

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.

Links

LM2011020, research and development project

Name: CEITEC ? open access

Investor: Ministry of Education, Youth and Sports of the CR

LM2015064, research and development project

Name: Český národní uzel Evropské infrastruktury pro translační medicínu (Acronym: EATRIS-ERIC-CZ)

Investor: Ministry of Education, Youth and Sports of the CR

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1106/2016, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit IV (Acronym: VýDiTeHeMA IV)

Investor: Masaryk University, Category A

NV16-29447A, research and development project

Name: Vyhledávání mutací predisponujících k familiárním hematologickým a onkologickým onemocněním

ROZV/24/LF/2016, interní kód MU

Name: LF - Příspěvek IP 2016

Investor: Ministry of Education, Youth and Sports of the CR

TE02000058, research and development project

Name: Centrum kompetence pro molekulární diagnostiku a personalizovanou medicínu (Acronym: MOLDIMED)

Investor: Technology Agency of the Czech Republic

Citovat

KUBEŠOVÁ, Blanka, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Jitka KABÁTHOVÁ, Lenka RADOVÁ, Nikola TOM, Boris TICHÝ, Karla PLEVOVÁ, Barbara KANTOROVÁ, Kristýna FIEDOROVÁ, M. SLAVIKOVA, Vojtěch BYSTRÝ, Jarmila KISSOVÁ, B. GISSLINGER, H. GISSLINGER, Miroslav PENKA, Jiří MAYER, R. KRALOVICS, Šárka POSPÍŠILOVÁ and Michael DOUBEK. 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.). Leukemia. London: Nature Publishing Group, 2018, vol. 32, No 2, p. 450-461. ISSN 0887-6924. Available from: https://dx.doi.org/10.1038/leu.2017.230.

@article{1404544,
   author = {Kubešová, Blanka and Pavlová, Šárka and Malčíková, Jitka and Kabáthová, Jitka and Radová, Lenka and Tom, Nikola and Tichý, Boris and Plevová, Karla and Kantorová, Barbara and Fiedorová, Kristýna and Slavikova, M. and Bystrý, Vojtěch and Kissová, Jarmila and Gisslinger, B. and Gisslinger, H. and Penka, Miroslav and Mayer, Jiří and Kralovics, R. and Pospíšilová, Šárka and Doubek, Michael},
   article_location = {London},
   article_number = {2},
   doi = {http://dx.doi.org/10.1038/leu.2017.230},
   keywords = {TP53 mutations; myeloproliferative neoplasms},
   language = {eng},
   issn = {0887-6924},
   journal = {Leukemia},
   title = {Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status},
   volume = {32},
   year = {2018}
}

TY  - JOUR
ID  - 1404544
AU  - 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
PY  - 2018
TI  - Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status
JF  - Leukemia
VL  - 32
IS  - 2
SP  - 450-461
EP  - 450-461
PB  - Nature Publishing Group
SN  - 08876924
KW  - TP53 mutations
KW  - myeloproliferative neoplasms
N2  - 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.
ER  -

KUBEŠOVÁ, Blanka, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Jitka KABÁTHOVÁ, Lenka RADOVÁ, Nikola TOM, Boris TICHÝ, Karla PLEVOVÁ, Barbara KANTOROVÁ, Kristýna FIEDOROVÁ, M. SLAVIKOVA, Vojtěch BYSTRÝ, Jarmila KISSOVÁ, B. GISSLINGER, H. GISSLINGER, Miroslav PENKA, Jiří MAYER, R. KRALOVICS, Šárka POSPÍŠILOVÁ and Michael DOUBEK. 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.). \textit{Leukemia}. London: Nature Publishing Group, 2018, vol.~32, No~2, p.~450-461. ISSN~0887-6924. Available from: https://dx.doi.org/10.1038/leu.2017.230.

Detailed Information on Publication Record