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.

Základní údaje

Originální název

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

Autoři

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 9.944

Kód RIV

RIV/00216224:14110/18:00101843

Organizační jednotka

Lékařská fakulta

DOI

https://doi.org/10.1038/leu.2017.230

UT WoS

000424517300022

EID Scopus

2-s2.0-85042279722

Klíčová slova anglicky

TP53 mutations; myeloproliferative neoplasms

Štítky

14110212, CF GEN, EL OK, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 13. 3. 2019 17:48, Mgr. Pavla Foltynová, Ph.D.

Anotace

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.

Návaznosti

LM2011020, projekt VaV

Název: CEITEC ? open access

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC - open access

LM2015064, projekt VaV

Název: Český národní uzel Evropské infrastruktury pro translační medicínu (Akronym: EATRIS-ERIC-CZ)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Involvement of Czech Translational Medicine Infrastructure to the European Advanced Translational Research Infrastructure in Medicine

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

MUNI/A/1106/2016, interní kód MU

Název: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit IV (Akronym: VýDiTeHeMA IV)

Investor: Masarykova univerzita, Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit IV, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

NV16-29447A, projekt VaV

Název: Vyhledávání mutací predisponujících k familiárním hematologickým a onkologickým onemocněním

ROZV/24/LF/2016, interní kód MU

Název: LF - Příspěvek IP 2016

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, LF - Příspěvek IP 2016

TE02000058, projekt VaV

Název: Centrum kompetence pro molekulární diagnostiku a personalizovanou medicínu (Akronym: MOLDIMED)

Investor: Technologická agentura ČR, Centrum kompetence pro molekulární diagnostiku a personalizovanou medicínu

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 a Michael DOUBEK. 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, roč. 32, č. 2, s. 450-461. ISSN 0887-6924. Dostupné z: https://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 = {https://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 a Michael DOUBEK. 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, roč.~32, č.~2, s.~450-461. ISSN~0887-6924. Dostupné z: https://doi.org/10.1038/leu.2017.230.

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