Implications ofTP53allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

被引：461

作者：

Bernard, Elsa ^{[1
,2
]}

Nannya, Yasuhito ^{[3
]}

Hasserjian, Robert P. ^{[4
]}

Devlin, Sean M. ^{[5
]}

Tuechler, Heinz ^{[5
]}

Medina-Martinez, Juan S. ^{[1
,2
]}

Yoshizato, Tetsuichi ^{[3
]}

Shiozawa, Yusuke ^{[3
]}

Saiki, Ryunosuke ^{[3
]}

Malcovati, Luca ^{[6
,7
]}

Levine, Max F. ^{[1
,2
]}

Arango, Juan E. ^{[1
,2
]}

Zhou, Yangyu ^{[1
,2
]}

Sole, Francesc ^{[8
]}

Cargo, Catherine A. ^{[9
]}

Haase, Detlef ^{[10
,11
]}

Creignou, Maria ^{[12
]}

Germing, Ulrich ^{[13
]}

Zhang, Yanming ^{[14
]}

Gundem, Gunes ^{[1
]}

Sarian, Araxe ^{[2
]}

van de Loosdrecht, Arjan A. ^{[15
]}

Jadersten, Martin ^{[12
]}

Tobiasson, Magnus ^{[12
]}

Kosmider, Olivier ^{[16
,17
]}

Follo, Matilde Y. ^{[18
]}

Thol, Felicitas ^{[19
]}

Pinheiro, Ronald F. ^{[20
]}

Santini, Valeria ^{[21
]}

Kotsianidis, Ioannis ^{[22
]}

Boultwood, Jacqueline ^{[23
,24
]}

Santos, Fabio P. S. ^{[25
]}

Schanz, Julie ^{[10
,11
]}

Kasahara, Senji ^{[26
]}

Ishikawa, Takayuki ^{[27
]}

Tsurumi, Hisashi ^{[28
]}

Takaori-Kondo, Akifumi ^{[29
]}

Kiguchi, Toru ^{[30
]}

Polprasert, Chantana ^{[31
]}

Bennett, John M. ^{[32
]}

Klimek, Virginia M. ^{[33
]}

Savona, Michael R. ^{[34
]}

Belickova, Monika ^{[35
]}

Ganster, Christina ^{[10
,11
]}

Palomo, Laura ^{[8
]}

Sanz, Guillermo ^{[36
,37
]}

Ades, Lionel ^{[38
,39
]}

Della Porta, Matteo Giovanni ^{[40
,41
]}

Smith, Alexandra G. ^{[42
]}

Werner, Yesenia ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Computat Oncol Serv, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Ctr Hematol Malignancies, 1275 York Ave, New York, NY 10021 USA

[3] Kyoto Univ, Dept Pathol & Tumor Biol, Kyoto, Japan

[4] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[6] Univ Pavia, Dept Mol Med, Pavia, Italy

[7] IRCCS Fdn Policlin S Matteo, Dept Hematol, Pavia, Italy

[8] Inst Recerca Leucemia Josep Carreras, MDS Grp, Barcelona, Spain

[9] St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England

[10] Univ Med Ctr, Clin Hematol, Gottingen, Germany

[11] Univ Med Ctr, Clin Med Oncol, Gottingen, Germany

[12] Karolinska Univ Hosp, Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Stockholm, Sweden

[13] Heinrich Heine Univ, Dept Hematol Oncol & Clin Immunol, Dusseldorf, Germany

[14] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[15] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Hematol, Amsterdam, Netherlands

[16] Hop Cochin, AP HP, Dept Hematol, Paris, France

[17] Univ Paris 05, Univ Paris, Paris, France

[18] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy

[19] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany

[20] Univ Fed Ceara, Drug Res & Dev Ctr, Fortaleza, Ceara, Brazil

[21] Univ Florence, AOU Careggi, Hematol, MDS Unit, Florence, Italy

[22] Democritus Univ Thrace, Sch Med, Dept Hematol, Alexandroupolis, Greece

[23] Univ Oxford, Radcliffe Dept Med, Oxford, England

[24] Oxford BRC Haematol Theme, Oxford, England

[25] Hosp Israelita Albert Einstein, Oncol Hematol Ctr, Sao Paulo, Brazil

[26] Gifu Municipal Hosp, Dept Hematol, Gifu, Japan

[27] Kobe City Med Ctr Gen Hosp, Dept Hematol, Kobe, Hyogo, Japan

[28] Gifu Univ, Dept Hematol, Grad Sch Med, Gifu, Japan

[29] Kyoto Univ, Dept Hematol & Oncol, Grad Sch Med, Kyoto, Japan

[30] Chugoku Cent Hosp, Dept Hematol, Fukuyama, Hiroshima, Japan

[31] Chulalongkorn Univ, King Chulalongkorn Mem Hosp, Dept Med, Bangkok, Thailand

[32] Univ Rochester, Med Ctr, Lab Med & Pathol, Hematol Oncol, Rochester, NY 14642 USA

[33] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[34] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37212 USA

[35] Inst Hematol & Blood Transfus, Dept Genom, Prague, Czech Republic

[36] Hosp Univ & Politecn La Fe, Dept Hematol, Valencia, Spain

[37] Inst Salud Carlos III, CIBERONC, Madrid, Spain

[38] Hop St Louis, Dept Hematol, Paris, France

[39] Paris Univ, Paris, France

[40] Humanitas Res Hosp, Canc Ctr, Milan, Italy

[41] Humanitas Univ, Milan, Italy

[42] Univ York, Dept Hlth Sci, York, N Yorkshire, England

[43] Mem Sloan Kettering Canc Ctr, Integrated Genom Operat, 1275 York Ave, New York, NY 10021 USA

[44] Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02115 USA

[45] Univ Leipzig, Hematol & Cellular Therapy, Med Clin & Policlin 1, Leipzig, Germany

[46] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria

[47] Med Univ Vienna, Ludwig Boltzmann Inst Hematol & Oncol, Vienna, Austria

[48] Univ Tsukuba, Fac Med, Dept Hematol, Tsukuba, Ibaraki, Japan

[49] Nagasaki Univ, Atom Bomb Dis Inst, Dept Hematol, Nagasaki, Japan

[50] S Orsola Malpighi Univ Hosp, Inst Hematol, Bologna, Italy

来源：

NATURE MEDICINE | 2020年 / 26卷 / 10期

基金：

日本学术振兴会; 奥地利科学基金会;

关键词：

ACUTE MYELOID-LEUKEMIA; MUTATIONAL LANDSCAPE; MONOSOMAL KARYOTYPE; ALLELE FREQUENCY; POINT MUTATIONS; TP53; MUTATIONS; SCORING SYSTEM; P53; PROGNOSIS; CLASSIFICATION;

D O I：

10.1038/s41591-020-1008-z

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states ofTP53and clinical presentation Tumor protein p53 (TP53) is the most frequently mutated gene in cancer(1,2). In patients with myelodysplastic syndromes (MDS),TP53mutations are associated with high-risk disease(3,4), rapid transformation to acute myeloid leukemia (AML)(5), resistance to conventional therapies(6-8)and dismal outcomes(9). Consistent with the tumor-suppressive role ofTP53, patients harbor both mono- and biallelic mutations(10). However, the biological and clinical implications ofTP53allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS forTP53mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third ofTP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only.TP53multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)(11). Surprisingly, monoallelic patients did not differ fromTP53wild-type patients in outcomes and response to therapy. This study shows that consideration ofTP53allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.

引用

页码：1549 / +

页数：27

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