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Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
Elsa Bernard ,
Yasuhito Nannya ,
Robert P. Hasserjian ,
Sean M. Devlin ,
Heinz Tuechler ,
Juan S. Medina-Martinez ,
Tetsuichi Yoshizato ,
Yusuke Shiozawa ,
Ryunosuke Saiki ,
Luca Malcovati ,
Max F. Levine ,
Juan E. Arango ,
Yangyu Zhou ,
Francesc Solé ,
Catherine A. Cargo ,
Detlef Haase ,
Maria Creignou ,
Ulrich Germing ,
Yanming Zhang ,
Gunes Gundem ,
Araxe Sarian ,
Arjan A. van de Loosdrecht ,
Martin Jädersten ,
Magnus Tobiasson ,
Olivier Kosmider ,
Matilde Y. Follo ,
Felicitas Thol ,
Ronald F. Pinheiro ,
Valeria Santini ,
Ioannis Kotsianidis ,
Jacqueline Boultwood ,
Fabio P. S. Santos ,
Julie Schanz ,
Senji Kasahara ,
Takayuki Ishikawa ,
Hisashi Tsurumi ,
Akifumi Takaori-Kondo ,
Toru Kiguchi ,
Chantana Polprasert ,
John M. Bennett ,
Virginia M. Klimek ,
Michael R. Savona ,
Monika Belickova ,
Christina Ganster ,
Laura Palomo ,
Guillermo Sanz ,
Lionel Ades ,
Matteo Giovanni Della Porta ,
Alexandra G. Smith ,
Yesenia Werner ,
Minal Patel ,
Agnès Viale ,
Katelynd Vanness ,
Donna S. Neuberg ,
Kristen E. Stevenson ,
Kamal Menghrajani ,
Kelly L. Bolton ,
Pierre Fenaux ,
Andrea Pellagatti ,
Uwe Platzbecker ,
Michael Heuser ,
Peter Valent ,
Shigeru Chiba ,
Yasushi Miyazaki ,
Carlo Finelli ,
Maria Teresa Voso ,
Lee-Yung Shih ,
Michaela Fontenay ,
Joop H. Jansen ,
José Cervera ,
Yoshiko Atsuta ,
Norbert Gattermann ,
Benjamin L. Ebert ,
Rafael Bejar ,
Peter L. Greenberg ,
Mario Cazzola ,
Eva Hellström-Lindberg ,
Seishi Ogawa ,
Elli Papaemmanuil
August 3 2020
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Abstract
<p class="first" id="d5053415e1161">Tumor protein p53 (TP53) is the most frequently
mutated gene in cancer1,2. In patients
with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk
disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional
therapies6-8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53,
patients harbor both mono- and biallelic mutations10. However, the biological and
clinical implications of TP53 allelic state have not been fully investigated in MDS
or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and
allelic imbalances and delineated two subsets of patients with distinct phenotypes
and outcomes. One-third of TP53-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. TP53 multi-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
from TP53 wild-type patients in outcomes and response to therapy. This study shows
that consideration of TP53 allelic state is critical for diagnostic and prognostic
precision in MDS as well as in future correlative studies of treatment response.
</p>