美国斯隆·凯特琳纪念癌症中心Elli Papaemmanuil课题组在研究中取得进展。他们分析了TP53等位基因状态对骨髓增生异常综合症的基因组稳定性、临床表现和预后的影响。该研究于2020年8月3日发表于《自然-医学》。

他们分析了3,324名MDS患者的TP53突变和等位基因失衡，并描绘了具有不同表型和结果的患者的两个亚群。TP53突变的患者中有三分之一具有单等位基因突变，而三分之二的患者具有多突变（多位点突变），与双等位基因靶向一致。已建立的具有复杂核型，很少同时发生突变，高风险表现和不良预后的关联仅针对多发患者。TP53多发状态独立于修订的国际预后评分系统（IPSS-R），预测死亡和白血病转化的风险。

令人惊讶的是，单等位基因患者与TP53野生型患者在预后和对治疗的反应方面没有差异。这项研究表明，考虑TP53等位基因状态对于MDS的诊断和预后准确性以及未来治疗反应的相关研究至关重要。

据悉，肿瘤蛋白p53（TP53）是癌症中最常见的突变基因。在患有骨髓增生异常综合症（MDS）的患者中，TP53突变与高危疾病，快速转化为急性髓细胞性白血病（AML），对常规疗法的耐药性和预后不良有关。与TP53的肿瘤抑制作用一致，患者同时携带单等位基因突变和双等位基因突变。但是，尚未在MDS或任何其他癌症类型中对TP53等位基因状态的生物学和临床意义进行全面研究。

附：英文原文

Title: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Author: 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 Sol, Catherine A. Cargo, Detlef Haase, Maria Creignou, Ulrich Germing, Yanming Zhang, Gunes Gundem, Araxe Sarian, Arjan A. van de Loosdrecht, Martin Jdersten, 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, Agns 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, Jos Cervera, Yoshiko Atsuta, Norbert Gattermann

Issue&Volume: 2020-08-03

Abstract: 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 therapies6,7,8 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 3,324patients 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.

DOI: 10.1038/s41591-020-1008-z

Source: https://www.nature.com/articles/s41591-020-1008-z