Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.
Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.
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DOI：
10.1038/s41591-020-1008-z
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发表时间：
2020-10
期刊：
影响因子：
82.9
通讯作者：
Papaemmanuil E
中科院分区：
文献类型：
--
作者：
Bernard E;Nannya Y;Hasserjian RP;Devlin SM;Tuechler H;Medina-Martinez JS;Yoshizato T;Shiozawa Y;Saiki R;Malcovati L;Levine MF;Arango JE;Zhou Y;Solé F;Cargo CA;Haase D;Creignou M;Germing U;Zhang Y;Gundem G;Sarian A;van de Loosdrecht AA;Jädersten M;Tobiasson M;Kosmider O;Follo MY;Thol F;Pinheiro RF;Santini V;Kotsianidis I;Boultwood J;Santos FPS;Schanz J;Kasahara S;Ishikawa T;Tsurumi H;Takaori-Kondo A;Kiguchi T;Polprasert C;Bennett JM;Klimek VM;Savona MR;Belickova M;Ganster C;Palomo L;Sanz G;Ades L;Della Porta MG;Elias HK;Smith AG;Werner Y;Patel M;Viale A;Vanness K;Neuberg DS;Stevenson KE;Menghrajani K;Bolton KL;Fenaux P;Pellagatti A;Platzbecker U;Heuser M;Valent P;Chiba S;Miyazaki Y;Finelli C;Voso MT;Shih LY;Fontenay M;Jansen JH;Cervera J;Atsuta Y;Gattermann N;Ebert BL;Bejar R;Greenberg PL;Cazzola M;Hellström-Lindberg E;Ogawa S;Papaemmanuil E
肿瘤蛋白P53(Tumor Protein P53，TP53)是肿瘤中最常见的突变基因。在骨髓增生异常综合征(MDS)患者中，TP53突变与高危疾病、快速转化为急性髓系白血病(AML)、对传统治疗的抵抗和令人沮丧的结果有关。与TP53的肿瘤抑制作用一致，患者同时存在单等位基因突变和双等位基因突变。然而，在MDS或任何其他癌症类型中，尚未充分研究TP53等位基因状态的生物学和临床意义。我们分析了3324名MDS患者的TP53突变和等位基因失衡，并描述了两组具有不同表型和结果的患者。三分之一的TP53突变患者具有单等位基因突变，而三分之二的患者具有与双等位基因靶向一致的多重命中(多命中)。已建立的与复杂的核型、很少的共生突变、高风险表现和不良预后的关联仅限于多发患者。TP53多次打击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，单等位基因患者与野生型TP53患者在结果和治疗反应上没有不同。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。
Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. 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). 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.
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影响因子：
11.4
作者：
通讯作者：
--
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
28.2
作者：
Chang MT;Bhattarai TS;Schram AM;Bielski CM;Donoghue MTA;Jonsson P;Chakravarty D;Phillips S;Kandoth C;Penson A;Gorelick A;Shamu T;Patel S;Harris C;Gao J;Sumer SO;Kundra R;Razavi P;Li BT;Reales DN;Socci ND;Jayakumaran G;Zehir A;Benayed R;Arcila ME;Chandarlapaty S;Ladanyi M;Schultz N;Baselga J;Berger MF;Rosen N;Solit DB;Hyman DM;Taylor BS
通讯作者：
Taylor BS
DOI：
10.1056/nejmoa1013343
发表时间：
2011-06-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bejar R;Stevenson K;Abdel-Wahab O;Galili N;Nilsson B;Garcia-Manero G;Kantarjian H;Raza A;Levine RL;Neuberg D;Ebert BL
通讯作者：
Ebert BL
影响因子：
20.3
作者：
Malcovati L;Papaemmanuil E;Bowen DT;Boultwood J;Della Porta MG;Pascutto C;Travaglino E;Groves MJ;Godfrey AL;Ambaglio I;Gallì A;Da Vià MC;Conte S;Tauro S;Keenan N;Hyslop A;Hinton J;Mudie LJ;Wainscoat JS;Futreal PA;Stratton MR;Campbell PJ;Hellström-Lindberg E;Cazzola M;Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative
通讯作者：
Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative