Identifying novel mechanisms of biallelic TP53 loss refines poor outcome for patients with multiple myeloma.
Identifying novel mechanisms of biallelic TP53 loss refines poor outcome for patients with multiple myeloma.
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DOI：
10.1038/s41408-023-00919-2
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发表时间：
2023-09-11
影响因子：
12.8
通讯作者：
Walker, Brian A.
中科院分区：
文献类型：
--
作者：
Liu, Enze;Sudha, Parvathi;Becker, Nathan;Jaouadi, Oumaima;Suvannasankha, Attaya;Lee, Kelvin;Abonour, Rafat;Abu Zaid, Mohammad;Walker, Brian A.
双等位基因TP53失活是多发性骨髓瘤患者生存不良的最重要的高危因素。在大多数研究中，经典的双等位基因TP53失活被定义为同时突变和拷贝数丢失；然而，大量研究表明，其他因素也可能导致TP53失活。在这里，我们假设多发性骨髓瘤人群中存在新的双等位基因TP53灭活样本。随后建立了一个随机森林回归模型，该模型利用了经典双等位基因TP53和野生型TP53之间的16个差异表达基因的表达特征，并用于从单等位基因TP53中识别新的双等位基因TP53。该模型在新诊断的复发和难治性人群中反映了高准确性和稳健的表现。经典和新型双等位基因TP53样本的患者存活率始终比单等位基因或野生型TP53样本差得多。我们还证明了一些预测的双等位基因TP53样本同时存在拷贝数丢失和异常剪接，导致高危转录变异体过度表达，导致双等位基因失活。我们发现剪接位点突变和剪接因子MED18的过度表达是导致剪接异常的原因。综上所述，我们的研究揭示了TP53的复杂转录组，其中一些可能有助于未来针对异常TP53的研究。
Biallelic TP53 inactivation is the most important high-risk factor associated with poor survival in multiple myeloma. Classical biallelic TP53 inactivation has been defined as simultaneous mutation and copy number loss in most studies; however, numerous studies have demonstrated that other factors could lead to the inactivation of TP53. Here, we hypothesized that novel biallelic TP53 inactivated samples existed in the multiple myeloma population. A random forest regression model that exploited an expression signature of 16 differentially expressed genes between classical biallelic TP53 and TP53 wild-type samples was subsequently established and used to identify novel biallelic TP53 samples from monoallelic TP53 groups. The model reflected high accuracy and robust performance in newly diagnosed relapsed and refractory populations. Patient survival of classical and novel biallelic TP53 samples was consistently much worse than those with mono-allelic or wild-type TP53 status. We also demonstrated that some predicted biallelic TP53 samples simultaneously had copy number loss and aberrant splicing, resulting in overexpression of high-risk transcript variants, leading to biallelic inactivation. We discovered that splice site mutation and overexpression of the splicing factor MED18 were reasons for aberrant splicing. Taken together, our study unveiled the complex transcriptome of TP53, some of which might benefit future studies targeting abnormal TP53.
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影响因子：
82.9
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
通讯作者：
Papaemmanuil E
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
3.7
作者：
Boyd, Kevin D.;Ross, Fiona M.;Morgan, Gareth J.
通讯作者：
Morgan, Gareth J.
影响因子：
20.3
作者：
Drach, J;Ackermann, J;Huber, H
通讯作者：
Huber, H
影响因子：
10.1
作者：
Caers J;Garderet L;Kortüm KM;O'Dwyer ME;van de Donk NWCJ;Binder M;Dold SM;Gay F;Corre J;Beguin Y;Ludwig H;Larocca A;Driessen C;Dimopoulos MA;Boccadoro M;Gramatzki M;Zweegman S;Einsele H;Cavo M;Goldschmidt H;Sonneveld P;Delforge M;Auner HW;Terpos E;Engelhardt M
通讯作者：
Engelhardt M