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Patient-specific computational models predict prognosis in B cell lymphoma by quantifying pro-proliferative and anti-apoptotic signatures from genetic sequencing data.
Norris, Richard; Jones, John; Mancini, Erika; Chevassut, Timothy; Simoes, Fabio A; Pepper, Chris; Pepper, Andrea; Mitchell, Simon.
Afiliación
  • Norris R; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK.
  • Jones J; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK.
  • Mancini E; School of Life Sciences, University of Sussex, Brighton, UK.
  • Chevassut T; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK.
  • Simoes FA; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK.
  • Pepper C; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK.
  • Pepper A; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK.
  • Mitchell S; Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UK. S.A.Mitchell@bsms.ac.uk.
Blood Cancer J ; 14(1): 105, 2024 Jul 04.
Article en En | MEDLINE | ID: mdl-38965209
ABSTRACT
Genetic heterogeneity and co-occurring driver mutations impact clinical outcomes in blood cancers, but predicting the emergent effect of co-occurring mutations that impact multiple complex and interacting signalling networks is challenging. Here, we used mathematical models to predict the impact of co-occurring mutations on cellular signalling and cell fates in diffuse large B cell lymphoma and multiple myeloma. Simulations predicted adverse impact on clinical prognosis when combinations of mutations induced both anti-apoptotic (AA) and pro-proliferative (PP) signalling. We integrated patient-specific mutational profiles into personalised lymphoma models, and identified patients characterised by simultaneous upregulation of anti-apoptotic and pro-proliferative (AAPP) signalling in all genomic and cell-of-origin classifications (8-25% of patients). In a discovery cohort and two validation cohorts, patients with upregulation of neither, one (AA or PP), or both (AAPP) signalling states had good, intermediate and poor prognosis respectively. Combining AAPP signalling with genetic or clinical prognostic predictors reliably stratified patients into striking prognostic categories. AAPP patients in poor prognosis genetic clusters had 7.8 months median overall survival, while patients lacking both features had 90% overall survival at 120 months in a validation cohort. Personalised computational models enable identification of novel risk-stratified patient subgroups, providing a valuable tool for future risk-adapted clinical trials.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Blood Cancer J Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Blood Cancer J Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos