Identification of novel chronic lymphocytic leukemia subtypes using pathway mutation scores and consensus clustering

Kód výsledku v IS VaVaI

RIV/65269705:_____/19:00071771 - isvavai.cz

Nalezeny alternativní kódy

RIV/00216224:14740/19:00108577

Výsledek na webu

https://www.nature.com/articles/s41431-019-0494-2

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

Identification of novel chronic lymphocytic leukemia subtypes using pathway mutation scores and consensus clustering

Popis výsledku v původním jazyce

Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia with variable clinical course underlain by striking genetic heterogeneity. CLL features a handful of putative driver genes and, more interestingly, a large number of non-recurrently mutated genes with elusive clinical implications. The aim of this study was to unravel the prognostic impact of pathway somatic mutation patterns in CLL. Materials and Methods: We focused on a cohort of 316 CLL patients defined by mutated IGHV with somatic mutation data gathered by International Cancer Genome Consortium. In this cohort we collected 4739 genes affected by nonsynonymous point and/or frameshift mutations. We performed gene set enrichment analysis to identify affected biological pathways, applied set theory to reduce redundancy in enriched gene sets, calculated pathway mutation scores for each patient and performed consensus clustering. Finally, we evaluated the difference in time to therapy (TTT) between identified CLL clusters. Results: We identified eight clusters differing in TTT (p<0.0001); seven of these were characterized by distinct affected biological processes: namely, cell adhesion (21/23 mutated cases in the cluster), membrane depolarization (27/32), synapse organization (18/22), glycosylation (19/25), Rho protein signal transduction (27/37), oxytocin signalling and/or renin secretion (26/40), and transport through ABC transporters (11/20; patients with the earliest need for therapy). Conclusion: Among CLL patients with mutated IGHV we identified distinct subgroups with non-recurrently mutated genes involved in a limited number of biological pathways. Our findings have far-reaching implications for CLL diagnostics.

Název v anglickém jazyce

Identification of novel chronic lymphocytic leukemia subtypes using pathway mutation scores and consensus clustering

Popis výsledku anglicky

Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia with variable clinical course underlain by striking genetic heterogeneity. CLL features a handful of putative driver genes and, more interestingly, a large number of non-recurrently mutated genes with elusive clinical implications. The aim of this study was to unravel the prognostic impact of pathway somatic mutation patterns in CLL. Materials and Methods: We focused on a cohort of 316 CLL patients defined by mutated IGHV with somatic mutation data gathered by International Cancer Genome Consortium. In this cohort we collected 4739 genes affected by nonsynonymous point and/or frameshift mutations. We performed gene set enrichment analysis to identify affected biological pathways, applied set theory to reduce redundancy in enriched gene sets, calculated pathway mutation scores for each patient and performed consensus clustering. Finally, we evaluated the difference in time to therapy (TTT) between identified CLL clusters. Results: We identified eight clusters differing in TTT (p<0.0001); seven of these were characterized by distinct affected biological processes: namely, cell adhesion (21/23 mutated cases in the cluster), membrane depolarization (27/32), synapse organization (18/22), glycosylation (19/25), Rho protein signal transduction (27/37), oxytocin signalling and/or renin secretion (26/40), and transport through ABC transporters (11/20; patients with the earliest need for therapy). Conclusion: Among CLL patients with mutated IGHV we identified distinct subgroups with non-recurrently mutated genes involved in a limited number of biological pathways. Our findings have far-reaching implications for CLL diagnostics.

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

NV16-29447A: Vyhledávání mutací predisponujících k familiárním hematologickým a onkologickým onemocněním

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů