Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.

de Smith, Adam J; Ojha, Juhi; Francis, Stephen S; Sanders, Erica; Endicott, Alyson A; Hansen, Helen M; Smirnov, Ivan; Termuhlen, Amanda M; Walsh, Kyle M; Metayer, Catherine; Wiemels, Joseph L

de Smith, Adam J; Ojha, Juhi; Francis, Stephen S; Sanders, Erica; Endicott, Alyson A; Hansen, Helen M; Smirnov, Ivan; Termuhlen, Amanda M; Walsh, Kyle M; Metayer, Catherine; Wiemels, Joseph L.

Afiliación

de Smith AJ; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Ojha J; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Francis SS; Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Sanders E; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Endicott AA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Hansen HM; Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Smirnov I; Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Termuhlen AM; Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Walsh KM; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Metayer C; Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Wiemels JL; School of Public Health, University of California Berkeley, Berkeley, California, United States of America.

Oncotarget ; 7(45): 72733-72745, 2016 Nov 08.

Article en En | MEDLINE | ID: mdl-27683039

RESUMEN

High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches.

Asunto(s)

Evolución Clonal/genética; Heterogeneidad Genética; Mutación; Poliploidía; Leucemia-Linfoma Linfoblástico de Células Precursoras/genética; Epigénesis Genética; Regulación Neoplásica de la Expresión Génica; Predisposición Genética a la Enfermedad; Secuenciación de Nucleótidos de Alto Rendimiento; Humanos; Sistema de Señalización de MAP Quinasas; Oncogenes; Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo; Transducción de Señal; Proteínas ras/genética; Proteínas ras/metabolismo

Palabras clave

DOT1L; high hyperdiploid acute lymphoblastic leukemia; microclonal mutations; targeted deep-sequencing; tumor heterogeneity

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poliploidía / Heterogeneidad Genética / Leucemia-Linfoma Linfoblástico de Células Precursoras / Evolución Clonal / Mutación Límite: Humans Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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