Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

Blood. 2012 Mar 1;119(9):1963-71. doi: 10.1182/blood-2011-11-391474. Epub 2011 Dec 30.

Abstract

Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Base Sequence
  • Benzodiazepinones / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D1 / genetics
  • Exons
  • Female
  • Gene Expression Profiling
  • Humans
  • Lymphoma, Mantle-Cell / genetics*
  • Lymphoma, Mantle-Cell / mortality
  • Male
  • Middle Aged
  • Mutation*
  • Prognosis
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / genetics*
  • Sequence Analysis, RNA*
  • Signal Transduction / drug effects
  • Survival Analysis
  • Transcriptome*

Substances

  • 2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
  • Benzodiazepinones
  • Receptor, Notch1
  • Cyclin D1
  • Amyloid Precursor Protein Secretases