Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma
Menée initialement sur 18 échantillons tumoraux et deux lignées cellulaires de lymphomes à cellules du manteau, une forme agressive de lymphome non hodgkinien, puis confirmée sur 108 échantillons cliniques et 8 lignées cellulaires, cette étude identifie la présence fréquente de mutations du gène NOTCH1
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 biological 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=0.003). 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.