Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma.
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.
Centre for Lymphoid Cancer, British Columbia Cancer Agency, 675 W.10th Ave.,Vancouver, BC, Canada.
Robert
R
Kridel
Barbara
B
Meissner
Sanja
S
Rogic
Merrill
M
Boyle
Adele
A
Telenius
Bruce
B
Woolcock
Jay
J
Gunawardana
Catherine E
CE
Jenkins
Chris
C
Cochrane
Susana
S
Ben-Neriah
King
K
Tan
Ryan D
RD
Morin
Stephen
S
Opat
Laurie H
LH
Sehn
Joseph M
JM
Connors
Marco A
MA
Marra
Andrew P
AP
Weng
Christian
C
Steidl
Randy D
RD
Gascoyne
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001570:Benzodiazepinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D059467:Transcriptome
C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; D051881:Receptor, Notch1; D019938:Cyclin D1; D053829:Amyloid Precursor Protein Secretases