Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.
Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Mark J
MJ
Kiel
Thirunavukkarasu
T
Velusamy
Bryan L
BL
Betz
Lili
L
Zhao
Helmut G
HG
Weigelin
Mark Y
MY
Chiang
David R
DR
Huebner-Chan
Nathanael G
NG
Bailey
David T
DT
Yang
Govind
G
Bhagat
Roberto N
RN
Miranda
David W
DW
Bahler
L Jeffrey
LJ
Medeiros
Megan S
MS
Lim
Kojo S J
KS
Elenitoba-Johnson
D000368:Aged; D005260:Female; D015894:Genome, Human; D006801:Humans; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017434:Protein Structure, Tertiary; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013160:Splenic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate
C497764:NOTCH2 protein, human; D051883:Receptor, Notch2