{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:21:23Z","timestamp":1791267683758,"version":"4.1.0"},"reference-count":47,"publisher":"Rockefeller University Press","issue":"9","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,8,27]]},"abstract":"<jats:p>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 (\u223c25%) cases of SMZL and in 1 of 19 (\u223c5%) 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.<\/jats:p>","DOI":"10.1084\/jem.20120910","type":"journal-article","created":{"date-parts":[[2012,8,14]],"date-time":"2012-08-14T01:51:59Z","timestamp":1344909119000},"page":"1553-1565","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":262,"title":["Whole-genome sequencing identifies recurrent somatic <i>NOTCH2<\/i> mutations in splenic marginal zone lymphoma"],"prefix":"10.1084","volume":"209","author":[{"given":"Mark J.","family":"Kiel","sequence":"first","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thirunavukkarasu","family":"Velusamy","sequence":"additional","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L.","family":"Betz","sequence":"additional","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut G.","family":"Weigelin","sequence":"additional","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Y.","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Huebner-Chan","sequence":"additional","affiliation":[{"name":"Southern California Permanente Medical Group, Los Angeles, CA 92807 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathanael G.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Pathology 1 , 2 , 3"},{"name":"Department of Biostatistics 1 , 2 , 3"},{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 1 , 2 , 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Yang","sequence":"additional","affiliation":[{"name":"University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Govind","family":"Bhagat","sequence":"additional","affiliation":[{"name":"The Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto N.","family":"Miranda","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, TX 77030 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Bahler","sequence":"additional","affiliation":[{"name":"The University of Utah Health Sciences Center, Salt Lake City, UT 84112 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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