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000142962 1001_ $$aLeeksma, Alexander C$$b0
000142962 245__ $$aClonal diversity predicts adverse outcome in chronic lymphocytic leukemia.
000142962 260__ $$aLondon$$bSpringer Nature$$c2019
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000142962 520__ $$aGenomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 'progressors' and 17 matched 'non-progressors') using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.
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000142962 7001_ $$00000-0003-4407-6325$$aTaylor, Justin$$b1
000142962 7001_ $$0P:(DE-He78)f385b8b832d53e921e7af2af3c625418$$aWu, Bian$$b2$$eFirst author
000142962 7001_ $$aGardner, Jeffrey R$$b3
000142962 7001_ $$aHe, Jie$$b4
000142962 7001_ $$aNahas, Michelle$$b5
000142962 7001_ $$aGonen, Mithat$$b6
000142962 7001_ $$aAlemayehu, Wendimagegn G$$b7
000142962 7001_ $$aTe Raa, Doreen$$b8
000142962 7001_ $$0P:(DE-He78)e8feda17d03b95bda3e8717e79dc07b8$$aWalther, Tatjana$$b9
000142962 7001_ $$0P:(DE-He78)c9be4ab60d1090c3d315a2ca6905e9ea$$aHüllein, Jennifer$$b10
000142962 7001_ $$aDietrich, Sascha$$b11
000142962 7001_ $$aClaus, Rainer$$b12
000142962 7001_ $$ade Boer, Fransien$$b13
000142962 7001_ $$ade Heer, Koen$$b14
000142962 7001_ $$aDubois, Julie$$b15
000142962 7001_ $$aDampmann, Maria$$b16
000142962 7001_ $$aDürig, Jan$$b17
000142962 7001_ $$avan Oers, Marinus H J$$b18
000142962 7001_ $$aGeisler, Christian H$$b19
000142962 7001_ $$aEldering, Eric$$b20
000142962 7001_ $$aLevine, Ross L$$b21
000142962 7001_ $$aMiller, Vincent$$b22
000142962 7001_ $$aMughal, Tariq$$b23
000142962 7001_ $$aLamanna, Nicole$$b24
000142962 7001_ $$aFrattini, Mark G$$b25
000142962 7001_ $$aHeaney, Mark L$$b26
000142962 7001_ $$aZelenetz, Andrew$$b27
000142962 7001_ $$0P:(DE-He78)f3d5f16b49eb47520def635be98d5576$$aZenz, Thorsten$$b28$$eLast author
000142962 7001_ $$aAbdel-Wahab, Omar$$b29
000142962 7001_ $$aKater, Arnon P$$b30
000142962 773__ $$0PERI:(DE-600)2008023-2$$a10.1038/s41375-018-0215-9$$gVol. 33, no. 2, p. 390 - 402$$n2$$p390 - 402$$tLeukemia$$v33$$x1476-5551$$y2019
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