A Quantitative Analysis of Subclonal and Clonal Gene Mutations before and after Therapy in Chronic Lymphocytic Leukemia.
A Quantitative Analysis of Subclonal and Clonal Gene Mutations before and after Therapy in Chronic Lymphocytic Leukemia.
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DOI：
10.1158/1078-0432.ccr-15-3103
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发表时间：
2016-09-01
期刊：
影响因子：
--
通讯作者：
Malek SN
中科院分区：
文献类型：
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作者：
Amin NA;Seymour E;Saiya-Cork K;Parkin B;Shedden K;Malek SN
CLL-associated gene mutations that influence CLL cell fitness and chemotherapy resistance should increase in clonal representation when measured before therapy and at relapse. To uncover mutations associated with CLL relapse, we have performed whole exome sequencing (WES) in a discovery cohort of sixty-one relapsed CLL patients identifying eighty-six recurrently mutated genes. The variant allele fractions (VAFs) of nineteen genes with mutations in ≥ 3/61 cases were measured in fifty-three paired pre- and post-treatment CLL samples sorted to purity using panel-based deep re-sequencing or by droplet digital PCR (ddPCR). We identify mutations in TP53 as the dominant subclonal gene driver of relapsed CLL often demonstrating substantial increases in VAFs. Subclonal mutations in SAMHD1 also recurrently demonstrated increased VAFs at relapse. Mutations in ATP10A, FAT3, FAM50A and MGA, although infrequent, demonstrated enrichment in ≥2 cases each. In contrast, mutations in NOTCH1, SF3B1, POT1, FBXW7, MYD88, NXF1, XPO1, ZMYM3 or CHD2 were predominantly already clonal prior to therapy indicative of a pre-treatment pathogenetic driver role in CLL. Quantitative analyses of clonal dynamics uncovers rising, stable and falling clones and subclones without clear evidence that gene mutations other than in TP53 and possibly SAMHD1 are frequently selected for at CLL relapse. Data in aggregate support a provisional categorization of CLL-associated recurrently mutated genes into three classes i) often subclonal pre-therapy and strongly enriched after therapy, or, ii) mostly clonal pre-therapy or without further enrichments at relapse, or, iii) subclonal before and after therapy and enriching only in sporadic cases.
