Recently, the molecular aberration of chronic lymphocytic leukemia (CLL) has been widely investigated in the Western population. Genes mutation detecting by next generation sequencing (NGS) provided a fair-new view to explain the pathogenesis of CLL and guide the clinical practices. Limited primary data indicated the mutation signature of CLL in China might be different from the Western reports, which deserved further systematical investigation.


A panel with 76 genes was designed to identify mutation status by NGS in 129 CLL patients. This 76 genes panel had been reported as recurrent mutation in CLL and other lymphoproliferative disorders. Whole exomes of each gene were sequenced with a mean read depth of 1957 and a coverage of target region of 99.6%.


We finally revealed the presence of recurrent mutations (n ≥ 2) in 63 genes. The most frequency of mutational genes were as follow: FAT1, 35 cases (27.1%); KMT2D/MLL2, 29 cases (22.5%); TP53, 26 cases (20.2%); FAT4 24 cases (18.6%); NOTCH1, 22 cases (17.1%); ATM, 19 cases (14.7%); FBXW7, 16 cases (12.4%); SPEN, 16 cases (12.4%); BRAF, 15 cases (11.6%); MYD88 14 cases (10.9%); SF3B1, 14 cases (10.9%); APC, 13 cases (10.1%); CREBBP 13 cases (10.1%); TET2, 13 cases (10.1%); POT1, 11 cases (8.5%); EP300, 10 cases (7.8%); KMT2B, 10 cases (7.8%); MAP3K14, 10 cases (7.8%); TCF3, 10 cases (7.8%); NOTCH2, 9 cases (7.0%); KLF2, 8 cases (6.2%); SMARCA4, 8 cases (6.2%); BIRC3, 7 cases (5.4%); EGR2, 7 cases (5.4%); KLHL31, 7 cases (5.4%); KLHL6, 7 cases (5.4%), et al.

We compared the mutated sites of each gene in this study with other established studies, and found that the mutation sites distribution of each recurrent mutated gene were comparable to the well-known mutated sites, which indicated the similar function change. Then, we classified these recurrent mutation genes into different signaling pathway, according to their affected function. We found that chromatin modification pathway was the most affected pathway, accounting for 74 patients (57.4%), followed by NF-κB pathway (58 patients, 45.0%), NOTHC1 pathway (52 patients, 40.3%), Hippo pathway (50 patients, 38.8%), DNA damage pathway (48 patients, 37.2%), Wnt/β-catenin pathway (31 patients, 24.0%) and post-transcriptional modification (19 patients, 14.7%).

The IGHV mutation rate in the 115 patients was 67.0%, which was significantly higher than the Western reports. In aspect of prognostic role of these mutation genes, IGHV mutation status, the TP53 abnormality (deletion and mutation) and mutated EGFR impacted both PFS and OS independently, while mutated FAT1 was additional independent prognostic factor for PFS and mutated POT1 and KLF2 were another two independent factors for OS. IGHV mutation status and mutated TRAF2 were both independent factors for TTT.

Integrating the function of these high frequency mutated genes, high proportion of IGHV gene mutation and cell-of-origin of CLL model initiated recently, these prevalent mutation genes in this study were supposed to precipitate the pathogenesis of CLL from the initial tumor stem cell to germinal center B cell.


The gene mutation signature of CLL in China is different from the Western population, which may skew the cell-of-origin of CLL in China towards the germinal center B cell maturation route, other than other maturation way, such as marginal zone B cell origin.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.