Comparison of mutation frequencies (%) between Caucasians and Koreans.

<p>Frequencies of mutation in Caucasian were calculated, based on the data of Landau et al. (2015) and Puente et al.(2015).</p

Kaplan-Meier survival curves according to cytogenetic abnormality.

<p>Kaplan-Meier survival curves according to cytogenetic abnormality.</p

Genomic Profile of Chronic Lymphocytic Leukemia in Korea Identified by Targeted Sequencing

<div><p>Chronic lymphocytic leukemia (CLL) is extremely rare in Asian countries and there has been one report on genetic changes for 5 genes (<i>TP53</i>, <i>SF3B1</i>, <i>NOTCH1</i>, <i>MYD88</i>, and <i>BIRC3</i>) by Sanger sequencing in Chinese CLL. Yet studies of CLL in Asian countries using Next generation sequencing have not been reported. We aimed to characterize the genomic profiles of Korean CLL and to find out ethnic differences in somatic mutations with prognostic implications. We performed targeted sequencing for 87 gene panel using next-generation sequencing along with G-banding and fluorescent in situ hybridization (FISH) for chromosome 12, 13q14.3 deletion, 17p13 deletion, and 11q22 deletion. Overall, 36 out of 48 patients (75%) harbored at least one mutation and mean number of mutation per patient was 1.6 (range 0–6). Aberrant karyotypes were observed in 30.4% by G-banding and 66.7% by FISH. Most recurrent mutation (>10% frequency) was <i>ATM</i> (20.8%) followed by <i>TP53</i> (14.6%), <i>SF3B1</i> (10.4%), <i>KLHL6</i> (8.3%), and <i>BCOR</i> (6.25%). Mutations of <i>MYD88</i> was associated with moderate adverse prognosis by multiple comparisons (<i>P</i> = 0.055). Mutation frequencies of <i>MYD88</i>, <i>SAMHD1</i>, <i>EGR2</i>, <i>DDX3X</i>, <i>ZMYM3</i>, and <i>MED12</i> showed similar incidence with Caucasians, while mutation frequencies of <i>ATM</i>, <i>TP53</i>, <i>KLHL6</i>, <i>BCOR</i> and <i>CDKN2A</i> tend to be higher in Koreans than in Caucasians. Especially, <i>ATM</i> mutation showed 1.5 fold higher incidence than Caucasians, while mutation frequencies of <i>SF3B1</i>, <i>NOTCH1</i>, <i>CHD2</i> and <i>POT1</i> tend to be lower in Koreans than in Caucasians. However, mutation frequencies between Caucasians and Koreans were not significantly different statistically, probably due to low number of patients. Collectively, mutational profile and adverse prognostic genes in Korean CLL were different from those of Caucasians, suggesting an ethnic difference, while profile of cytogenetic aberrations was similar to those of Caucasians.</p></div

Hazard ratios with 95% confidence intervals for overall survival for each gene variant.

<p>Data of gene mutations which are shown only in one patient are not shown. Raw <i>P</i>-values are shown in this figure. After applying FDR for multiple comparison, <i>MYD88</i> mutation is the only statistically significant gene which had high hazard ratio (<i>P</i> = 0.045).</p

Kaplan-Meier survival curves in patients with somatic mutations.

<p>(A) <i>TP53</i>, (B) <i>MYD88</i>, and (C) <i>ATM</i> gene mutation or 11q22 deletion in Korean CLL. After applying multiple comparison by using FDR, only <i>MYD88</i> showed a tendency for adverse prognosis (P = 0.055).</p

Kaplan-Meier survival curves of patients who transformed to Richter’s syndrome.

<p>Kaplan-Meier survival curves of patients who transformed to Richter’s syndrome.</p

Somatic mutations found in 48 patients with CLL.

<p>Somatic mutations found in 48 patients with CLL.</p

Kaplan-Meier survival curves according to abnormalities detected by FISH.

<p>Kaplan-Meier survival curves according to abnormalities detected by FISH.</p

Disease-free survival curves for patients with mutations.

<p>(A) <i>TP53</i> and (B) <i>MYD88</i> genes After applying multiple comparison by using FDR, <i>TP53</i> and <i>MYD88</i> showed a tendency for shorter disease-free survival (<i>P</i> = 0.054, both).</p

Correlation between various gene mutations and between gene mutation and cytogenetics.

<p>Correlation coefficients with raw P<0.05 were presented as colored boxes. Applying FDR correction for multiple comparison, there were no statistically significant correaltions.</p