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. 2025 Sep 30.
doi: 10.3343/alm.2025.0274. Online ahead of print.

Clonal Burden, Immunoglobulin Heavy Chain Variable Gene Somatic Hypermutations, and Immunoglobulin Gene Repertoire in Korean Patients with Chronic Lymphocytic Leukemia Assessed by Next-generation Sequencing

Taegeun Lee  1   2 , Daehyun Chu  2   3 , Miyoung Kim  2   3 , Young-Uk Cho  2   3 , Sang-Hyun Hwang  2   3 , Jung-Hee Lee  4 , Dok Hyun Yoon  5 , Hyungwoo Cho  5 , Seongsoo Jang  2   3
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Free article

Clonal Burden, Immunoglobulin Heavy Chain Variable Gene Somatic Hypermutations, and Immunoglobulin Gene Repertoire in Korean Patients with Chronic Lymphocytic Leukemia Assessed by Next-generation Sequencing

Taegeun Lee et al. Ann Lab Med. .
Free article

Abstract

Background: We compared the immunoglobulin (IG) heavy chain (IGH) leader and FR1 primer sets to measure clone sizes and detect immunoglobulin heavy chain variable (IGHV) region somatic hypermutations (SHMs) in Korean patients with chronic lymphocytic leukemia (CLL). We also analyzed IGH and immunoglobulin kappa (IGK) to identify Korean-specific IGs in CLL.

Methods: Next-generation sequencing (NGS)-based gene rearrangements and IGHV SHMs were assessed in 40 patients using IGH leader, IGH FR1, and IGK primers. Flow cytometry, karyotyping, interphase FISH, and NGS-based variant analyses were performed for 165 genes.

Results: Clonal IGH and IGK rearrangements were detected in 100.0% and 97.5% of patients, respectively. Clonal size was generally smaller per NGS than per flow cytometry, particularly when using the IGH leader (median: 52.5%) versus the IGH FR1 primer set (73.2%). IGHV SHMs occurred in approximately 70% of patients; 10% showed primer set discrepancies. The incidence of IGHV SHMs was low in patients at high risk (i.e., with TP53 abnormalities; complex karyotypes; and ATM, NOTCH1, SF3B1, or BIRC3 variants). IGHV3 was the most common IGHV (58.3%), and IGHV4-34 was most frequently identified (14.6%). IGHV1 and IGHV1-69 usage differed significantly between Koreans and westerners. IGHJ4 was the most common IGHJ (56.3%). A single IGKV-IGKJ gene rearrangement was most frequently observed (18.9%), whereas intron-KDE was the most common rearrangement (30.6%).

Conclusions: NGS may underestimate CLL clonal size, particularly when using the IGH leader primer set. IGHV SHMs were inversely associated with negative prognostic factors. Our data suggest ethnic differences in CLL pathogenesis.

Keywords: Chronic lymphocytic leukemia; Immunoglobulin genes; Immunoglobulin heavy chain; Next-generation sequencing; Somatic hypermutation.

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