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98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia.

ABSTRACT: Immunoglobulin heavy chain variable region (IGHV) mutational status has been an important prognostic factor for chronic lymphocytic leukemia (CLL) for decades. Patients with unmutated IGHV (?98% identity to the germline sequence) have inferior prognosis and tend to carry unfavorable genetic markers compared to those with mutated IGHV (<98% identity to the germline sequence). However, 98% as the cutoff for IGHV mutational status is a mathematical choice and remains controversial. We have previously reported distinct IGHV repertoire features between Chinese and western CLL populations. Here, we retrospectively studied 595 Chinese CLL patients to determine the best cutoff value for IGHV in Chinese CLL population. Using 1% as the interval for IGHV identity, we divided the studied cohort into seven subgroups from 95% to 100%. Briefer time to first treatment (TTFT) and overall survival (OS) were observed in cases with ?98% compared to those with <98%, while the differences were obscure within subgroups ?98% (98%-98.99%, 99%-99.99%, and 100%) and <98% (<94.99%, 95%-95.99%, 96%-96.99%, and 97%-97.99%). Multivariate analysis confirmed the independent prognostic value of 98% being the cutoff for IGHV identity in terms of both TTFT and OS. All the prognostic factors, including del(17p13), del(11q22.3), TP53 mutation, MYD88 mutation, NOTCH1 mutation, SF3B1 mutation, CD38, ZAP-70, Binet staging, gender, and ?2-microglobulin, were significantly different in distribution between group <98% and group ?98%, but not among subgroups 98%-98.99%, 99%-99.99%, and 100%. In conclusion, 98% is the optimal cutoff of IGHV identity for the prognosis evaluation of Chinese CLL patients.

SUBMITTER: Shi K

PROVIDER: S-EPMC6997101 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia.

Shi Ke K Sun Qian Q Qiao Chun C Zhu Huayuan H Wang Li L Wu Jiazhu J Wang Lili L Fu Jianxin J Young Ken H KH Fan Lei L Xia Yi Y Xu Wei W Li Jianyong J

Cancer medicine 20191217 3

Immunoglobulin heavy chain variable region (IGHV) mutational status has been an important prognostic factor for chronic lymphocytic leukemia (CLL) for decades. Patients with unmutated IGHV (≥98% identity to the germline sequence) have inferior prognosis and tend to carry unfavorable genetic markers compared to those with mutated IGHV (<98% identity to the germline sequence). However, 98% as the cutoff for IGHV mutational status is a mathematical choice and remains controversial. We have previous ...[more]

PMID: 31849198

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Project description:BackgroundIGHV mutation status is a crucial prognostic biomarker for CLL. In the present study, we investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis.MethodsThe co-expression modules and hub genes correlating with IGHV status, were identified using the GSE28654, by 'WGCNA' package and R software (version 4.0.2). The over-representation analysis was performed to reveal enriched cell pathways for genes of correlating modules. Then 9 external cohorts were used to validate the correlation of hub genes expression with IGHV status or clinical features (treatment response, transformation to Richter syndrome, etc.). Moreover, to elucidate the significance of hub genes on disease course and prognosis of CLL patients, the Kaplan-Meier analysis for the OS and TTFT of were performed between subgroups dichotomized by the median expression value of individual hub genes.Results2 co-expression modules and 9 hub genes ((FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10) correlating with IGHV status were identified by WGCNA, and validated by external datasets. The modules were found to be enriched in NF-kappaB, HIF-1 and other important pathways, involving cell proliferation and apoptosis. The expression of hub genes was revealed to be significantly different, not only between CLL and normal B cell, but also between various types of lymphoid neoplasms. HELQ expression was found to be related with response of immunochemotherapy treatment significantly (p = 0.0413), while HELQ and ZNF667 were expressed differently between stable CLL and Richter syndrome patients (p < 0.0001 and p = 0.0278, respectively). By survival analysis of subgroups, EGR3 expression was indicated to be significantly associated with TTFT by 2 independent cohorts (GSE39671, p = 0.0311; GSE22762, p = 0.0135). While the expression of HELQ and EGR3 was found to be associated with OS (p = 0.0291 and 0.0114 respectively).The Kras, Hedgehog and IL6-JAK-STAT3 pathways were found to be associating with the expression of hub genes, resulting from GSEA.ConclusionsThe expression of HELQ and EGR3 were correlated with IGHV mutation status in CLL patients. Additionally, the expression of HELQ/EGR3 were prognostic markers for CLL associating with targetable cell signaling pathways.

Dataset Information

98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia.

Publications

98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia.

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