Abstract
Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a potential CLL precursor state which can be detected in up to 17% in aged individuals. Recently, we described significant B-cell receptor immunoglobulin heavy chain (BCR IGH) gene repertoire skewing and clonotypic evolution up to 22 years before CLL diagnosis. However, pathobiological drivers during the earliest stages of MBL development remain incompletely characterized. In this study, we utilized the EuroClonality-NDC panel to sequence recurrently mutated genes in CLL in 39 peripheral blood samples from 16 CLL patients sampled up to 16 years prior to diagnosis. CLL diagnosis ranged from 5 months to 16 years after first blood sampling. Of 16 CLL patients, 8 (50%) presented with variants of interest in genes recurrently mutated in CLL such as NOTCH1, ATM, and SF3B1 . ATM variants and the IGLV3-21R110 mutation were present from the early stages of (pre)MBL development, while NOTCH1, SF3B1, and XPO1 variants arose closer to diagnosis. We additionally detected variants in FAT1 and PLCG2 as early as 10 years prior to CLL diagnosis. Overall, our data shows specific genetic drivers of CLL are associated with early and late stages of CLL development.
| Original language | English |
|---|---|
| Pages (from-to) | 1399-1403 |
| Number of pages | 5 |
| Journal | Blood |
| Volume | 142 |
| Issue number | 16 |
| Early online date | 31 Jul 2023 |
| DOIs | |
| Publication status | Published - 19 Oct 2023 |
Bibliographical note
Funding Information:This study was supported by TRANSCAN/Dutch Cancer Society grant 179; NOVEL Consortium, research grants from the Swedish Cancer Society , the Cancer Research Foundation in Northern Sweden , and the regional agreement between Umeå University and Region Västerbotten .
Funding Information:
The study was approved by the local institutional medical ethical committee at the Erasmus MC (protocol number MEC 2019-0484) and the Ethical Review Board at Ume University (Dnr 2017/242-31). The EPIC steering committee approved the use of the material for the purpose of this study. All patients gave their written consent and the use of the material and data in this study were approved by the IARC Ethics Committee. The study was performed in compliance with the Declaration of Helsinki.The authors gratefully acknowledge Kostas Stamatopoulos for critical reading of the manuscript. In particular, the authors thank all participants in the initial EPIC and NSHDS studies for providing the samples that enabled our research. This study was supported by TRANSCAN/Dutch Cancer Society grant 179, the NOVEL Consortium, research grants from the Swedish Cancer Society, the Cancer Research Foundation in Northern Sweden, and the regional agreement between Umeå University and Region Västerbotten. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Contribution: P.M.K. and M.K. performed the experiments; P.M.K. and M.K. analyzed the data; P.M.K. F.S. M.K. P.J.H. L.v.d.S. M.H. J.D.M. C.P. R.C.H.V. and A.W.L. interpreted results; P.M.K. F.S. M.K. C.P. R.C.H.V. and A.W.L. wrote the manuscript; P.J.H. L.v.d.S. N.D. M.H. and J.D.M. critically reviewed and edited the manuscript; N.D. designed and built the bioinformatics pipeline; F.S. and M.H. facilitated acquisition of patient material and data; and C.P. R.C.H.V. and A.W.L. designed and supervised the study.