Abstract
Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants.
Original language | English |
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Pages (from-to) | 2853-2866 |
Number of pages | 14 |
Journal | Blood |
Volume | 141 |
Issue number | 23 |
Early online date | 23 Mar 2023 |
DOIs | |
State | Published - 8 Jun 2023 |
Bibliographical note
Publisher Copyright:© 2023 The American Society of Hematology
Funding
The authors thank Lotta Katainen and Minna Eriksson for the skillful technical help, and Olavi Koivisto for valuable consulting in biostatistics. The authors thank Kimmo Porkka and Esa Pitkänen for supporting our research. The authors acknowledge the participants and investigators of the FinnGen study. This study was supported by grants from the Sigrid Jusélius Foundation; Cancer Foundation Finland; Finnish Special Governmental Subsidy for Health Sciences, Research, and Training; Helsinki University Hospital Comprehensive Cancer Research Funding; Blood Disease Research Foundation; Finnish Medical Foundation; and the Finnish Association of Hematology. Contribution: M.H. collected and analyzed the clinical data, drafted the manuscript, and performed the statistical analyses; I.K. created the figures, performed the statistical analyses, and contributed to the final content of the manuscript; S.P.M.D. shared the collected data of Finnish patients and revised the manuscript; O.K. and U.W.-K. designed the study, coordinated data collection from multinational collaborators, and finalized the manuscript; T. Vulliamy, I.D. J.S. L.L. R.P.d.L. T.L. F.S.d.F. T.S. O.L. E.H.-L. G.B. B.T. A.S. F.B. S.J. A.A.K. T.F.Z. H.T. C.M. I.C. K.J. U.S. and R.N. contributed to the recruitment of patients in the study and to their management; T. Varilo performed genealogical studies; and all authors revised and approved the final version of the manuscript. This study was supported by grants from the Sigrid Jusélius Foundation ; Cancer Foundation Finland ; Finnish Special Governmental Subsidy for Health Sciences, Research, and Training ; Helsinki University Hospital Comprehensive Cancer Research Funding ; Blood Disease Research Foundation ; Finnish Medical Foundation ; and the Finnish Association of Hematology .
Funders | Funder number |
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Finnish Association of Hematology | |
Helsinki University Hospital Comprehensive Cancer Research Funding | |
Kimmo Porkka and Esa Pitkänen | |
Blood Disease Research Foundation | |
Suomen Lääketieteen Säätiö | |
Sigrid Juséliuksen Säätiö | |
Syöpäsäätiö |