Page 265 - 2021_03-Haematologica-web

Letters to the Editor
clinical features and persistence of the GATA2 variant in complete remission finally led to the diagnosis of a germline GATA2-mutated disorder (reported by Pasquet et al.11).
Patient n. 3 was a 16-year old boy who carried a frameshift GATA2 pathogenic variant (NM_032638:c.1008del (p.Lys336Asnfs*51)) (Figure 2C) which was located between the two zinc finger domains of the GATA2 protein. This patient had no particular per- sonal or family history (Online Supplementary Figure S2). Of note, absence of family history is common in germline GATA2-mutated children/adolescents with hematologic malignancies,15 suggesting a de novo muta- tion in this patient.
Patient n. 4 was a 9-year old girl with a pathogenic variant in the highly conserved homology domain (RHD) of the RUNX1 protein (NM_001754.4:c.601C>T (p.Arg201*)) (Figure 2D). Pathogenic variants involving this codon have been reported several times as somatic or germline.16 The family history of this patient identi- fied solid tumors (testicular cancer in her father, 2 breast cancers and colorectal cancer in her paternal grandmoth- er) but neither thrombocytopenia nor hematologic malignancies (Online Supplementary Figure S2).
Patient n. 5 was followed up for a thrombocytopenia since the age of 2 years. At 14 years old, she developed AML shortly after a phase of refractory anemia with excess blasts (Online Supplementary Figure S2). Cytogenetics revealed a constitutional triple X syndrome and an acquired trisomy 21. SNP-array analysis revealed a complete deletion of the RUNX1 locus (Online Supplementary Figure S1). This case was previously reported by Preudhomme et al.9
This study emphasizes the complexity of identifying inherited syndromes without any extra-hematologic fea- tures. In such cases, high-throughput sequencing appears to be an informative tool for identifying syn- dromes predisposing to hematologic malignancies.5,7,8 When using amplicon-based high-throughput sequenc- ing, copy number analysis (i.e. comparative genome hybridization/SNP-array) should also be used since large deletions could be missed with the sequencing approach. Current capture-based high-throughput sequencing techniques are good alternatives to detect both mutations and copy-number alterations with spe- cific pipelines. Assessment of both the inherited nature of variants and their pathological significance remains a challenge in practice. Cultured skin fibroblasts are rec- ommended to ascertain the germline status of a specific variant. Particular attention should be paid to epidemio- logical data, functional studies and expert recommenda- tions. Recent guidelines on the interpretation of variants written by the ACMG-AMP working group may help to refine the clinical significance of variants.12,13,17,18
We restricted our study to transcription factor alter- ations reported to be involved in predisposition syn- dromes. Other well-known targets, such as ANKRD26, DDX41 (which is mostly present in adult patients) and SAMD9/SAMD9L were not studied here. Consequently, we were not able to evaluate the incidence of germline disorders in pediatric AML with known predisposing gene mutations.19
The identification of germline pathogenic variants has a strong impact on patients’ management. The down- stream genetic counseling requires cautious considera- tion of potential, related donors, excluding mutation car- riers and searching for a matched, unrelated donor if necessary.
account the characteristics of the predisposition syn- drome and its penetrance. A few guidelines are being produced to help with genetic counseling in daily prac- tice.2,17,20,21 Further efforts are needed to provide a more formal passage from suspicion to genetic counseling relying on a multidisciplinary approach integrating the expertise of clinicians, hematologists and geneticists.
In conclusion, this study highlights the complexity of identifying predisposition syndromes to myeloid malig- nancies in the absence of extra-hematologic symptoms. Although focusing on transcription factor genes, predis- position syndromes to pediatric AML were not rare in this cohort (5/38 patients, 13%) and should be sought. In this setting, we show here the performance of high- throughput sequencing and a SNP-array. Non-mosaic deletions smaller than 5 Mb should foster further inves- tigations to identify germline pathogenic variants. Interestingly, in our series of patients, none of the select- ed pathogenic or likely pathogenic variants with allele frequencies comprised between 30% and 40% remained in complete remission, corroborating the previously sug- gested7 threshold of 40% as that for seeking an underly- ing predisposition syndrome in daily practice.
Laurène Fenwarth,1 Nicolas Duployez,1 Alice Marceau- Renaut,1 Wadih Abou Chahla,2 Stéphane Ducassou,3 Virginie Gandemer,4 Marlène Pasquet,5 Thierry Leblanc,6 Pascale Schneider,7 Carine Domenech,8 Paul Saultier,9
Guy Leverger,10 Hélène Lapillonne,11 Claude Preudhomme1 and Arnaud Petit10
1Laboratory of Hematology, CHU Lille, INSERM UMR-S 1277 - 9020 CNRS, Lille; 2Pediatric Hematology Department, CHU Lille, Lille; 3Pediatric Hematology and Oncology Department, CHU Bordeaux, Bordeaux; 4Pediatric Hematology and Oncology Department, CHU Rennes, Rennes; 5Pediatric Hematology and Immunology Department, CHU Toulouse, Toulouse; 6Pediatric Hematology Department, AP-HP Robert Debré Hospital, Paris; 7Pediatric Hematology Department, CHU Rouen, Rouen; 8Institute of Hematology and Pediatric Oncology, Lyon 1 University, Hospices Civils de Lyon, Lyon; 9Department of Pediatric Hematology and Oncology, Timone Enfants Hospital, APHM and Aix-Marseille University, Marseille; 10Pediatric Hematology and Oncology Department, Armand Trousseau Hospital, AP-HP, Sorbonne University, UMRS_938, CONECT- AML, Paris and 11Laboratory of Hematology, Armand Trousseau Hospital, Sorbonne University, UMRS_938, CONECT-AML, Paris, France.
Correspondence:
LAURENE FENWARTH - laurene.fenwarth@chru-lille.fr
doi:10.3324/haematol.2020.248872
Disclosures: no conflicts of interest to disclose.
Contributions: GL was the principal investigator of the ELAM02 trial. AP, GL, TL, VG, WAC, SD, MP, PS, CD, PS and CHD enrolled patients in the study. HL and AP created the patient data- base. HL centralized all the AML samples in the ELAM02 nation- al tumor bank. LF, AMR and ND performed the genomic analysis. LF performed the research and wrote the manuscript. CP revised the manuscript which was approved by all authors.
Acknowledgments: the authors would like to thank all the patients, their families and the staff of all the centers of the Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent (SFCE) for their involvement in the ELAM02 trial. The authors are grateful to the ELAM02 national bank and the Tumor Bank at Lille University Hospital (certification NF 96900- 2014/65453-1) for handling, conditioning and storing patients’ samples.
Genetic counseling should be adapted taking into
Funding: the ELAM02 trial was supported by a grant from the
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