Page 262 - 2021_03-Haematologica-web

Letters to the Editor
Germline pathogenic variants in transcription fac- tors predisposing to pediatric acute myeloid leukemia: results from the French ELAM02 trial
Genetic predisposition to hematologic malignancies represents a heterogeneous group of rare disorders that have been included as distinct entities in the revised World Health Organization 2016 classification of myeloid neoplasms and acute leukemia.1 The diagnosis of patients with these disorders is of clinical relevance, as they can benefit from specific clinical care, adapted surveillance and genetic counseling.2-4 Clinical features as well as personal or family history may help to ascertain genetic predisposition to hematologic malignancies. However, up to 40% of patients diagnosed with a cancer predisposition syndrome or inherited bone marrow fail- ure do not have any of these features.5 The very broad variations in the type of hematologic malignancies, age at onset and penetrance also contribute to a lack of clin- ical recognition. Consequently, many patients present with a diagnosis of an apparently sporadic hematologic malignancy and it is assumed that cases with a genetic predisposition are currently underestimated.
The wide use of high-throughput sequencing tech- nologies has revolutionized the genetic characterization of malignant diseases. Leukemogenesis is now usually considered as a multistep process involving many gene classes and pathways. Notably, some relevant genes, including transcription factors (CEBPA, ETV6, GATA2, RUNX1 and TP53), are targets of both somatic and germline pathogenic variants or more rarely deletions.6,7 Sequencing gene panels used clinically for the genetic characterization of hematologic malignancies usually include transcription factor genes, and may represent a gateway to the identification of germline variants.7,8 High-throughput sequencing offers the possibility to estimate variant allele frequencies (VAF) and a broad view of tumor architecture. Specifically, pathogenic vari- ants with low VAF are assumed to be somatically
acquired while pathogenic variants with a VAF of ≥50% may indicate either somatic or germline origin requiring the study of non-tumor samples. Additionally, several studies have pointed out somatic mechanisms, including variant amplification (chromosome doubling, uni- parental disomies) or double mutations that are associat- ed with transformation in patients with a germline dis- order.3,9
Here we aimed at retrospectively identifying syn- dromes with a genetic predisposition due to germline pathogenic variants or deletions in transcription factors (CEBPA, ETV6, GATA2, RUNX1 and TP53) using a prac- tical, molecular-based algorithm in pediatric patients with acute myeloid leukemia (AML) from the French ELAM02 cohort.
The randomized, prospective, multicenter, phase III ELAM02 trial (clinicaltrials.gov identifier: NCT00149162) was conducted from March, 2005 to December, 2011 in pediatric patients (aged 0-18 years old) with AML.10 Children with secondary AML and AML with an underlying known predisposition disorder (Down syndrome, chromosomal breakage diseases, Kostman and Schwachman-Diamond diseases) were excluded. Of note, two patients have been previously reported: one with a germline GATA2 pathogenic variant and the other one with a germline RUNX1 deletion.9,11 Patients with available amplicon-based high-throughput sequencing data and information from single nucleotide polymorphism (SNP)-array analyses at the time of diag- nosis of AML were selected for the present study (385 patients out of the 438 patients included in the ELAM02 trial). The molecular profiling using a 36-gene panel with a high depth of coverage (>1500×) at AML diagnosis was reported previously10 (Online Supplementary Table S1). CEBPA mutations were systematically sought by Sanger sequencing because of insufficient coverage by the high- throughput sequencing. Single nucleotide variants were selected based on the absence of a description in public databases of human polymorphisms, and their function- al effect was assessed by in silico predictions as previous-
Figure 1. Study workflow. HTS: high-throughput sequencing; SNP: single nucleotide polymorphism; VAF: variant allele frequency; CR: complete remission.
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haematologica | 2021; 106(3)