Germline and Somatic Variants Co-Ocurrence Profile in Early Onset Adult Myelodysplastic Syndromes without a Preexisting Disorder

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.2595-2595
• Main Authors: Chen-Liang, Tzu Hua, Carrillo-Tornel, Salvador, Santiago, Marta, López Andrade, Bernardo, Hernandez, Francisca Maria, García-Martín, Paloma, López Cadenas, Félix, Tormo, Mar, Hermosín, María Lourdes, Bernal del Castillo, Teresa, Tuset, Esperanza, Medina Perez, Ángeles, Pomares, Helena, Arquero, Teresa, Montoro, María Julia, Xicoy, Blanca, Solé, Francesc, Sanz, Guillermo, Valcarcel, David, Diez-Campelo, Maria, Jerez, Andres
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-152128

Introduction: De novo myelodysplastic syndromes (MDS) usually present in the elderly, within the context of the progressive acquisition of somatic mutations throughout the patient's life. On the other hand, MDS in children and younger adults are often associated with predisposing germline mutations. Early-onset MDS in adults (16-60 years old) accounts for »10% of all MDS cases. We aim to depict profiles of co-occurrence between germline and acquired variants in a Spanish multicenter cohort of patients with data from paired tumor-germinal whole exome sequencing (WES). Methods: Prospective cohort study (2014-2021) of 197 patients from 25 Spanish Group of Myelodysplastic Syndrome (GESMD) centers with a de novo diagnosis of MDS and chronic myelomonocytic leukemia (CMML) between 16-60 yo, without prior organ dysfunction. In each case, we annotated 107 clinical variables in relation to family and personal history, diagnosis, treatment, HSCT and disease evolution. WES was performed in paired tumor-germline samples with 100x average depth, 150 million reads per sample, and >95% Phred Quality Score 30(Q30 a). WES libraries were prepared using SureSelectXT Target Enrichment System for Illumina Version B.2 and sequenced on a HiSeq4000-NovaSeq6000-Illumina platform. The analysis of the variants was carried out by means of an in-house pipeline. The germline variants were categorized according to American College of Medical Genetics and Genomics (ACMG) criteria. Results: The median age of the cohort at diagnosis was 49 years old (16-60) with the following WHO 2017 diagnoses: 13.7% MDS with single lineage dysplasia, 10.4% MDS with ring sideroblasts, 30.6% MDS with multilineage dysplasia, 17.9% MDS with excess blasts, 6% MDS with isolated del(5q), 2.2% MDS-unclassifiable, and 9.3% CMML. We found germline variants categorized as pathogenic (P), likely pathogenic (LP) or uncertain significance (VUS) in 83.2% (n=162) of 197 patients, with 24.4% (n=48) harboring LP and/or P variants. A gene pathway-driven classification of germline variants (VUS+LP+P) categorized carrier patients as follows: 38.1% (n=75) with, at least, a variant in DNA damage response pathway (DDR), 2% (n=4) in telomere function maintenance (TF), 9.6% (n=19) in hematopoiesis regulators (HR), 6.1%(n=12) in ribosome function (RB), 14.7%(n=29) in immune response (IR), 13.3%(n=13) in chromatin modifiers, 14.2%(n=28) in cell cycle and proliferation (CP), 12.7%(n=25) in platelet function (PF), 7.1%(n=14) in erythr