The genomic landscape of pediatric myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are uncommon in children and have a poor prognosis. In contrast to adult MDS, little is known about the genomic landscape of pediatric MDS. Here, we describe the somatic and germline changes of pediatric MDS using whole exome sequencing, targeted amplicon sequencing, and/or RNA-sequencing of 46 pediatric primary MDS patients. Our data show that, in contrast to adult MDS, Ras/MAPK pathway mutations are common in pediatric MDS (45% of primary cohort), while mutations in RNA splicing genes are rare (2% of primary cohort). Surprisingly, germline variants in SAMD9 or SAMD9L were present in 17% of primary MDS patients, and these variants were routinely lost in the tumor cells by chromosomal deletions (e.g., monosomy 7) or copy number neutral loss of heterozygosity (CN-LOH). Our data confirm that adult and pediatric MDS are separate diseases with disparate mechanisms, and that SAMD9/SAMD9L mutations represent a new class of MDS predisposition.

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

“…Exome sequencing revealed 5 different missense heterozygous mutations in the 6 SAMD9 cases and 4 different missense mutations in the 6 SAMD9L cases. Their genomic details and pathogenicity assessment of variants are summarized in Table 2 and cross-referenced [5,7,8,12,13,[17][18][19][20]. Six of 12 cases were familial.…”

“…Germline mutations in SAMD9 and SAMD9L cause the multisystem disorders, MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) and ataxia-pancytopenia syndromes, respectively [4][5][6]. Recent studies in children reported a rate of SAMD9 and SAMD9L mutations in 18.6% and 17% cases with suspected inherited bone marrow failure syndromes and those with primary MDS, respectively [7,8]. Biology of Blood and Marrow Transplantation journal homepage : www.bbmt.org SAMD9 and SAMD9L proteins are involved in endosomal trafficking and negatively regulate cell proliferation [9].…”

“…Interestingly, in many cases, there is a nonrandom loss of the mutated allele via full or partial deletion of chromosome 7 [4,[10][11][12]. The resultant monosomy 7 or deletion 7q can result in the development of MDS and acute myeloid leukemia (AML) [8,11,12]. Conversely, other "genetic correction" events such as in cis missense, nonsense, or loss of heterozygosity through uniparental disomy can result in normal hematopoiesis.…”

Challenges in Diagnosing Myelodysplastic Syndromes in the Era of Genetic Testing: Proceedings of the 13th Workshop of the European Bone Marrow Working Group

“…The monosomy 7 is not present at birth but is acquired within haematopoietic cells due to an inherited genetic predisposition that leads to mosaicism of chromosome 7 in peripheral blood and/or bone marrow. Germline SAMD9 and SAMD9L variants have been recently linked to familial and sporadic cases of paediatric MDS with monosomy 7 [37]. Abnormal haematologic findings and mosaic monosomy 7 can already appear in young children with familial monosomy 7.…”

Myeloid Neoplasms with Germline Predisposition

“…Germline variants in SAMD9 and SAMD9L have been recently reported in clinical syndromes associated with familial MDS, usually accompanied by abnormalities of chromosome 7q. Schwartz et al [42] identified these mutations in 17% of pediatric MDS patients. Germline variants in SAMD9 and SAMD9L have been associated with multisystem disorders with a range of systemic abnormalities, including cytopenia, infection, intrauterine restriction of growth, adrenal hypoplasia, abnormal genital phenotypes, progressive cerebellar dysfunction, and enteropathy [43][44][45][46].…”