Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes
| Autor: | Wong, Jasmine C, Bryant, Victoria, Lamprecht, Tamara, Ma, Jing, Walsh, Michael, Schwartz, Jason, Del Pilar Alzamora, Maria, Mullighan, Charles G, Loh, Mignon L, Ribeiro, Raul, Downing, James R, Carroll, William L, Davis, Jeffrey, Gold, Stuart, Rogers, Paul C, Israels, Sara, Yanofsky, Rochelle, Shannon, Kevin, Klco, Jeffery M |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Myeloid Evolution Childhood Leukemia Pediatric Cancer Chromosome Disorders Acute Chromosomes Rare Diseases Clinical Research Neoplasms Leukemias Genetics Humans 2.1 Biological and endogenous factors Genetic Predisposition to Disease Aetiology Germ-Line Mutation Cancer Pediatric Neoplastic Leukemia Tumor Suppressor Proteins Cell Cycle Intracellular Signaling Peptides and Proteins Proteins Molecular Hematology Pedigree Gene Expression Regulation Hematologic Neoplasms Myelodysplastic Syndromes Disease Progression Pair 7 Female Chromosome Deletion Human |
| Zdroj: | JCI insight, vol 3, iss 14 |
| Popis: | Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families. |
| Databáze: | OpenAIRE |
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