title: 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies.
abstract: Two types of acquired loss of heterozygosity are possible in cancer: deletions and copy-neutral uniparental disomy (UPD). Conventionally, copy number losses are identified using metaphase cytogenetics, whereas detection of UPD is accomplished by microsatellite and copy number analysis and as such, is not often used clinically. Recently, introduction of single nucleotide polymorphism (SNP) microarrays has allowed for the systematic and sensitive detection of UPD in hematologic malignancies and other cancers. In this study, we have applied 250K SNP array technology to detect previously cryptic chromosomal changes, particularly UPD, in a cohort of 301 patients with myelodysplastic syndromes (MDS), overlap MDS/myeloproliferative disorders (MPD), MPD, and acute myeloid leukemia. We show that UPD is a common chromosomal defect in myeloid malignancies, particularly in chronic myelomonocytic leukemia (CMML; 48%) and MDS/MPD-unclassifiable (38%). Furthermore, we show that mapping minimally overlapping segmental UPD regions can help target the search for both known and unknown pathogenic mutations, including newly identified missense mutations in the proto-oncogene c-Cbl in 7 of 12 patients with UPD11q. Acquired mutations of c-Cbl E3 ubiquitin ligase may explain the pathogenesis of a clonal process in a subset of MDS/MPD, including CMML.
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dunbar
authors.forename: Lukasz P
authors.initials: LP
authors.lastname: Gondek
authors.forename: Christine L
authors.initials: CL
authors.lastname: O'Keefe
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Manjot S
authors.initials: MS
authors.lastname: Rataul
authors.forename: Hadrian
authors.initials: H
authors.lastname: Szpurka
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Xiao Fei
authors.initials: XF
authors.lastname: Wang
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006801:Humans; D007621:Karyotyping; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000235:genetics*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics*; D055815:Young Adult
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human