title: Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes.
abstract: Low-risk myelodysplastic syndrome (MDS) with normal cytogenetics accounts for approximately 50% of MDS patients. There are no pathognomonic markers in these cases and the diagnosis rests on cytomorphologic abnormalities in bone marrow and/or peripheral blood. Affymetrix high-resolution single-nucleotide polymorphism (SNP) genotyping microarrays allow detection of cytogenetically cryptic genomic aberrations. We have studied 119 low-risk MDS patients (refractory anemia [RA] = 22; refractory cytopenia with multilineage dysplasia [RCMD] = 51; refractory anemia with ringed sideroblasts [RARS] = 12; refractory cytopenia with multilineage dysplasia with ringed sideroblasts [RCMD-RS] = 12; 5q- syndrome = 16; refractory anemia with excess blasts [RAEB] = 6) using SNP microarrays to seek chromosomal markers undetected by conventional cytogenetics. Loss of heterozygosity (LOH) detected by 50K arrays was verified using 250K and 500K arrays. We demonstrate the presence of uniparental disomy (UPD) in 46%, deletions in 10%, and amplifications in 8% of cases. Copy number (CN) changes were acquired, whereas UPDs were also detected in constitutional DNA. UPD on 4q was identified in 25% of RARS, 12% of RCMD with normal cytogenetics, 17% of RAEB, and 6% of 5q- syndrome cases. Univariate analysis showed deletions (P = .04) and International Prognostic Scoring System (IPSS; P < .001) scores correlated with overall survival; however, on multivariate analysis only IPSS scores retained prognostic significance (P < .001). We show, for the first time, that SNP microarray analysis in low-risk MDS patients reveals hitherto unrecognized UPD and CN changes that may allow stratification of these patients for early therapeutic interventions.
authors.affiliation: Department of Haematological Medicine, King's College Hospital, King's College London School of Medicine, Denmark Hill, London, United Kingdom.
authors.forename: Azim
authors.initials: A
authors.lastname: Mohamedali
authors.forename: Joop
authors.initials: J
authors.lastname: Gäken
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Twine
authors.forename: Wendy
authors.initials: W
authors.lastname: Ingram
authors.forename: Nigel
authors.initials: N
authors.lastname: Westwood
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Lea
authors.forename: Janet
authors.initials: J
authors.lastname: Hayden
authors.forename: Nora
authors.initials: N
authors.lastname: Donaldson
authors.forename: Carlo
authors.initials: C
authors.lastname: Aul
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
authors.forename: Aristotle
authors.initials: A
authors.lastname: Giagounidis
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis