BACKGROUND: Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45-50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples. DESIGN AND METHODS: Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis. RESULTS: Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region. CONCLUSIONS: This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.
BACKGROUND:Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45-50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples. DESIGN AND METHODS: Thirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis. RESULTS: Eighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of either mutant FLT3 (2 cases), JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region. CONCLUSIONS: This study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.
Authors: Charles G Mullighan; Salil Goorha; Ina Radtke; Christopher B Miller; Elaine Coustan-Smith; James D Dalton; Kevin Girtman; Susan Mathew; Jing Ma; Stanley B Pounds; Xiaoping Su; Ching-Hon Pui; Mary V Relling; William E Evans; Sheila A Shurtleff; James R Downing Journal: Nature Date: 2007-04-12 Impact factor: 49.962
Authors: J Fitzgibbon; S Iqbal; A Davies; D O'shea; E Carlotti; T Chaplin; J Matthews; M Raghavan; A Norton; T A Lister; B D Young Journal: Leukemia Date: 2007-05-10 Impact factor: 11.528
Authors: Brian A Walker; Paola E Leone; Matthew W Jenner; Cheng Li; David Gonzalez; David C Johnson; Fiona M Ross; Faith E Davies; Gareth J Morgan Journal: Blood Date: 2006-05-16 Impact factor: 22.113
Authors: Lucy A Godley; John Cunningham; M Eileen Dolan; R Stephanie Huang; Sandeep Gurbuxani; Megan E McNerney; Richard A Larson; Hoyee Leong; Yves Lussier; Kenan Onel; Olatoyosi Odenike; Wendy Stock; Kevin P White; Michelle M Le Beau Journal: Semin Oncol Date: 2011-04 Impact factor: 4.929
Authors: Christopher J Walker; Jessica Kohlschmidt; Ann-Kathrin Eisfeld; Krzysztof Mrózek; Sandya Liyanarachchi; Chi Song; Deedra Nicolet; James S Blachly; Marius Bill; Dimitrios Papaioannou; Christopher C Oakes; Brian Giacopelli; Luke K Genutis; Sophia E Maharry; Shelley Orwick; Kellie J Archer; Bayard L Powell; Jonathan E Kolitz; Geoffrey L Uy; Eunice S Wang; Andrew J Carroll; Richard M Stone; John C Byrd; Albert de la Chapelle; Clara D Bloomfield Journal: Clin Cancer Res Date: 2019-08-02 Impact factor: 12.531