Impact of Trisomy 8 on Expression of Genes Located on Chromosome 8 in Different AML Subgroups.
Authors: Schoch Claudia , Kern Wolfgang , Kohlmann Alexander , Dugas Martin , Hiddemann Wolfgang , Merk Sylvia , Schnittger Susanne , Haferlach Torsten 
Published: October 2019

Abstract
Trisomy 8 is the most frequently observed trisomy in acute myeloid leukemia (AML). It occurs as a sole karyotype abnormality or in addition to other chromosome aberrations. It was the aim of this study to analyze the impact of trisomy 8 on the expression of genes located on chromosome 8 in different AML subgroups. Therefore, gene expression analyses were performed in a total of 567 AML cases using Affymetrix U133A+B oligonucleotide microarrays. The following 14 subgroups were analyzed: +8 sole (n=19), +8 within a complex aberrant karyotype (n=11), +8 with t(15;17) (n=7), +8 and inv(16) (n=3), +8 with t(8;21) (n=3), +8 and 11q23/MLL (n=8), and +8 with other abnormalities (n=10). These were compared to 200 AML with normal karyotype and the following subgroups without trisomy 8: complex aberrant karyotype (n=73), t(15;17) (n=36), inv(16) (n=46), t(8;21) (n=37), 11q23/MLL (n=37), and other abnormalities (n=77). In total 1188 probe sets cover sequences located on chromosome 8 representing 580 genes. A significant higher mean expression of all genes located on chromosome 8 was observed in subgroups with +8 in comparison to their respective control groups (for all comparisons, p<0.05). Significantly higher expressed genes in groups with +8 in comparison to the respective groups without +8 were identified in all comparisons. The number of identified genes ranged from 40 in 11q23/MLL to 326 in trisomy 8 sole vs. normal. There was no common gene significantly overexpressed in all comparisons. Three genes (TRAM1, CHPPR, MGC40214) showed a significantly higher expression in 5 out of 7 comparisons. Between 19 and 107 genes with an exclusive overexpression in trisomy 8 cases in only one subtype comparison were identified. In addition, we performed class prediction using support vector machines (SVM) including all probe sets on the arrays. In one approach all 14 different subgroups were analyzed as one class each. Only 3 out of 61 cases with trisomy 8 were assigned into their correct subclass, while 40 cases were assigned to their corresponding genetic subclass without trisomy 8. In a second approach only two classes were defined: all cases with trisomy 8 combined vs. all cases without trisomy 8. Only 26 out of 61 (42.6%) with trisomy 8 were identified correctly underlining the fact that no distinct gene expression pattern is associated with trisomy 8 in general. Performing SVM only with genes located on chromosome 8 did not improve the correct assignment of cases with trisomy 8 overall. Only cases with trisomy 8 sole were correctly predicted in 58% as compared to 11% in SVM using all genes. In conclusion, overall the gain of chromosome 8 leads to a higher expression of genes located on chromosome 8. However, no consistent pattern of genes was identified which shows a higher expression in all AML subtypes with trisomy 8. This data suggest that the higher expression of genes located on chromosome 8 only in part is directly related to a gene dosage effect. Trisomy 8 may rather provide a platform for a higher expression of chromosome 8 genes which are specifically upregulated by accompanying genetic abnormalities in the respective AML subtypes. Therefore, trisomy 8 does not seem to be an abnormality determining specific disease characteristics such as the well known primary aberrations (t(8;21), inv(16), t(15;17), MLL/11q23) but rather a disease modulating secondary event in addition to primary cytogenetic or moleculargenetic aberrations.