Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies

Abstract Background Proper expression and functioning of transcription factors (TFs) are essential for regulation of different traits and thus could be crucial for the development of complex diseases. Subjects with Down syndrome (DS) have a higher incidence of acute lymphoblastic leukemia (ALL) while solid tumors, like breast cancer (BC) and oral cancer (OC), show rare incidences. Triplication of the human chromosome 21 in DS is associated with altered genetic dosage of different TFs. V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and Single Minded 2 (SIM2) are two such TFs that regulate several downstream genes involved in developmental and neurological pathways. Here we studied functional genetic polymorphisms (fSNP) in ETS2 and SIM2 encoding genes in a group of patients and control subjects to better understand association of these variants with DS phenotypes. Methods We employed an in silico approach to identify potential target pathways of ETS2 and SIM2. fSNPs in genes encoding for these two TFs were identified using available databases. Selected sites were genotyped in individuals with DS, their parents, ALL, BC, OC as well as ethnically matched control individuals. We further analyzed these data by population-based statistical methods. Results Allelic/genotypic association analysis showed significant (P Conclusions We infer from the present investigation that the difference in frequencies of fSNPs and their independent as well as interactive effects may be the cause for altered expression of SIM2 and ETS2 in DS and malignant groups, which affects different downstream biological pathways. Thus, altered expression of SIM2 and ETS2 could be one of the reasons for variable occurrence of different malignant conditions in DS.