Background: People with trisomy 21 (T21) are predisposed to developing hematological tumors, but have significantly lower-than-expected age-adjusted incidence rates of having a solid tumor. Material and methods: To identify novel genetic factors implicated in the lower breast cancer (BC) frequency observed in women with T21 than in the general population, we compared the transcriptome pattern of women with a homogeneous T21, aged more than 30 years, with or without BC, and tumoral BC tissue of control women with a normal karyotype from the study of Varley et al. (2014). Results: Differential analysis of gene expression between the 15 women in the T21 without BC group and BC patients in the other groups (two women with T21 and fifteen control women, respectively) revealed 154 differentially expressed genes, of which 63 were found to have similar expression profile (up-or downregulated). Of those 63 genes, four were in the same family, namely GIMAP4, GIMAP6, GIMAP7 and GIMAP8, and were strongly upregulated in the T21 without BC group compared to the other groups. A significant decrease in mRNA levels of these genes in BC tissues compared to non-tumor breast tissues was also noted. Conclusion: We found that the expression of some GIMAPs is significantly higher in women with T21 without BC than in patients with sporadic BC. Our findings support the hypothesis that GIMAPs may play a tumor-suppressive role against BC, and open the possibility that they may also have the same role for other solid tumors in T21 patients. The search for new prognostic factors and hopefully new therapeutic or preventive strategies against BC are discussed. Trisomy 21 (T21) or Down syndrome is a common genetic disorder that results from the presence of all or part of an extra chromosome 21. It is one of the most frequent and most recognizable form of intellectual disability, appearing in approximately one out of every 700 to 2000 newborns. More than 100 features of people with T21 have been described, encompassing physical, medical, and psychological features 1. Epidemiological studies have shown that people with T21 are more predisposed to developing hematological tumors than the general population, yet their risk of developing solid tumors is at least 12 times lower 2-8. For instance, breast cancer (BC) is almost absent in women with T21 8-10 , even though this group shows a higher prevalence of known risk factors for BC, such as nulliparity, higher body mass index and obesity rates, sedentary life, increased chromosomal instability, dysfunctional mitochondria, overexpression of several known oncogenes and attenuation of known tumor suppressors, premature aging, DNA repair anomalies, immune deficiency, and