Why do people with Down syndrome get fewer cancers?

Question

I'm coming across some conflicting information regarding the correlation between cancer incidents and trisomy 21. I read a report from nature that discusses how Downs are only a tenth as likely to develop cancers, but at the same time are 20x more likely to develop certain B cell malignancies. One of the more prominent findings show that a regulator of angiogenesis, *DSRC1* plays a significant role. What I'm trying to find out is what gene(s) on 21 contribute to the associated risk for lymphoma? And does there exist a good list of those genes on 21 that suppress or enhance tumor genesis.

Answer 1

I did some research in order to be able to provide you the best information and data to answer your questions.

A brief clarification, patients with Down Syndrome (DS), do have an increased risk of developing of developing Leukemias/Lymphomas (AML/ALL, etc.)…

I believe there might have been some confusion, since even though they do have a higher risk of developing these hematologic malignancies, according to the research I found and thoroughly went over, DSRC1 seems to have a protective function against the progression of solid tumors such as pancreatic or liver cancer, not leukemias/lymphomas. 

The DSRC1 gene which “encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signaling by the calcineurin pathway,” does not appear to play a major role in the development of B-cell malignancies in Down Syndrome patients. 

In mice, increased expression of this gene, especially with Dyrk1a (another chromosome 21 gene), may be sufficient to markedly diminish angiogenesis in tumours arising from suppression of the calcineurin pathway.  This makes it an interesting therapeutic target for such cancers.

"Down syndrome critical region-1 (Dscr1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic KrasG12D. In addition, we show that Dscr1trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by up regulation of the p15Ink4b tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin–NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of Dscr1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals."

Links that will provide further clarification as well as the list of the tumor suppressor genes and/or oncogenes on chromosome 21.

https://www.nature.com/articles/s41375-020-0854-5

https://www.sciencedirect.com/science/article/abs/pii/S0006291X13015040

https://pubmed.ncbi.nlm.nih.gov/32433508/

https://www.ncbi.nlm.nih.gov./pmc/articles/PMC3432955/

https://link.springer.com/article/10.1007/s12288-020-01295-8