Genetic basis for reduced cancer risk in Down's syndrome

25 May 2009

Down's Syndrome (DS) or trisomy 21, the most common form of aneuploidy to affect liveborn children, is a condition associated with the presence of a whole or partial additional (third) copy of chromosome 21. The condition is the most common genetic cause of learning disability, affecting around one in every 700 births. The characteristic clinical features of DS are presumed to arise from the abnormal dosage of certain genes present on the additional copy of chromosome 21. Similarly, abnormally high expression of chromosome 21 genes is thought to be involved in the altered risk of developing specific diseases associated with DS – for example, an increased risk of early onset Alzheimer’s type dementia and of leukaemia, and a substantially decreased risk of many other forms of cancer.

A new paper in Nature presents a possible mechanism for this decreased risk of solid tumours in individuals with DS [Baek KH et al. (2009) Nature May 20, doi:10.1038/nature08062]. A team led by researchers from the Vascular Biology Program at the Children’s Hospital Boston in the US investigated the idea that the suppression of angiogenesis (the formation of new blood vessels) could be involved. The growth of new blood vessels is an important stage in the formation of solid tumours; individuals with DS have also been noted to have a reduced incidence of other diseases related to angiogenesis such as atherosclerosis. Additionally, the Down's syndrome candidate region-1 (DSCR1) gene on chromosome 21 encodes a molecule that suppresses vascular endothelial growth factor (VEGF)-mediated signalling involved in angiogenesis, via the calcineurin pathway.

The authors report a 1.8-fold increased level of DSCR1 expression in tissues from DS fetuses compared with control fetuses of the same gestational age. Analysis of a mouse model of DS revealed a 1.7-fold increase in expression levels of the corresponding DSCR1 protein compared with that in normal mice. They then examined the growth of two forms of tumour in DS mice (induced by transplantation), and observed significantly suppressed tumour growth and fewer small blood vessels (microvessels) associated with the tumours compared with normal mice. Microvessel density was also compared for tumours created from samples of induced pluripotent stem (iPS) cells derived from normal and Down’s Syndrome human cells and transplanted into immunodeficient mice; as expected, microvessel density was lower in the DS-derived than the normal tumours.

The authors propose that other chromosome 21 genes might well inhibit tumour formation via similar mechanisms, and report evidence to support an additional inhibition of angiogenesis and tumour growth mediated by the mouse Dyrk1a gene, which has previously been implicated in other phenotypic features of DS. Lead researcher Dr Sandra Ryeom said:"I think there may be four or five genes on chromosome 21 that are necessary for angiogenesis suppression…In huge databases of cancer patients with solid tumors, there are very few with Down syndrome. This suggests that protection from chromosome 21 genes is pretty complete" (see press release). However, the paper notes that individuals with DS also “have less exposure to environmental and other factors that contribute to tumour incidence”.

Comment: This paper contributes a plausible explanation of the genetic basis and pathway by which another of the observed features of Down’s Syndrome may arise. This not only contributes towards the expanding understanding of this condition, but also identifies the DSCR1 molecule as a potential target for drugs to help prevent or to treat selected cancers in individuals with DS, and potentially also in the general population – another example of how the study of genetic and chromosomal forms of disease can provide insights potentially relevant to much wider patient populations.

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