Genetic Linkage between Down syndrome and reduced cancer incidence revealed

Down syndrome is the leading genetic cause of mental retardation, affecting about one in 800 live births. It results from a trisomy of all or most of human chromosome 21 (Chr 21). Symptoms include varying degrees of mental retardation, characteristic craniofacial features, Alzheimer-like pathology after the third or fourth decade of life and, occasionally, problems such as childhood leukemia and gastro-intestinal disorders (National Association for Down Syndrome).

People with Down syndrome are 10 times less susceptible to most solid tumor cancers and develop fewer angiogenic diseases, such as diabetic retinopathy and atherosclerosis, than the general population. In 2009, a collaborative research team led by Kwan-Hyuck Baek, Ph.D., from the Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Mass., demonstrated a genetic link between reduced cancer incidence and angiogenesis (blood vessel generation) in people with Down syndrome. Using mouse models, the team showed that overexpression of two genes on the extra copy of Chr21 suppresses solid tumor growth by reducing tumor blood supply (Baek et al. 2009).

The research team found that overexpression of the first gene, Down syndrome critical region-1 (gene symbol DSCR1 in humans, Dcsr1 in mice; now called regulator of calcineurin 1, RCAN1 and Rcan1 in humans and mice, respectively) correlates with reduced tumor angiogenesis in people with Down syndrome. They found similar correlations in a Down syndrome mouse model (JAX^® Mice strain B6EiC3Sn a/A-Ts(17¹⁶)65Dn (001924), more commonly known as the "Ts65Dn" mouse), and in a B6 mouse transgenic for an extra copy of the Dscr1 gene. Increased levels of DSCR1 had previously been shown to downregulate vascular endothelial growth factor (VEGF)-mediated angiogenic signaling by the calcineurin pathway. The team also found that, in vitro, the combined overexpression of a second gene, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (gene symbol DYRK1A in humans, Dyrk1a in mice), and Dscr1 seems to further attenuate the same calcineurin pathway.

The findings not only help explain why people with Down syndrome are less susceptible to cancer than the general public, but they indicate that targeting the calcineurin signaling pathway and its regulators, such as DSCR1 and DYRK1A, may have wide applications as cancer therapies.

Reference

Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S. 2009. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459:1126-30.

JAX^® Mice models for Down syndrome

The most widely used animal model of Down syndrome is JAX^® Mice strain B6EiC3Sn a/A-Ts(17¹⁶)65Dn (001924), a strain constructed almost 20 years ago by JAX Professor Muriel Davisson, Ph.D. Selected features of this and two other Down syndrome JAX^® Mice models are summarized below.

B6EiC3Sn a/A-Ts(17¹⁶)65Dn (Ts65Dn) 001924

• This model has an extra chromosome containing a third copy of most of the mouse Chromosome (Chr) 16 genes that are orthologous to human chr 21 genes (trisomic for 104 of the 231 genes on human chr 21, including Dscr1 and Dyrk1a).
• Exhibits spatial learning and memory defects, developmental delays in sensorimotor milestones, locomotor hyperactivity, lack of behavioral inhibition and stereotypic behavior.
• Performs similar to controls in visual placing, balance, prehensile reflex and traction on a horizontal bar, motor coordination, swimming ability and olfaction orienting.
• By six months, shows altered noradrenergic transmission in the hippocampus and cerebral cortex and degeneration of basal forebrain cholinergic neurons.
• Subtle craniofacial dysmorphology.
• Females subfertile, only about 25% of pups with the trisomic chromosome survive, males effectively sterile and hypo- or a-spermic.
• Recently used to demonstrate that memantine can reverse DS-associated learning deficits. (Costa et al. 2007)

B6EiC3Sn-Ts(16C-tel)1Cje 004861

• Extra segment of Chr 16 is translocated to Chr 12 with a third copy of ~3/4 of the genes triplicated in Ts65Dn, including Dscr1 and Dyrk1a.
• Decreased exploratory behavior but spatial learning deficits less severe than Ts65Dn.
• Unlike Ts65Dn, no basal forebrain cholinergic neuron degeneration in 6-month olds.
• Males fertile.
• Displays much of the same craniofacial dysmorphology as Ts65Dn.

B6.129S6-Dp(16Cbr1-ORF9)1Rhr/J 005383

• Trisomic for mouse chromosome segment orthologous to the human chr 21 Down syndrome critical region (DSCR); has three copies of ~1/4-1/3 of the genes triplicated in Ts65Dn, including Dyrk1a (but not Dscr1).
• Borders of the 3.9 Mb DSCR defined by the carbonyl reductase 1 (Cbr1) gene and a site adjacent to the myxovirus (influenza virus) resistance 2 locus.
• Viable, fertile and significantly larger than euploid littermates.
• Mandible and skull larger and rostrocaudal aspect longer than in euploid littermates.