1. Department of Physiology and The Institute for Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
2. Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA
3. Present address: Department of Environmental Health Sciences, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Correspondence to: Roger H. Reeves¹ Correspondence and requests for materials should be addressed to R.H.R. (Email: rreeves@jhmi.edu).

Abstract

Epidemiological studies spanning more than 50 yr reach conflicting conclusions as to whether there is a lower incidence of solid tumours in people with trisomy 21 (Down's syndrome)^{1, 2}. We used mouse models of Down's syndrome and of cancer in a biological approach to investigate the relationship between trisomy and the incidence of intestinal tumours. Apc^Min-mediated tumour number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr and Ms1Rhr. Trisomy for orthologues of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumours. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumours. Further studies demonstrated that the Ets2 gene contributed most of the dosage-sensitive effect on intestinal tumour number. The action of Ets2 as a repressor when it is overexpressed differs from tumour suppression, which requires normal gene function to prevent cellular transformation. Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.

1. Department of Physiology and The Institute for Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
2. Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA
3. Present address: Department of Environmental Health Sciences, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Correspondence to: Roger H. Reeves¹ Correspondence and requests for materials should be addressed to R.H.R. (Email: rreeves@jhmi.edu).

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