Sussan Thomas E, Yang Annan, Li Fu, Ostrowski Michael C, Reeves Roger H
Department of Physiology and The Institute for Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nature. 2008 Jan 3;451(7174):73-5. doi: 10.1038/nature06446.
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). 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.
五十多年来的流行病学研究对于21三体综合征（唐氏综合征）患者实体瘤发病率是否较低得出了相互矛盾的结论。我们采用生物学方法，利用唐氏综合征和癌症的小鼠模型来研究三体性与肠道肿瘤发病率之间的关系。在非整倍体小鼠模型Ts65Dn、Ts1Rhr和Ms1Rhr中测定Apc(Min)介导的肿瘤数量。Ts65Dn小鼠中约一半21号染色体（Hsa21）上基因的直系同源基因三体性，或Ts1Rhr小鼠中仅33个此类基因的三体性，均导致肠道肿瘤数量显著减少。在Ms1Rhr中，与Ts1Rhr中三倍体化的相同33个基因的节段性单体性导致肿瘤数量增加。进一步研究表明，Ets2基因对肠道肿瘤数量的剂量敏感效应贡献最大。Ets2过度表达时作为阻遏物的作用不同于肿瘤抑制，肿瘤抑制需要正常基因功能来防止细胞转化。Ets2以及可能参与这种保护作用的其他基因的上调可能对所有个体都具有预防作用，无论其倍性如何。
