Boveri observed nearly 100 years ago that aneuploidy, an abnormal chromosome number, is a common characteristic of tumor cells. From this, he proposed that aneuploidy causes tumorigenesis, a proposal that has remained untested due to the difficulty of selectively generating aneuploidy in the absence of other defects. Cells and mice with reduced levels of the mitosis-specific, centromere-linked motor protein CENP-E develop aneuploidy and chromosomal instability in vitro and in vivo in the absence of other defects including DNA damage. Spectral karyotyping reveals that aneuploidy from reduction in CENP-E is due to missegregation of whole chromosomes. Whole chromosome aneuploidy is shown to promote transformation of cells expressing the SV40 large T antigen and suppresses transformation in most cells lacking the p19/ARF tumor suppressor. Splenocytes, peripheral blood lymphocytes and colonic crypt cells exhibit significant near-diploid aneuploidy in CENP-E heterozygous mice that increases with age and is accompanied by higher rates of chromosome loss than gain. Aneuploidy from reduced levels of CENP-E drives a modest elevation in spontaneous lymphomas and lung tumors in aged animals. Aneuploidy also increases the latency of tumor initiation and/or progression in spontaneous liver tumors, in tumors caused by treatment with the carcinogen DMBA, and in animals lacking the tumor suppressor p19/ARF. These findings both confirm Boveri’s hypothesis and reveal a previously unsuspected role of aneuploidy and chromosomal instability in preventing tumorigenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA