Coincidence of evolutionarily plastic regions and cancer breakpoints
The Elimination test developed by us is based on chr 3 transfer into tumor cells by microcell fusion. The MCHs are tested for the elimination vs. retention of specific chromosome regions after passages in SCID mice. We ideintified a common eliminated region on 3p21.3 designated CER1. CER1 was similar in both human chr 3/mouse fibrosarcoma and chr 3/ human RCC MCHs. It contains 33 genes, 7 (incl LF, LIMD1 and TMEM7) may be considered as tumor suppressors. New evidence on that will be presented
Tumor breakpoints at the CER1 borders are clustered in approximately 200-300 kb regions both telomerically and centromerically. Sequence conservation analysis has been performed in C.elegans, Drosophila, Fugu, Gallus, Mus, Rattus and Canis. Four independent synteny breaks were found within the CER1 telomeric breakpoint cluster region, when compared human, dog and chicken genomes, and two independent synteny breaks within the CER1 centromeric breakpoint cluster region, when compared human, mouse and chicken genomes suggesting a non-random involvement of tumor breakpoint regions in chromosome evolution. Both CER1 breakpoint cluster regions show recent duplications (7 Zn finger protein family genes at the telomeric and 8 CCRs at the centromeric side). Finally, all genes from these regions underwent horizontal evolution in mammalian species, with formation of new genes and expansion of gene families, which were displayed in the human genome as tandem gene duplications and pseudogene insertions. These indicate that the tumor breakpoint cluster regions of CER1 have features that we call “evolutionary plasticity”. In contrast CER1 middle region contained well conserved solitary genes and minimal amount of retropositions. The coincidence of evolutionary plasticity with CER1 breakpoints may suggest that regional instability is expressed in both evolutionary and cancer associated chromosome rearrangements. Evolutionary plasticity studies are now extended on the whole chr 3