Involvement of evolutionarily plastic regions in cancer associated CHR3 aberrations

摘要: A functional test to identify tumor antagonizing regions on chromosome 3 (chr3), called the Elimination Test, was developed in our group. It is based microcell mediated transfer of human chr3 into mouse or cells and analysis monochromosomal hybrids after their growth vivo. We identified three 3p14-p22, which were frequently lost derived tumors (common eliminated regions). In order understand role these development, we continued study following two leads: breakpoint clusters characterize possible instability features search for suppressor genes within deleted regions. First, characterized a common region 1 (CER1) homologous sequence mouse, where it divided syntenic blocks 9. blocks, gene content maintained with exception duplications. Comparative helped us five previously not (Kiss et al. 2002). more extensive comparative CER1 showed that its border are by evolutionary plasticity: synteny breaks several species, recent tandem duplications, retroposed pseudogene insertions, horizontal evolution genes. Thus cancer associated have plasticity. These results other publications from group suggested structural at borders Test (Darai 2005) (Kost-Alimova 2003; Kost-Alimova 2004). As next step, analyze rearrangements entire cells, compared high resolution methods, array-CGH mpFISH. proved although 1Mb BAC/PAC array could single copy number changes even pentaploid mpFISH provided accurate dissection complex karyotypes ploidy levels. heterogeneous normal cell contaminated samples most precise can be made due ability give information level (Darai-Ramqvist 2006). Using methods analyzed ten carcinoma lines new hot spots breakpoints 3p12-p13 3q21. carried large segmental retrotransposable elements satellite repeats, participated primate and, as suggest, chromosomal (CIN). CIN an ongoing dynamic process. Therefore prove characterizes phenotype required development progression, must done. This may elucidate mechanism development; help develop markers useful choice consequent treatment. Following second lead study, putative LIMD1, located central part CER1. found binds specifically pRb suppresses E2F driven transcription. effect this proven vitro vivo experiments, well biopsies (Sharp another details renal nasopharyngeal (chr3) aneuploid maintain mandatory segment balance stringency concerning no gain 3p14-21 loss 3q26-27. concluded suppression alternative quantitative model. According model does tolerate increased dosage relevant segment, either exogeneous endogenous origin 2007). LIST OF PUBLICATIONS I. H Kiss, E Darai, Cs M Kost-Alimova, G Klein, JP. Dumanski, S Imreh. human/murine 3p21.3. Mammalian Genome, 2002, Nov;13(11):646-55. II. M, Kiss H, Kansoul Klein & Imreh S. Evolutionarily plastic coincide “Elimination Test” Genomics 2005 Jul;86(1):1-12. III. TV. Sharp, F Munoz, D Bourboulia, N Presneau, HW Wang, Cannon, DN. Butcher, AG. Nicholson, Imreh, C Boshoff. LIM domains-containing protein (LIMD1), encoded chr3p21.3, pRB represses E2F-driven PNAS, 2004, November 23, vol. 101, no. 47, 16531–16536. IV. Darai-Ramqvist, T Diaz de Stahl, Sandlund, K Mantripragada, J Kost-Alimova. Array-CGH multipoint FISH decode rearrangements. BMC Genomics. 2006 Dec 29;7:330. V. W Lung Yau, L Fedorova, Y Yang, I Kholodnyuk, Cheng, Li Lung, Stanbridge, Mandatory cells. Cancer. 2007 Jan 26;7:21. VI. Characterisation cancer-associated frequent break 3. manuscript.