Dominant genetic alterations in immortalization: role for 20q gain.
Gain of 20q has been observed in many cancer types, including bladder cancers. However, the biological significance of low-copy-number 20q gain in human cancer pathogenesis has not yet been defined. We reported that immortalization of human uroepithelial cells (HUC) transformed with human papillomavirus 16 (HPV 16) E7 is associated with single-copy 20q gain (P = 2 x 10(-7)). We also observed 20q13.2 amplification in some cell lines, but only after 20 passages. Thus, we hypothesized that low-copy gain of 20q gene(s) contributes in a dominant way to bypassing HUC senescence. To test this hypothesis, we fused precrisis E7-transformed HUCs (pcE7s) with three independent immortal E7-HUCs that acquired a single-copy 20q gain at immortalization. In one of these lines, a single-copy gain of 20q and a 10p12.1-pter loss were the only cytogenetic alterations. Immortal cell hybrids were obtained with all three crosses. Southern analysis for unique HPV16 insertion sites, as well as fluorescence in situ hybridization (FISH) with whole chromosome 20 painting probes (WCP20) for marker chromosomes in the immortal clones, confirmed the hybrid and independent nature of representative immortal clones. In contrast, when we used the same protocol, no immortal somatic cell hybrids were obtained when HPV16 E6 immortal HUC (E6-HUC) that showed 3p and 9p losses, but no 20q gain, were fused with precrisis E6-transformed HUC (pcE6s). This latter observation is consistent with many results demonstrating that recessive changes are required for cell immortalization. Therefore, the new results reported herein for the first time demonstrate that dominant changes can contribute to bypassing senescence, and that such genes may be located on 20q. Genes Chromosomes Cancer 26:304-311, 1999.
Cuthill
S
S
Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin, USA.
Agarwal
P
P
Sarkar
S
S
Savelieva
E
E
Reznikoff
C A
CA
D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D004847:Epithelial Cells; D005784:Gene Amplification; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D014513:Ureter; D016662:Virus Integration / Q000235:genetics
D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16