title: A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions.
abstract: The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.forename: Thomas
authors.initials: T
authors.lastname: Kitzing
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roessler
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Alexander
authors.initials: A
authors.lastname: Krasnitz
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Kate
authors.initials: K
authors.lastname: Revill
authors.forename: Susann
authors.initials: S
authors.lastname: Weissmueller
authors.forename: Amy R
authors.initials: AR
authors.lastname: Rappaport
authors.forename: Janelle
authors.initials: J
authors.lastname: Simon
authors.forename: Jack
authors.initials: J
authors.lastname: Zhang
authors.forename: Weijun
authors.initials: W
authors.lastname: Luo
authors.forename: James
authors.initials: J
authors.lastname: Hicks
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Powers
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D023281:Genomics / Q000379:methods*; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008099:Liver / Q000166:cytology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009006:Monosomy; D034622:RNA Interference; D013234:Stem Cells / Q000166:cytology