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.cancer genomics | chromosome 8p deletion | RNAi screen

8p deletion is strongly linked to poor prognosis in breast cancer

“…Such an analysis has been performed in liver cancer, suggesting that alterations of multiple genes might cooperatively drive tumor progression. 63 In conclusion, our results identify 8p deletions as a frequent event in breast cancer with marked prognostic impact. Several lines of evidence suggest, that 8p deletions exert their biological effect through combined haplo-insufficiency of multiple genes.…”

“…62 These findings raise the possibility that biologically relevant consequences of 8p deletion might involve subtle expression changes of one or (more likely) several 8p genes resulting from mono-allelic loss. In fact, studies in murine models of hepatocellular carcinomas, another cancer type frequently affected by large 8p deletions, have shown that partial inactivation of several 8p genes can cooperatively drive cancer development, 63 thus supporting a model of compound haplo-insufficiency as the main underlying mechanism rendering 8p-deleted breast cancers particularly aggressive. The absence of homozygous deletions in 597 8p deleted cancer is additional indirect support for haplo-insufficiency of 8p genes being effective in breast cancer and suggest that one or several in the vicinity of 8p are essential for survival of breast cancer cells.…”

Systems consequences of amplicon formation in human breast cancer

“…Deletions at this locus routinely inactivate both cell-cycle regulators Stott et al 1998). Recent evidence also suggests that oncogenes and tumor suppressor genes (TSGs) are clustered, including several TSGs on 8p21-23 in hepatocellular carcinoma, three oncogenes (NKX2-1, NKX2-8, and PAX9) on 14q13 in lung cancer, two oncogenes (CCND1 and FGF19) on 11q13, and two oncogenes (BIRC2 and YAP1) on 11q22 in liver cancer (Zender et al 2006;Kendall et al 2007;Sawey et al 2011;Solimini et al 2012;Xue et al 2012). Similar to the results presented here, phenotypes induced by the manipulation of individual genes are relatively weak, whereas the concerted deregulation of entire cancer gene clusters result in more significant effects.…”

CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice

“…Hepatic loss-of-function screening has been performed using RNAi-based gene knock-down in transplantation models (e.g., intrasplenic implantation of bipotent liver progenitor cells) (46) or by HTVI-based/transposon-mediated genome integration of shRNAs (47). Our results show that RNAi and CRISPR/Cas9 are complementary tools with unique beneficial characteristics, depending on the experimental context.…”