Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ.. New genes involved in cancer identified by retroviral tagging. Nat Genet 32: 166-174

Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702, USA.
Nature Genetics (Impact Factor: 29.65). 10/2002; 32(1):166-74. DOI: 10.1038/ng949
Source: PubMed

ABSTRACT Retroviral insertional mutagenesis in BXH2 and AKXD mice induces a high incidence of myeloid leukemia and B- and T-cell lymphoma, respectively. The retroviral integration sites (RISs) in these tumors thus provide powerful genetic tags for the discovery of genes involved in cancer. Here we report the first large-scale use of retroviral tagging for cancer gene discovery in the post-genome era. Using high throughput inverse PCR, we cloned and analyzed the sequences of 884 RISs from a tumor panel composed primarily of B-cell lymphomas. We then compared these sequences, and another 415 RIS sequences previously cloned from BXH2 myeloid leukemias and from a few AKXD lymphomas, against the recently assembled mouse genome sequence. These studies identified 152 loci that are targets of retroviral integration in more than one tumor (common retroviral integration sites, CISs) and therefore likely to encode a cancer gene. Thirty-six CISs encode genes that are known or predicted to be genes involved in human cancer or their homologs, whereas others encode candidate genes that have not yet been examined for a role in human cancer. Our studies demonstrate the power of retroviral tagging for cancer gene discovery in the post-genome era and indicate a largely unrecognized complexity in mouse and presumably human cancer.

Download full-text


Available from: Herbert C Morse, Aug 26, 2015
1 Follower
  • Source
    • "-myc, the EviN (N = 1, 2, 3,..) numbering system was applied by Copeland et al. to summarize the MLV integration site [Suzuki et al., 2002; Akagi et al, 2004] "
    Introduction to Sequence and Genome Analysis (BK025A), 01/2012; iConcept Press Ltd.
  • Source
    • " metastatic transforma tion ( Rhodes et al . , 2004 ) . High levels of Sox4 mRNA expression have been observed in a large number of human tumors including breast , lung , brain , prostate and ovarian cancer , and the Sox4 gene locus has been repeatedly found to be targeted by tumor - promoting retroviral integration in mice ( Lund et al . , 2002 ; Suzuki et al . , 2002 ; Shin et al . , 2004 ) . Together , these studies support the inclusion of Sox4 as one of the 64 genes that constitute a general cancer signature ( Rhodes et al . , 2004 ) . Sox4 may thus be considered as a master regulator of cell fate and differentiation in numerous cell types and appears to have a dominant role in the development of"
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitin-independent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.
    Oncogene 10/2011; 31(21):2668-79. DOI:10.1038/onc.2011.445 · 8.56 Impact Factor
  • Source
    • "The non-random nature of viral integration and the potential for integration events to cause toxicity and cancer have long been realized [17] [18]. However, a formal VIS hot-spot definition was not described until the turn of the century when Suzuki et al. (2002) developed a definition for retroviral integration in cancer cells to discover potential cancer-related genes [19]. The authors referred to a hot-spot as a Common Insertion Site (CIS) and defined them as ≥4 integrations within a 100 kb region, 3 integrations within 50 kb or 2 within 30 kb. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Modern gene therapy methods have limited control over where a therapeutic viral vector inserts into the host genome. Vector integration can activate local gene expression, which can cause cancer if the vector inserts near an oncogene. Viral integration hot-spots or 'common insertion sites' (CIS) are scrutinized to evaluate and predict patient safety. CIS are typically defined by a minimum density of insertions (such as 2-4 within a 30-100 kb region), which unfortunately depends on the total number of observed VIS. This is problematic for comparing hot-spot distributions across data sets and patients, where the VIS numbers may vary. We develop two new methods for defining hot-spots that are relatively independent of data set size. Both methods operate on distributions of VIS across consecutive 1 Mb 'bins' of the genome. The first method 'z-threshold' tallies the number of VIS per bin, converts these counts to z-scores, and applies a threshold to define high density bins. The second method 'BCP' applies a Bayesian change-point model to the z-scores to define hot-spots. The novel hot-spot methods are compared with a conventional CIS method using simulated data sets and data sets from five published human studies, including the X-linked ALD (adrenoleukodystrophy), CGD (chronic granulomatous disease) and SCID-X1 (X-linked severe combined immunodeficiency) trials. The BCP analysis of the human X-linked ALD data for two patients separately (774 and 1627 VIS) and combined (2401 VIS) resulted in 5-6 hot-spots covering 0.17-0.251% of the genome and containing 5.56-7.74% of the total VIS. In comparison, the CIS analysis resulted in 12-110 hot-spots covering 0.018-0.246% of the genome and containing 5.81-22.7% of the VIS, corresponding to a greater number of hot-spots as the data set size increased. Our hot-spot methods enable one to evaluate the extent of VIS clustering, and formally compare data sets in terms of hot-spot overlap. Finally, we show that the BCP hot-spots from the repopulating samples coincide with greater gene and CpG island density than the median genome density. The z-threshold and BCP methods are useful for comparing hot-spot patterns across data sets of disparate sizes. The methodology and software provided here should enable one to study hot-spot conservation across a variety of VIS data sets and evaluate vector safety for gene therapy trials.
    BMC Bioinformatics 09/2011; 12:367. DOI:10.1186/1471-2105-12-367 · 2.67 Impact Factor
Show more