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  current news   Press   selected story    
     
  23 January 2015  
  Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression
 
 




Authors
Haruna Takeda1,2, Zhubo Wei3, Hideto Koso1,4, Alistair G Rust5, Christopher Chin Kuan Yew1, Michael B Mann1,3, Jerrold M Ward1, David J Adams5, Neal G Copeland1,3 & Nancy A Jenkins1,3

 

1  Division of Genomics and Genetics, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
2  Department of Oncologic Pathology, School of Medicine, Kanazawa Medical University, Ishikawa, Japan.
3  Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
4  Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo,    Tokyo, Japan.
5  Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

Correspondence should be addressed to N.A.J. (njenkins2@houstonmethodist.org).

Published online ahead of print in Nature Genetics on 5 January 2015.

Abstract
To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) transposon mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC.

Figure:

Figure Legend: Tumor formation was accelerated and mouse survival times were shortened by SB-mediated mutagenesis. (a) Vogelstein’s CRC progression model (adapted from ref. 55, © 1990, with permission from Elsevier; see also ref. 2). (b) The number of tumors per mouse was significantly increased by SB mutagenesis in all cohorts, displayed as the average ± s.e.m.: Apcmin (Apcmin/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 32.6 ± 3.3 (n = 8); Apcmin:SB (Apcmin/+; Vil1-creERT2/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 43.6 ± 3.8 (n = 17); KrasG12D (Vil1-creERT2/+; KrasG12D/+), 1.3 ± 0.8 (n = 6); KrasG12D:SB (Vil1-creERT2/+; KrasG12D/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 24.8 ± 4.0 (n = 17); Smad4KO (Smad4KO/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 8.8 ± 1.2 (n = 6); Smad4KO:SB (Vil1-creERT2/+; Smad4KO/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 17.5 ± 1.7 (n = 30); p53R172H (Vil1-creERT2/+; Trp53R172H/+), 3.0 ± 0.8 (n = 4); p53R172H:SB (Vil1-creERT2/+; Trp53R172H/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 15.2 ± 2.8 (n = 37); wild type (WT), 0.6 ± 0.6 (n = 5); and SB (Vil1-creERT2/+; Rosalox-STOP-lox-SBase/+; Onc2/+), 20.8 ± 4.2 (n = 19). *P < 0.05, **P < 0.001, one-sided unpaired t test. (c) There were differences in mouse survival times between the cohorts: Apcmin:SB versus KrasG12D:SB (P < 0.0001), KrasG12D:SB versus Smad4KO:SB (P < 0.0001), Smad4KO:SB versus p53R172H:SB (P = 0.024), and p53R172H:SB versus SB (P < 0.0001) by log-rank test. (df) Representative images of a KrasG12D:SB adenoma (d), a KrasG12D:SB adenocarcinoma (e) and a p53R172H:SB lymph node metastasis (f). Scale bars: 200 μm for d and e, 100 μm for f. (g) The percentages of adenocarcinomas, adenomas and gastrointestinal neoplasias diagnosed in each cohort. KrasG12D:SB: adenocarcinomas, 51% (n = 27); adenomas, 38% (n = 20); gastrointestinal neoplasias, 11% (n = 6). Smad4KO:SB: adenocarcinomas, 37% (n = 35); adenomas, 55% (n = 52); gastrointestinal neoplasias, 8% (n = 8). p53R172H:SB: adenocarcinomas, 54% (n = 21); adenomas, 23% (n = 52); gastrointestinal neoplasias, 23% (n = 9).