A transposon-based genetic screen in mice identifies genes altered in colorectal cancer.
Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.
Starr
Timothy K
TK
Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. star0044@umn.edu
Allaei
Raha
R
Silverstein
Kevin A T
KA
Staggs
Rodney A
RA
Sarver
Aaron L
AL
Bergemann
Tracy L
TL
Gupta
Mihir
M
O'Sullivan
M Gerard
MG
Matise
Ilze
I
Dupuy
Adam J
AJ
Collier
Lara S
LS
Powers
Scott
S
Oberg
Ann L
AL
Asmann
Yan W
YW
Thibodeau
Stephen N
SN
Tessarollo
Lino
L
Copeland
Neal G
NG
Jenkins
Nancy A
NA
Cormier
Robert T
RT
Largaespada
David A
DA
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003433:Crosses, Genetic; D004251:DNA Transposable Elements; D005784:Gene Amplification; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D052138:Genes, Neoplasm; D005820:Genetic Testing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009010:Monte Carlo Method; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics
D004251:DNA Transposable Elements; D051901:Smad4 Protein; D051059:PTEN Phosphohydrolase