Aneuploidy arises at early stages of Apc-driven intestinal tumorigenesis and pinpoints conserved chromosomal loci of allelic imbalance between mouse and human.
Although chromosomal instability characterizes the majority of human colorectal cancers, the contribution of genes such as adenomatous polyposis coli (APC), KRAS, and p53 to this form of genetic instability is still under debate. Here, we have assessed chromosomal imbalances in tumors from mouse models of intestinal cancer, namely Apc(+/1638N), Apc(+/1638N)/KRAS(V12G), and Apc(+/1638N)/Tp53-/-, by array comparative genomic hybridization. All intestinal adenomas from Apc(+/1638N) mice displayed chromosomal alterations, thus confirming the presence of a chromosomal instability defect at early stages of the adenoma-carcinoma sequence. Moreover, loss of the Tp53 tumor suppressor gene, but not KRAS oncogenic activation, results in an increase of gains and losses of whole chromosomes in the Apc-mutant genetic background. Comparative analysis of the overall genomic alterations found in mouse intestinal tumors allowed us to identify a subset of loci syntenic with human chromosomal regions (eg, 1p34-p36, 12q24, 9q34, and 22q) frequently gained or lost in familial adenomas and sporadic colorectal cancers. The latter indicate that, during intestinal tumor development, the genetic mechanisms and the underlying functional defects are conserved across species. Hence, our array comparative genomic hybridization analysis of Apc-mutant intestinal tumors allows the definition of minimal aneuploidy regions conserved between mouse and human and likely to encompass rate-limiting genes for intestinal tumor initiation and progression.
Alberici
Paola
P
Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
de Pater
Emma
E
Cardoso
Joana
J
Bevelander
Mieke
M
Molenaar
Lia
L
Jonkers
Jos
J
Fodde
Riccardo
R
D000782:Aneuploidy; D000818:Animals; D043171:Chromosomal Instability; D002877:Chromosomes, Human; D017491:Genes, APC; D016158:Genes, p53; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009693:Nucleic Acid Hybridization; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013045:Species Specificity
D011518:Proto-Oncogene Proteins