Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas.
Carcinomas that develop in the pancreatic islets of transgenic mice expressing the SV40 T-antigens (Tag) under transcriptional control of the rat insulin II promoter (RIP) progress through well-characterized stages that are similar to aspects of human tumor progression, including hyperplastic growth, increased angiogenesis and reduced apoptosis. The latter two stages have been associated with recurrent loss of heterozygosity (LOH) and reduced genome copy number on chromosomes 9 (LOH9) and 16 (LOH16), aberrations which we believe contribute to these phenotypes. Earlier analyses localized LOH9 to approximately 3 Mb and LOH16 to approximately 30 Mb (both syntenic with human 3q21-q25) but were limited by low throughput and a lack of informative polymorphic markers. Here we show that comparative genomic hybridization to DNA microarrays (array CGH) overcomes these limitations by allowing efficient, genome-wide analyses of relative genome copy number. The CGH arrays used in these experiments carried BACs distributed at 2-20-MB intervals across the mouse genome and at higher density in regions of interest. Using array CGH, we further narrowed the loci for LOH9 and LOH16 and defined new or previously unappreciated recurrent regions of copy-number decrease on chromosomes 6, 8 and 14 (syntenic with human chromosomes 12p11-p13, 16q24.3 and 13q11-q32, respectively) and regions of copy-number increase on chromosomes 2 and 4 (syntenic to human chromosomes 20q13.2 and 1p32-p36, respectively). Our analyses of human genome sequences syntenic to these regions suggest that CYP24, PFDN4, STMN1, CDKN1B, PPP2R3 and FSTL1 are candidate oncogenes or tumor-suppressor genes. We also show that irradiation and genetic background influence the spectrum of aberrations present in these tumors.
Hodgson
G
G
Cancer Genetics and Breast Oncology Programs, UCSF Cancer Center, University of California at San Francisco, Box 0808, San Francisco, California 94143-0808, USA.
Hager
J H
JH
Volik
S
S
Hariono
S
S
Wernick
M
M
Moore
D
D
Nowak
N
N
Albertson
D G
DG
Pinkel
D
D
Collins
C
C
Hanahan
D
D
Gray
J W
JW
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D016678:Genome; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology*; D019656:Loss of Heterozygosity; D051379:Mice; D008822:Mice, Transgenic; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics*
D017931:DNA Primers