A region within murine chromosome 7F4, syntenic to the human 11q13 amplicon, is frequently amplified in 4NQO-induced oral cavity tumors.
Our previous reports have shown that two thirds of 4-nitroquinoline-1-oxide (4NQO)-induced murine oral squamous cell carcinomas (SCC) have Hras1 mutations. Loss of heterozygosity (LOH) involving the distal portion of chromosome (Chr) 7 occurred in half of the tumors with Hras1 mutations. Here, we demonstrate that five of six tumors with LOH have 4-8-fold amplification involving the distal portion of Chr 7 (7F4). Ccnd1. Fgf4 and Fgf3, within the most telomeric region of Chr 7 (70.5 cM), are co-amplified. The region is syntenic to a previously identified human amplicon at 11q13. Only one out of eight tumors without LOH at Chr 7 had twofold amplification; the other seven had no detectable amplification. Significant amplification is restricted to the chromosome with the Hras1 mutation. Gene amplification occurred without overexpression since only one of five tumors with amplification and one of six tumors without Ccnd1 amplification expressed increased protein. Although amplification of 11q13 occurs rather frequently in human tumors, 4NQO-induced oral cavity tumors in inbred mice are the first example of a murine tumor with consistent amplification. Our observations are strikingly similar to human head and neck SCC where overexpression of genes within the 11q13 amplicon is inconsistently detected. The amplification of genes localized to human 11q13 and the syntenic region on murine Chr 7 during tumorigenesis suggests that similar structural elements are present which predispose these regions to amplification during malignant transformation.
Yuan
B
B
Department of Biochemistry, J Graham Brown Cancer Center, Louisville, Kentucky, USA.
Oechsli
M N
MN
Hendler
F J
FJ
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D019938:Cyclin D1; D016213:Cyclins / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors / Q000235:genetics; D005784:Gene Amplification; D017353:Gene Deletion; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013045:Species Specificity
D016213:Cyclins; D004273:DNA, Neoplasm; C496444:FGF3 protein, human; C489197:Fgf3 protein, mouse; D051518:Fibroblast Growth Factor 3; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D015112:4-Nitroquinoline-1-oxide; D005346:Fibroblast Growth Factors; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)