Definitive functional evidence for a tumor suppressor gene on human chromosome 7q31.1 neighboring the Fra7G site.
We have previously shown that loss of heterozygosity (LOH) on human chromosome (hchr) 7 at q31.1 is common in a variety of tumors of epithelial origin. Frequent LOH of a specific chromosomal marker is indicative of a closely linked tumor suppressor gene (TSG). However, recent reports have also indicated that such a high frequency of LOH could be due to the presence in this region of the second most common aphidicolin-inducible fragile site in the human genome (Fra7G). To address this controversy, we introduced single copies of hchr7 or hchr12 into a highly aggressive human prostate carcinoma cell line (PC3) by microcell-mediated transfer. The tumorigenicity of six clones of PC3/hchr7 hybrids and three clones of PCRhchr12 hybrids, obtained in four separate fusion experiments, were studied in BALB/c nude mice. All but one of the PC3/hchr7 hybrids increased tumor latency by at least twofold, whereas none of the PC3/hchr12 hybrids delayed tumor onset. No differences in the in vitro growth rate were observed among any of the cell lines assayed (parental and hybrids) suggesting that the observed tumor suppression was due to factors other than cell cycle regulation. Deletion mapping of the PC3/hchr7 tumors obtained after reversion to the malignant phenotype revealed a common region of loss centred around 7q31.1, supporting the TSG hypothesis. The smallest commonly deleted region was approximately 1.5 Mb in size and flanked by the markers D7S486 and D7S655.
Zenklusen
J C
JC
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hodges
L C
LC
LaCava
M
M
Green
E D
ED
Conti
C J
CJ
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D006822:Hybrid Cells; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018895:Microsatellite Repeats; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D017384:Sequence Deletion; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000637:transplantation
D005819:Genetic Markers