Around the world, 200,000 people a year are affected by oral cancer, and the incidence of this disease is 10 times higher in India than Japan, mainly due to the custom of chewing tobacco. Loss of heterozygosity (LOH) on the long arm of chromosome 2 (2q), the short arm of chromosome 3 (3p) and the long arm of chromosome 21 (21q) are observed in several human cancers. We identified novel tumor suppressor loci on these regions in primary oral squamous cell carcinomas (OSCCs) in Japanese. However, there has been no detailed analysis of LOH on these chromosomes in Indians. In the present study, we investigated LOH at 2q, 3p and 21q using 9 microsatellite markers in 26 Indian OSCCs. LOH was detected in 25 (96.2%) out of 26 informative samples at one or more of the loci examined. On the basis of the results, two commonly deleted regions were identified and a detailed deletion map was constructed. In the first region, a high frequency of LOH was observed at the D3S1007 locus (53.8%) on 3p25, which is located in the region neighboring the VHL (von Hippel-Lindau) gene. In the second region, LOH was concentrated at the D3S966 locus (50.0%) on 3p21.3, suggesting the presence of a putative tumor suppressor gene (TSG) associated with OSCCs. These results strongly suggest that there are at least two candidate TSGs located on chromosome 3p, and that alteration in them is associated with the tumorigenesis of OSCCs.
Abstract. The purpose of this study was to perform a wholegenome analysis of loss of heterozygosity (LOH) in tongue squamous cell carcinoma (SCC) using the Affymetrix 10K SNP Mapping Array. In the gene which had been identified by whole-genome analysis of LOH, we analyzed allelic imbalance to identify the role of the gene. We applied wholegenome analysis of LOH in the specimens from the 5 cases of tongue SCC using this array. In the chromosomal region which had been identified by whole-genome analysis of LOH, we reconfirmed the existence of LOH in 30 cases using microsatellite markers. The expression levels of the mRNA in the region were examined in 15 cases and in 5 tongue SCC-derived cell lines by real-time quantitative RT-PCR analysis. LOH was observed in all of the 5 cases in the 1q31.1 region. Only 3 microsatellite markers (D1S1189, D1S2151, and D1S2595) existed in the 1q31.1 region. A high frequency of LOH was found at the D1S1189 locus in 18/30 (60%), D1S2151 locus in 16/30 (53%) and D1S2595 locus in 21/30 (70%). Only the Family with sequence similarity 5, member C (FAM5C) gene was located in the 1q31.1 region. There was statistically significant difference in the FAM5C mRNA expression levels between tongue SCC and normal tissues. All tongue SCC-derived cell lines decreased FAM5C mRNA expression compared with normal oral keratinocytes (NOKs). We conclude that FAM5C may be a novel tumor suppressor gene (TSG) in tongue SCC.
Chromosomal loss of heterozygosity (LOH) is a common mechanism for the inactivation of tumor suppressor genes in human epithelial cancers. LOH patterns can be generated through allelotyping using polymorphic microsatellite markers; however, owing to the limited number of available microsatellite markers and the requirement for large amounts of DNA, only a modest number of microsatellite markers can be screened. Hybridization to single nucleotide polymorphism (SNP) arrays using Affymetarix GeneChip Mapping 10 K 2.0 Array is an efficient method to detect genome-wide cancer LOH. We determined the presence of LOH in oral SCCs using these arrays. DNA was extracted from tissue samples obtained from 10 patients with tongue SCCs who presented at the Hospital of Tokyo Dental College. We examined the presence of LOH in 3 of the 10 patients using these arrays. At the locus that had LOH, we examined the presence of LOH using microsatellite markers. LOH analysis using Affymetarix GeneChip Mapping 10K Array showed LOH in all patients at the 1q31.1. The LOH regions were detected and demarcated by the copy number 1 with the series of three SNP probes. LOH analysis of 1q31.1 using microsatellite markers (D1S1189, D1S2151, D1S2595) showed LOH in all 10 patients (100). Our data may suggest that a putative tumor suppressor gene is located at the 1q31.1 region. Inactivation of such a gene may play a role in tongue tumorigenesis.
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