Abstract
BackgroundPrevious studies have shown that the short arm of chromosome 5 (5p) exhibit frequent genetic changes in invasive cervical carcinoma (CC), and that these changes arise early during the carcinogenesis, in precancerous lesions. These data therefore suggest that loss of candidate tumor suppressor genes located on 5p is associated with the development of CC. However, the precise location of 5p deletions is not known.ResultsWe performed a detailed deletion mapping of 5p in 60 cases of invasive CC. We found that 60% of the tumors exhibit a 5p loss of heterozygosity (LOH). The patterns of LOH allowed us to identify two minimal regions of deletions, one at 5p15.3 spanning a 5.5 cM genetic distance and a second site of 7 cM at 5p15.2-15.3. In addition, we also identified 5p deletions in 16% lesions of high-grade cervical intraepithelial neoplasia (CIN). 5p LOH was found in 63% of HPV 16 positive tumors, while only 33% tumors with other HPV-types had 5p LOH. The differences in frequency of 5p LOH between tumors harboring HPV16 in combination with other HPV types and tumors harboring HPV16 DNA alone were significantly higher, suggesting a synergistic effect of high-risk types in causing genomic instability.ConclusionThese findings implicate the presence of tumor suppressor gene(s) on 5p relevant to CC tumorigenesis.
Highlights
Previous studies have shown that the short arm of chromosome 5 (5p) exhibit frequent genetic changes in invasive cervical carcinoma (CC), and that these changes arise early during the carcinogenesis, in precancerous lesions
Cytogenetic and molecular genetic analyses have identified the short arm of chromosome 5, 5p, as frequently affected by duplications and deletions in a high proportion of CCs [3,4,5,6]. These findings suggest the presence of positively regulated amplified oncogenes and negatively regulated tumor suppressor genes (TSGs) on this chromosomal arm
Identification of two regions of minimal deletions at 5p15.2-p15.3 Analysis of loss of heterozygosity (LOH) in 60 invasive CCs using 20 sequence tagged repeat polymorphic (STRP) markers mapped to 5p showed deletions in 36 of 60 (60%) tumors in at least one marker (Table 1)
Summary
Previous studies have shown that the short arm of chromosome 5 (5p) exhibit frequent genetic changes in invasive cervical carcinoma (CC), and that these changes arise early during the carcinogenesis, in precancerous lesions. These data suggest that loss of candidate tumor suppressor genes located on 5p is associated with the development of CC. Epidemiological and experimental data, show that only a small fraction of HPV-infected cervical intraepithelial neoplastic (CIN) lesions progress to invasive cervical carcinoma (CC) [2] These findings suggest somatic genetic (page number not for citation purposes). The genetic basis of this progression is poorly understood
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