| Sequence Variation in The Upstream Regulatory Region of Human Papillomavirus Type 16 isolated from The Uterine Cervix in Korean Women. |
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H W Jeon, H P Lee |
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| Abstract |
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It is widely accepted that human papillomaviruses (HPV), especially type 16 and type 18 are the primary causal agent for the development of invasive cervical cancer and its precursor lesions. Although the mechanisms by which HPV acts to transform cells are still not completely understood, complex interactions between virus and host cell seem to determine the biologic course of cervical cancer. In Korea, 50~60% of the patients with cervical cancer have been associated with HPV 16. Recently phylogenetically distinct HPV 16 variants that differ from the prototype HPV 16 sequence have been identified and the significance of them in carcinogenesis is being studied. The upstream regulatory region (URR) does not encode for proteins, but it contains a complex array of overlapping binding sites for many different transcriptional factors and their genomic sequences usually diverge more than coding regions. We were analyzed to detect HPV 16 URR enhancer region variants in Korean women and to determine whether risk of cancerous lesion was associated with HPV 16 variants. Cervical tissues were taken from the women with cervical cancerous (N=125) and normal cervical biopsies (N=307). Of the HPV 16 infections detected in 70 cervical cancerous tissues and 43 normal cervical tissues, 56.0% and 14.0%. We amplified by nested-PCR and sequenced a 364-bp noncoding segment of the HPV 16 genome (nucleotide 7458~7841). By direct sequencing of PCR product, a total of 11 point variations that differed from prototype HPV 16 sequence was detected in various combinations, giving rise to 8 distinct types of variants. Of the HPV 16 URR variants detected in 68 cervical cancerous tissues and 39 normal cervical tissues, 97.1% and 90.7%. In addition, four transcriptional factors binding sites (TEF-1, 2; YY1, 2) were found to be mutated; nucleotide 7797 variation was found in only cervical cancerous tissues. Variants of an YY1 binding site in cervical cancerous tissues were correlated to depth of invasion not to age, stage, tumor size, histologic type, and nodal metastasis. Variants of a TEF-1 binding site were not show any difference in the clinicopathologic factors. These results suggest that the URR variant is not a mutation that occurs during disease progression in susceptible individuals but is a distinct virus isolate of HPV type 16. The association with cervical cancer suggests that either the mutation may also influence the oncogenic properties of the HPV type 16 variant or that the base change is a marker of other mutations within the virus genome that may increase its oncogenicity. To trace the transmission route and natural history of HPV-associated disease, more than one gene segment` strategy using a highly variable one as a genetic marker will be necessary. |
| Key Words:
HPV type 16, Upstream regulatory region, Sequence variation, Uterine cervical cancer |
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