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Molecular and cytogenetic analysis of cervical and vulvar cancer

by Huang, Fung-yu

Abstract (Summary)
(Uncorrected OCR) Abstract

Abstract of thesis entitled

Molecular and Cytogenetic Analysis of Cervical and Vulvar Cancer

submitted by

Huang Fung Yu

for the Degree of Master of Philosophy at the University of Hong Kong

in December 2002

Cervical and vulvar cancers are both diseases of the lower female genital tract and share common association with human papillomavirus (HPV) infection. Cervical cancer is the third most common cancer in women worldwide while vulvar cancer is a relatively rare malignancy accounting for approximately 3-5% of all female genital tract malignancies. Up to 90% of squamous cell carcinoma of the cervix contained HPV DNA and about 50% of vulvar carcinomas have detectable HPV. Infection with the virus is not sufficient to cause carcinogenesis in both cervix and vulva. This suggests that additional molecular alterations or alternative molecular pathways are required for cancer development particularly in HPV negative cancers. However, the genetic changes at the molecular levels contributing to the pathogenesis in both cancers are not well understood.

Chromosomal cytogenetic abnormalities are commonly found in tumor cells and are often the basis for more detailed chromosomal mapping of tumor suppressor gene(s) and oncogene(s). Therefore, in this study, the likely chromosomal locations of tumorigenicityrelated gene(s) were detected by comparative genomic hybridization (CGR) method in 28 cervical carcinomas and 5 cervical cell lines; and in 8 vulvar carcinomas and 2 vulvar cell lines. Chromosomal gains are consistently observed on lq, 3q, 5p and 8q, while chromosomal losses were found in 2q and 3p, 4p and 11 p. Although amplifications of 5p and lq has been reported in some types of tumors including cervix, no known candidate gene(s) responsible for the development or progression of cervical and vulva cancers has been identified in these regions.

Based on the CGR results, we examined the involvement of seven candidate tumor associated genes including PRKAAl, POLS, ERBB2IP and CTNND2 mapped to chromosome 5 regions and Cox-2, LamC2 and TGFB2 mapped to chromosome lq regions for the status of gene amplifications by fluorescent differential PCR. At least one gene showed amplification in all samples with CGR gains in both chromosome 5 and lq.

The relationship between DNA amplification from chromosome 5 and disease outcome was studied in a retrospective series of 128 cervical and 32 normal samples by differential PCR. Spearman's rho analysis indicated a linear correlation (r = 0.492, p < 0.0001) between PRKAAI and ERBB2IP. Amplification of these two genes showed significant difference between normal and carcinoma samples when using two copies as a cut-off value by Chi-square test and as continuous variable using the Mann Whitney test. Both univariate and multivariate Cox regression analysis confirmed ERBB2IP was a significant factor in relation to patient survival. Gene expression analysis by RT-PCR

showed PRKAAI was up-regulated while no change in expression of POLS was observed in samples with gain in chromosome 5p.

The information obtained in this study revealed that cervical and vulvar carcinoma shared some common chromosomal aberrations. Identification and characterization of genes present in amplified regions can provide important insights into the pathogenesis of the cancer and may lead to a targeted approach to reduce morbidity.

Bibliographical Information:

Advisor:

School:The University of Hong Kong

School Location:China - Hong Kong SAR

Source Type:Master's Thesis

Keywords:vulva cancer genetic aspects cervix uteri generative organs

ISBN:

Date of Publication:01/01/2003

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