HLA, HUMAN PAPILLOMAVIRUS AND INVASIVE CERVICAL CANCER

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A number of risk factors for invasive cervical cancer (ICC) have been described: infection by human papillomavirus (HPV), cigarette smoking, dietary deficiencies, multiple sexual partners, and early age at first intercourse. The most consistent risk factor is human papillomavirus infection as 85% of cervical tumors contain HPV DNA integrated into the chromosomes of the cervical cells. However, HPV infection alone is not sufficient for the development of cervical cancer. Additional factors must be operating. Recently, the *03 family of alleles at the HLA DQ(Beta)1 locus have been reported at increased frequency among women diagnosed with ICC. This represents an intriguing association, since the DQ(Beta)1 molecule interacts with viral proteins to facilitate their recognition by T lymphocytes. Abnormalities in the DQ(Beta)1-HPV interaction may result in a defective activation of immune mechanisms that control the malignant transformation of HPV-infected epithelial cells. In addition, genetic changes affecting activation of oncogene(s) and even inactivation or mutation of certain tumor suppressor genes must be involved in the development of cervical cancer. This research proposal will characterize HLA and HPV in 200 women with pathologically confirmed ICC. The HLA DQ(Beta)1 locus will be typed in patients and their parents using polymerase chain reaction (PCR) amplification and sequencing of exon 2. The nontransmitted parental alleles will be used to construct an ethnic-matched control sample. HPV genotypes will be identified from tumor biopsies by PCR amplification of the L1 open reading frame and restriction fragment length polymorphism (RFLP) analysis. Associations will be tested between alleles at the HLA DQ(Beta)1 locus and high risk genotypes of HPV. Cervical cancer is a highly prevalent gynecologic malignancy. Its early detection through identification of genetic factors can greatly improve our understanding of disease mechanisms as well as enhance preventive efforts. In addition, these genetic factors can be used for future population screening through easily accessible exfoliated cervicovaginal cells.