Cervical Cancer Early Endpoints and Determinants
Cervical Cancer Early Endpoints and Determinants
This study, conducted by the National Cancer Institute and the University of Oklahoma, will
 look for changes in cervix cells and other samples that may be signs of cervical disease.
 Human papilloma virus, or HPV, is a common infection of the genitalia in women that usually
 goes away by itself. If HPV infection does not go away, it might turn into cancer of the
 cervix, although this is rare. This study will examine why many HPV infections go away and
 why a few persist and lead to cervical cancer.

 Women 18 years of age and older who are referred for colposcopy (examination of the vagina
 and cervix using an instrument with a magnifying lens) at the University of Oklahoma
 following Pap smear diagnosis may be eligible for this study. Women will be in one of the
 following diagnostic categories:

 -  Cancer: Stage 1-2 only.

 -  Precancer: Cervical intraepithelial neoplasia (CIN3).

 -  HPV-infected: Positive for any of the 13 known cancer-causing HPV types, but not
 diagnosed with cancer or CIN3.

 -  Normal: Negative for cancer-causing HPV and normal tissue laboratory results.

 Participants will undergo the following procedures:

 -  Questionnaire: Covers demographic information (such as age, race, ethnicity, marital
 status, etc.), pregnancy history, menstrual and sexual history, contraceptive history,
 hormone medication history, medical history, smoking history, physical development,
 family history, and health care access.

 -  Blood test: 2 tablespoons of blood drawn.

 -  Colposcopy.

 -  Procedure to collect a sample of cervical cells and fluids for HPV testing and research.
For the past twenty years, large epidemiologic natural history studies have played a crucial
 role in achieving our current understanding of cervical neoplasia. We now know that human
 papillomavirus (HPV) infection is necessary but not sufficient cause of cervical cancer.
 Cervical pathogenesis evolves as follows: normal 'yields' oncogenic HPV infection 'yields'
 precancer 'yields' invasive cancer. The majority of women with oncogenic HPV infections will
 not develop cancer, and most HPV infections, even those with associated cellular changes,
 regress in 1-2 years, probably eradicated or controlled by cellular immune response.
 Morevoer, while invasive cancer and precancer are histologically welldefined, the
 histological classification of low-grade lesions, now better defined as HPV infection, is
 very heterogeneous and poorly reproducible. Identifying women at highest risk for cancer
 prior to neoplastic progression is therefore a challenge. At present, we are unable to
 predict with any accuracy which HPV infections will progress and which are among the majority
 that regress. Currently, cytologic, histologic, and to some extent, HPV DNA assays are the
 basis for triage, treatment, and follow-up. While this approach has permitted successful
 cervical cancer prevention efforts, millions of women are diagnosed each year with HPV
 infections, and because of the inability to distinguish those who will progress from those
 who will regress, many women are over-treated as a result. It is therefore of etiologic
 interest and of public health benefit to develop a method for identifying the HPV-infected
 women at risk for progressing to precancer and invasion. To develop an accurate and
 reproducible division of precursor lesions (HPV infection and precancer) will require gaining
 knowledge about the molecular distinctions at each progressive disease state. Our goal is to
 therefore comprehensively assess biomarkers of risk for progressive cervical neoplasia, and
 thus develop a new set of biomarkers that can distinguish those at highest risk of cervical
 cancer from those with benign infection. Specifically, we will initially implement a
 cross-sectional study to develop a comprehensive list of potential risk biomarkers by
 examining cervical tissues of women with normal, HPV infection, precancer, and cancer. They
 will measure gene expression profiles to gain an accurate and comprehensive in vivo picture
 of cervical neoplasia carcinogenesis. We propose to then validate the most promising
 identified candidate biomarkers in a prospective design by assessing their predictive values
 for key outcomes related to progression (HPV persistence, diagnosis of precancer) or
 non-progression (HPV clearance).
-  INCLUSION CRITERIA:

 All women who are referred for cervical colposcopy to the University of Oklahoma will be
 considered eligible for the study. These women will be categorized into four groups: (i)
 cancer, (ii) precancer, (iii) HPV-infected, and (iv) normal. Cancers will be limited to
 women diagnosed with early cancer (Stage 1-2) to minimize potential disease effects.
 Precancers will be defined as women diagnosed histologically with cervical intraepithelial
 neoplasia 3 (CIN3). This is a highly specific and well-reproduced diagnosis which
 effectively represents carcinoma in situ. All women testing DNA positive for any of the 13
 known oncogenic HPV types (HPV-infected), but not diagnosed with CIN3 or cancer (all
 stages) will be placed in the HPV-positive group. This group will therefore encompass all
 HPV-infected women diagnosed with either cervical intraepithelial neoplasia 1 (CIN1), CIN2,
 low grade squamous intraepithelial lesion (LSIL), atypical squamous cells of undetermined
 significance (ASCUS), atypical glandular cells of underdetermined significance (AGUS), or
 found cytologically normal. Women referred to the colposcopy clinic but found to be
 negative for oncogenic HPV and normal upon histological diagnoses will be eligible as
 normal controls; this approach will be an ethical method for collecting biopsies from
 essentially "normal" women as there are many benign "look alike" conditions that are ruled
 out in colposcopy clinics. While this group may not be a random sample of the general
 population, the use of specimens from these women as controls will ensure a group of women
 who are truly confirmed as having no neoplasia.

 EXCLUSION CRITERIA:

 Women attending the clinic solely for vaginal colposcopies will be excluded from the study.
 Women who are under 18 years of age or pregnant at the visit will also be excluded from the
 study. In addition, women who have had prior treatment (women coming to the clinic for a
 follow-up visit subsequent to treatment (women coming to the clinic for a follow-up visit
 subsequent to treatment or women coming for their initial clinic visit following
 pretreatment with chemotherapy or radiation) will be excluded. All women with known HIV or
 AIDS will be excluded from the study. This information will not be readily available unless
 the woman has previously been seen at the University of Oklahoma clinic. This event is
 considered rare; recent studies of HIV and AIDS by the University of Oklahoma from the same
 population have been terminated due to the lack of HIV/AIDS detected in the population.