Benign Reproductive Tissue Analysis for Endometrial Cancer Markers
Condition: Oophorectomy for Benign Reasons; Hysterectomy
Study type: Observational

Summary: 
      Background:

        -  Endometrial cancer (cancer of the lining of the uterus) is the most common gynecologic
           cancer in the United States.

        -  Currently, there are no markers (components of blood and tissue that determine who might
           be at risk for developing cancer) for endometrial cancer.

      Objectives:

      -To see if women who are undergoing hysterectomy are willing to provide blood and tissue
      samples to help doctors identify markers that would indicate increased risk for developing
      endometrial cancer.

      Eligibility:

      -Women between 35 and 54 years of age who will undergo hysterectomy for a non-cancerous
      condition, such as uterine fibroids, uterine prolapse, abnormal uterine bleeding, and others
      at Magee-Women's Hospital in Pittsburgh, Penn.

      Design:

        -  Patients' medical records are reviewed and patients complete a questionnaire including
           information on race and ethnic background, education, marital status, family history,
           height, weight, pregnancy history, smoking history, medication history, history about
           menstrual periods and menopausal symptoms.

        -  Patients provide blood and urine samples before surgery.

        -  A sample of fat tissue is removed during surgery in patients undergoing abdominal
           surgery.

        -  Tissue samples from the removed uterus (and ovaries if the ovaries are also removed) are
           collected and analyzed for markers for endometrial cancer.
    

Detailed description: 
      Our hypothesis is that silent molecular lesions, defined as molecular alterations

      detectable in histologically normal endometrial, ovarian, and tubal tissues, represent
      markers of cancer risk. Incessant ovulation represents one of the most widely-recognized
      models to explain the pathogenesis of ovarian cancer, with women who have had a high number
      of lifetime ovulatory menstrual cycles being at increased cancer risk because of repeated
      ovulation-related injury to, and repair of, ovarian surface epithelium (OSE). This extremely
      delicate single layer of cells exfoliates easily on handling, with the majority of cells
      typically being lost in routine handling, when collected post-operatively. Furthermore, the
      identification of early stage ovarian cancer is uncommon, and the vast majority of ovarian
      cancers are not associated with recognizable precursors. The lack of effective techniques for
      collecting and studying OSE in the laboratory represents a major barrier to molecular studies
      designed to uncover the etiology and early pathogenesis of ovarian cancer. This proposal will
      develop a collection method for OSE, and demonstrate its utility for various molecular
      analyses. Recent evidence suggests that a subset of ovarian cancers may originate in the
      fallopian tubes. Therefore, we will pilot the collection of cells from the fallopian tubes.
      If successful, the collection of OSE and fallopian tube cells will provide the basis for
      larger studies aimed at identifying early molecular events in ovarian carcinogenesis.

      In this pilot, we will collect endometrial and ovarian tissues (that would otherwise have
      been discarded without histopathologic examination) from 125 hysterectomy and/or unilateral
      or bilateral oophorectomy specimens obtained from women ages 18 and older who were operated
      on for benign indications. As an amendment to this active protocol, we propose demonstrating
      the feasibility of obtaining intra-operative cytobrushings of ovarian surface epithelial
      cells on 50 women to be accrued onto the study, which will include women having hysterectomy
      (or unilateral oophorectomy) alone without removal of the ovaries at the time of surgery.
      Furthermore, we will extend the collection to cells from the fallopian tubes in 225 women for
      a total population of 400.

      We will administer a questionnaire assessing endometrial and ovarian cancer risk factors and
      gynecologic history; obtain blood and urine; and obtain carefully-mapped frozen and fixed
      endometrial and ovarian tissues. We will immunostain endometrial tissues to assess the
      presence, number, location, and size of foci containing PTEN-null glands, which represents a
      validated surrogate of mutations in the PTEN tumor suppressor gene. This pilot will
      demonstrate the feasibility of executing this complex protocol; determine the number and
      spacing of sections required to accurately and efficiently assess the PTEN status of the
      endometrium; and provide data for developing power estimates needed to propose a full-scale
      study with a sufficient number of subjects to test our hypothesis that PTEN abnormalities
      account for a substantial proportion of the risk associated with recognized epidemiologic
      endometrial cancer risk factors. It will assess the feasibility of performing molecular
      analyses on ovarian surface epithelial cells and tubal cells collected intra-operatively, and
      correlating molecular findings with known ovarian cancer risk factors. If successful, this
      will provide the basis for larger studies aimed at identifying early molecular events in

      ovarian carcinogenesis, particularly in the setting of women at increased genetic

      risk of ovarian cancer. The pilot itself will also provide an extremely valuable

      repository for future biomarker pilot studies.
    

Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Women undergoing hysterectomy and/or unilateral or bilateral oophorectomy for benign
        indications, women at high risk or ovarian cancer or women with diagnosed ovarian cancer at
        Magee Women s Hospital.
      
Keywords: Endometrium; PTEN; Hormones; Carcinogenesis; Etiology; Tissue Evaluation; Questionnaire