Benign Reproductive Tissue Analysis for Endometrial Cancer Markers
Benign Reproductive Tissue Analysis for Endometrial Cancer Markers
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.
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.
-  INCLUSION CRITERIA:

 -  Inclusion criteria include: 18 years of age and older with:

 -  a benign condition for which subject has decided to have a hysterectomy (removal
 of the uterus), performed through an abdominal incision (open procedure) or
 through a laparoscope (minimally invasive procedure). The hysterectomy can be
 performed with or without removal of the tubes, ovaries or cervix.

 -  a benign cyst on the ovary(s) which subject has decided to have removed, with or
 without removal of the entire ovary. The surgery will be done with either an
 abdominal incision (open) or through a laparoscope (minimally invasive
 procedure).

 -  positive test for the BRCA 1 or 2 gene, which puts subject at an increased risk
 for breast cancer, and subject has decided to undergo surgery (either with an
 abdominal incision or through a laparoscope) to remove the uterus, tubes and
 ovaries, or any combination

 -  diagnosis of ovarian cancer or possible ovarian cancer and subject has been
 advised to undergo a hysterectomy (removal of the uterus), removal of the tubes
 and ovaries or any combination, with an abdominal incision or through a
 laparoscope.

 EXCLUSION CRITERIA:

 Evidence on gross examination of the surgically removed uterus that there is a carcinoma
 invading the myometrium; however, post-operative diagnosis of early endometrial carcinoma
 will not be a cause for post-hoc exclusion after specimen and data collection. We will
 exclude women with a previous gynecologic or gastrointestinal cancer. At the discretion of
 the surgeon, we will exclude women with cancer in whom the study procedures may interfere
 with clinical management (e.g. staging of the cancer). We will exclude women who had
 neo-adjuvant chemotherapy and women who underwent chemoprevention of ovarian or breast
 cancer. We will also exclude women currently wearing an intrauterine device.