June 5, 2001 Researchers at Brigham and Women's Hospital (BWH) and The Ohio State University Comprehensive Cancer Center (OSUCCC) have discovered nearly half of pre-menopausal women carry sub-microscopic pre-malignant lesions that may mark them at higher risk of developing uterine cancer later on in life. These tiny lesions, linked to alterations in the PTEN tumor suppressor gene, are detectable even in normal-appearing tissues, suggesting there may be a way to predict future risk of endometrial cancer even when no pre-cancers are visible. Apparently they arise naturally in a small number of endometrial cells during normal monthly regeneration.
"We know from earlier research that mutations or deletions in the PTEN gene can signal the earliest endometrial pre-cancers," said George Mutter, MD, of BWH. "Pathologists have always had difficulty agreeing upon diagnosis of these lesions because we lacked objective methodology. Now that we know that changes in the PTEN gene are linked to the earliest stages of endometrial cancer, and are present in so many young women, we can refocus our concept of what contributes to real cancer risk. Progression to cancer is an inefficient process that can take years. During this period most lesions disappear on their own, and those that enlarge acquire a distinctive microscopic appearance readily diagnosed by pathologists before they become a cancer. Endometrial cancer is the most common gynecological malignancy, usually developing after menopause, and eventually affecting 2.5 per cent of American women.
In evaluating PTEN function, the researchers obtained 132 samples of uterine tissue and divided them into three diagnostic categories; normal (proliferative), persistent proliferative (slightly abnormal), or EIN (endometrial intraepithelial neoplasia , or clearly defined precancers). Utilizing laser capture microdissection and highly sensitive immunohistochemistry, they selected cells from each group and compared PTEN function across sample lines. Loss of PTEN function was apparent in 43, 56, and 63 per cent in proliferative, persistent proliferative, and EIN diagnostic categories respectively, with loss of PTEN function increasing with age.
"We were stunned to find the PTEN mutation in such a large number of young women whose tissues appeared perfectly normal under the microscope," added Charis Eng, MD, PhD, director of the Clinical Cancer Genetics Program at the OSUCCC. She adds, however, that only a small fraction of those women who have altered PTEN genes will actually develop cancer. "Loss of PTEN function is an important, but not sufficient step toward developing endometrial cancer."
"There are many other steps leading to endometrial cancer," says Eng, including such things as genetic change due to environmental factors, hormones, diet and lifestyle. "Now, we can link genetic factors with environmental factors. The beauty of our discovery is that it offers us a way to pursue a true molecular epidemiologic approach to cancer prevention."
Mutter says the findings should not change the way physicians are currently evaluating individual patients. "Diagnosis of pre-malignant disease should still be based upon routine histologic examination. The role of special PTEN studies in patient management has not yet been defined."
The findings appear in the June 1 edition of Cancer Research.
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