Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers (original) (raw)

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

Correspondence to: George L. Mutter, M.D., Department of Pathology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (e-mail: gmutter@rics.bwh.harvard.edu).

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Affiliations of authors: G. L. Mutter, J. T. Fitzgerald, Department of Pathology, Brigham and Women's Hospital, Boston, MA; M.-C. Lin, Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Taiwan National University Hospital, Taipei; J. B. Kum, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, Columbus, and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Boston; J. P. A. Baak, Department of Pathology, Medisch Centrum Alkmaar, and Amsterdam Free University Hospital, The Netherlands; J. A. Lees, Massachusetts Institute of Technology, Cambridge; L.-P. Weng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center; C. Eng, Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, U.K.

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Received:

21 October 1999

Revision received:

16 March 2000

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George L. Mutter, Ming-Chieh Lin, Jeffrey T. Fitzgerald, Jennifer B. Kum, Jan P. A. Baak, Jacqueline A. Lees, Liang-Ping Weng, Charis Eng, Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers, JNCI: Journal of the National Cancer Institute, Volume 92, Issue 11, 7 June 2000, Pages 924–930, https://doi.org/10.1093/jnci/92.11.924
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Abstract

Background: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. Methods: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins—conditions known to increase cancer risk—were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis. Results: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P = .025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. Conclusions: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.

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