© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 11, 924-930,
June 7, 2000
© 2000 Oxford University Press
|
|
REPORTS |
Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers
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{at}rics.bwh.harvard.edu).
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. A. Crowell, V. E. Steele, and J. R. Fay Targeting the AKT protein kinase for cancer chemoprevention Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Kopelovich, J. R. Fay, C. C. Sigman, and J. A. Crowell The Mammalian Target of Rapamycin Pathway as a Potential Target for Cancer Chemoprevention Cancer Epidemiol. Biomarkers Prev., July 1, 2007; 16(7): 1330 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M Haughian, T. A Jackson, D. M Koterwas, and A. P Bradford Endometrial cancer cell survival and apoptosis is regulated by protein kinase C {alpha} and {delta} Endocr. Relat. Cancer, December 1, 2006; 13(4): 1251 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. McCampbell, R. R. Broaddus, D. S. Loose, and P. J.A. Davies Overexpression of the Insulin-Like Growth Factor I Receptor and Activation of the AKT Pathway in Hyperplastic Endometrium. Clin. Cancer Res., November 1, 2006; 12(21): 6373 - 6378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Hecht and G. L. Mutter Molecular and Pathologic Aspects of Endometrial Carcinogenesis J. Clin. Oncol., October 10, 2006; 24(29): 4783 - 4791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Pore, Z. Jiang, H.-K. Shu, E. Bernhard, G. D. Kao, and A. Maity Akt1 Activation Can Augment Hypoxia-Inducible Factor-1{alpha} Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin-Independent Pathway Mol. Cancer Res., July 1, 2006; 4(7): 471 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Orbo, C. E. Rise, and G. L. Mutter Regression of Latent Endometrial Precancers by Progestin Infiltrated Intrauterine Device Cancer Res., June 1, 2006; 66(11): 5613 - 5617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. I. Yoo, D. W. Liu, S. L. Vu, R. T. Bronson, H. Wu, and J. Yuan Pten Deficiency Activates Distinct Downstream Signaling Pathways in a Tissue-Specific Manner Cancer Res., February 15, 2006; 66(4): 1929 - 1939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Abdel-Rahman, Y. Yang, X.-P. Zhou, E. L. Craig, F. H. Davidorf, and C. Eng High Frequency of Submicroscopic Hemizygous Deletion Is a Major Mechanism of Loss of Expression of PTEN in Uveal Melanoma J. Clin. Oncol., January 10, 2006; 24(2): 288 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Vigano, E. Somigliana, I. Chiodo, A. Abbiati, and P. Vercellini Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis Hum. Reprod. Update, January 1, 2006; 12(1): 77 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sweet, J. Willis, X.-P. Zhou, C. Gallione, T. Sawada, P. Alhopuro, S. K. Khoo, A. Patocs, C. Martin, S. Bridgeman, et al. Molecular Classification of Patients With Unexplained Hamartomatous and Hyperplastic Polyposis JAMA, November 16, 2005; 294(19): 2465 - 2473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. V. Thomas, S. Horvath, B. L. Smith, K. Crosby, L. A. Lebel, M. Schrage, J. Said, J. De Kernion, R. E. Reiter, and C. L. Sawyers Antibody-Based Profiling of the Phosphoinositide 3-Kinase Pathway in Clinical Prostate Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8351 - 8356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. M. Woo, A. Alkushi, H. G. Verhage, A. M. Magliocco, P. C. K. Leung, C. B. Gilks, and N. Auersperg Gain of OGP, an Estrogen-Regulated Oviduct-Specific Glycoprotein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer Clin. Cancer Res., December 1, 2004; 10(23): 7958 - 7964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Thompson and C. B. Thompson Putting the Rap on Akt J. Clin. Oncol., October 15, 2004; 22(20): 4217 - 4226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Sansal and W. R. Sellers The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway J. Clin. Oncol., July 15, 2004; 22(14): 2954 - 2963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M B Delatycki, A Danks, A Churchyard, X-P Zhou, and C Eng De novo germline PTEN mutation in a man with Lhermitte-Duclos disease which arose on the paternal chromosome and was transmitted to his child with polydactyly and Wormian bones J. Med. Genet., August 1, 2003; 40(8): e92 - 92. [Full Text] [PDF]
|
|
|
|
|
|
C. Zhou, P. A. Gehrig, Y. E. Whang, and J. F. Boggess Rapamycin Inhibits Telomerase Activity by Decreasing the hTERT mRNA Level in Endometrial Cancer Cells Mol. Cancer Ther., August 1, 2003; 2(8): 789 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N Kazerouni, C Schairer, H B Friedman, J V Lacey Jr, and M H Greene Family history of breast cancer as a determinant of the risk of developing endometrial cancer: a nationwide cohort study J. Med. Genet., November 1, 2002; 39(11): 826 - 832. [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Girnun, W. M. Smith, S. Drori, P. Sarraf, E. Mueller, C. Eng, P. Nambiar, D. W. Rosenberg, R. T. Bronson, W. Edelmann, et al. APC-dependent suppression of colon carcinogenesis by PPARgamma PNAS, October 15, 2002; 99(21): 13771 - 13776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Miturski, M. Bogusiewicz, C. Ciotta, M. Bignami, M. Gogacz, and D. Burnouf Mismatch Repair Genes and Microsatellite Instability as Molecular Markers for Gynecological Cancer Detection Experimental Biology and Medicine, September 1, 2002; 227(8): 579 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-P. Zhou, A. Loukola, R. Salovaara, M. Nystrom-Lahti, P. Peltomaki, A. de la Chapelle, L. A. Aaltonen, and C. Eng PTEN Mutational Spectra, Expression Levels, and Subcellular Localization in Microsatellite Stable and Unstable Colorectal Cancers Am. J. Pathol., August 1, 2002; 161(2): 439 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-P. Weng, J. L. Brown, K. M. Baker, M. C. Ostrowski, and C. Eng PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway Hum. Mol. Genet., July 15, 2002; 11(15): 1687 - 1696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zysman, A. Saka, A. Millar, J. Knight, W. Chapman, and B. Bapat Methylation of Adenomatous Polyposis Coli in Endometrial Cancer Occurs More Frequently in Tumors with Microsatellite Instability Phenotype Cancer Res., July 1, 2002; 62(13): 3663 - 3666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fernandez and C. Eng The Expanding Role of PTEN in Neoplasia: A Molecule for All Seasons? : Commentary re: M. A. Davies, et al., Adenoviral-mediated Expression of MMAC/PTEN Inhibits Proliferation and Metastasis of Human Prostate Cancer Cells. Clin. Cancer Res., 8: 1904-1914, 2002. Clin. Cancer Res., June 1, 2002; 8(6): 1695 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Kuismanen, A.-L. Moisio, P. Schweizer, K. Truninger, R. Salovaara, J. Arola, R. Butzow, J. Jiricny, M. Nystrom-Lahti, and P. Peltomaki Endometrial and Colorectal Tumors from Patients with Hereditary Nonpolyposis Colon Cancer Display Different Patterns of Microsatellite Instability Am. J. Pathol., June 1, 2002; 160(6): 1953 - 1958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-P. Zhou, H. Hampel, J. Roggenbuck, N. Saba, T. W. Prior, and C. Eng A 39-bp Deletion Polymorphism in PTEN in African American Individuals: Implications for Molecular Diagnostic Testing J. Mol. Diagn., May 1, 2002; 4(2): 114 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G L Mutter Diagnosis of premalignant endometrial disease J. Clin. Pathol., May 1, 2002; 55(5): 326 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Soria, H.-Y. Lee, J. I. Lee, L. Wang, J.-P. Issa, B. L. Kemp, D. D. Liu, J. M. Kurie, L. Mao, and F. R. Khuri Lack of PTEN Expression in Non-Small Cell Lung Cancer Could Be Related to Promoter Methylation Clin. Cancer Res., May 1, 2002; 8(5): 1178 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, W. Douglas, M. Lia, W. Edelmann, R. Kucherlapati, K. Podsypanina, R. Parsons, and L. H. Ellenson DNA Mismatch Repair Deficiency Accelerates Endometrial Tumorigenesis in Pten Heterozygous Mice Am. J. Pathol., April 1, 2002; 160(4): 1481 - 1486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Zysman, W. B. Chapman, and B. Bapat Considerations When Analyzing the Methylation Status of PTEN Tumor Suppressor Gene Am. J. Pathol., March 1, 2002; 160(3): 795 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Zhou, S. Kuismanen, M. Nystrom-Lahti, P. Peltomaki, and C. Eng Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors Hum. Mol. Genet., February 1, 2002; 11(4): 445 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Hale, C. L. Hughes, and J. M. Cline Endometrial Cancer: Hormonal Factors, the Perimenopausal ""Window of Risk,"" and Isoflavones J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 3 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Roy, B. F. Olusola, D. L. Clemens, W. J. Karolski, A. Ratashak, H. T. Lynch, and T. C. Smyrk AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis Carcinogenesis, January 1, 2002; 23(1): 201 - 205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Lee, J.-C. Soria, K. A. Hassan, A. K. El-Naggar, X. Tang, D. D. Liu, W. K. Hong, and L. Mao Loss of PTEN Expression as a Prognostic Marker for Tongue Cancer Arch Otolaryngol Head Neck Surg, December 1, 2001; 127(12): 1441 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Mutter, T. A. Ince, J. P. A. Baak, G. A. Kust, X.-P. Zhou, and C. Eng Molecular Identification of Latent Precancers in Histologically Normal Endometrium Cancer Res., June 1, 2001; 61(11): 4311 - 4314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Mutter PTEN, a Protean Tumor Suppressor Am. J. Pathol., June 1, 2001; 158(6): 1895 - 1898. [Full Text] [PDF]
|
|
|
|
|
|
K. Kurose, X.-P. Zhou, T. Araki, S. A. Cannistra, E. R. Maher, and C. Eng Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas Am. J. Pathol., June 1, 2001; 158(6): 2097 - 2106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Gimm, H. Chi, P. L. M. Dahia, A. Perren, R. Hinze, P. Komminoth, H. Dralle, P. R. Reynolds, and C. Eng Somatic Mutation and Germline Variants of MINPP1, a Phosphatase Gene Located in Proximity to PTEN on 10q23.3, in Follicular Thyroid Carcinomas J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1801 - 1805. [Abstract] [Full Text]
|
|
|
|
|
|
J. D Fackenthal, D. J Marsh, A.-L. Richardson, S. A Cummings, C. Eng, B. G Robinson, and O. I Olopade Male breast cancer in Cowden syndrome patients with germline PTEN mutations J. Med. Genet., March 1, 2001; 38(3): 159 - 164. [Abstract] [Full Text]
|
|
|
|
|
|
L.-P. Weng, O. Gimm, J. B. Kum, W. M. Smith, X.-P. Zhou, D. Wynford-Thomas, G. Leone, and C. Eng Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death Hum. Mol. Genet., February 1, 2001; 10(3): 251 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Perren, P. Komminoth, P. Saremaslani, C. Matter, S. Feurer, J. A. Lees, P. U. Heitz, and C. Eng Mutation and Expression Analyses Reveal Differential Subcellular Compartmentalization of PTEN in Endocrine Pancreatic Tumors Compared to Normal Islet Cells Am. J. Pathol., October 1, 2000; 157(4): 1097 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. U. Ali Gatekeeper for Endometrium: the PTEN Tumor Suppressor Gene J Natl Cancer Inst, June 7, 2000; 92(11): 861 - 863. [Full Text] [PDF]
|
|