This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, X.-P. Articles by Eng, C. Search for Related Content PubMed PubMed Citation Articles by Zhou, X.-P. Articles by Eng, C.

(American Journal of Pathology. 2002;161:439-447.)
© 2002 American Society for Investigative Pathology

Regular Articles

PTEN Mutational Spectra, Expression Levels, and Subcellular Localization in Microsatellite Stable and Unstable Colorectal Cancers

Xiao-Ping Zhou^*, Anu Loukola, Reijo Salovaara, Minna Nystrom-Lahti^¶, Päivi Peltomäki, Albert de la Chapelle^*, Lauri A. Aaltonen and Charis Eng^*||

From the Clinical Cancer Genetics^*and Human Cancer GeneticsPrograms, Comprehensive Cancer Center and the Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio; the Departments of Medical Genetics,Pathology,and Biosciences,^¶University of Helsinki and Biomedicum Helsinki, Helsinki, Finland; and the Cancer Research Campaign Human Cancer Genetics Research Group,||University of Cambridge, Cambridge, United Kingdom

PTEN on 10q23.3 encodes a dual-specificity phosphatase that negatively regulates the phosphoinositol-3-kinase/Akt pathway and mediates cell-cycle arrest and apoptosis. Germline PTEN mutations cause Cowden syndrome and a range of several different hamartoma-tumor syndromes. Hereditary nonpolyposis colon cancer (HNPCC) syndrome is characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. Although both colorectal carcinoma and endometrial carcinoma are the most frequent component cancers in HNPCC, only endometrial cancer has been shown to be a minor component of Cowden syndrome. We have demonstrated that somatic inactivation of PTEN is involved in both sporadic endometrial cancers and HNPCC-related endometrial cancers but with different mutational spectra and different relationships to MSI. In the current study, we sought to determine the relationship of PTEN mutation, 10q23 loss of heterozygosity, PTEN expression, and MSI status in colorectal cancers (CRCs). Among 11 HNPCC CRCs, 32 MSI+ sporadic cancers, and 39 MSI- tumors, loss of heterozygosity at 10q23.3 was found in 0%, 8%, and 19%, respectively. Somatic mutations were found in 18% (2 of 11) of the HNPCC CRCs and 13% (4 of 32) of the MSI+ sporadic tumors, but not in MSI- cancers (P = 0.015). All somatic mutations occurred in the two 6(A) coding mononucleotide tracts in PTEN, suggestive of the etiological role of the deficient MMR. Immunohistochemical analysis revealed 31% (14 of 45) of the HNPCC CRCs and 41% (9 of 22) of the MSI+ sporadic tumors with absent or depressed PTEN expression. Approximately 17% (4 of 23) of the MSI- CRCs had decreased PTEN expression, and no MSI- tumor had complete loss of PTEN expression. Among the five HNPCC or MSI+ sporadic CRCs carrying frameshift somatic mutations with immunohistochemistry data, three had lost all PTEN expression, one showed weak PTEN expression levels, and one had mixed tumor cell populations with weak and moderate expression levels. These results suggest that PTEN frameshift mutations in HNPCC and sporadic MSI+ tumors are a consequence of mismatch repair deficiency. Further, hemizygous deletions in MSI- CRCs lead to loss or reduction of PTEN protein levels and contribute to tumor progression. Finally, our data also suggest that epigenetic inactivation of PTEN, including differential subcellular compartmentalization, occurs in CRCs.

This article has been cited by other articles:

				G. M. Blumenthal and P. A. Dennis Germline PTEN Mutations As a Cause of Early-Onset Endometrial Cancer J. Clin. Oncol., May 1, 2008; 26(13): 2234 - 2234. [Full Text] [PDF]

				M. Fassnacht, D. Weismann, S. Ebert, P. Adam, M. Zink, F. Beuschlein, S. Hahner, and B. Allolio AKT Is Highly Phosphorylated in Pheochromocytomas But Not in Benign Adrenocortical Tumors J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4366 - 4370. [Abstract] [Full Text] [PDF]

				C. Lee, J.-S. Kim, and T. Waldman PTEN Gene Targeting Reveals a Radiation-Induced Size Checkpoint in Human Cancer Cells Cancer Res., October 1, 2004; 64(19): 6906 - 6914. [Abstract] [Full Text] [PDF]

				Y.-C. Li, A. B. Korol, T. Fahima, and E. Nevo Microsatellites Within Genes: Structure, Function, and Evolution Mol. Biol. Evol., June 1, 2004; 21(6): 991 - 1007. [Abstract] [Full Text] [PDF]

				T. J. Yeatman Beyond p53 Ann. Surg. Oncol., October 1, 2003; 10(8): 831 - 831. [Full Text] [PDF]