Evidence for an hMSH3 defect in familial hamartomatous polyps S.C.H. and J.M.C. designed research; S.C.H., J.K.L., E.J.S., R.T.D., A.T., S.E.B., and J.M.C. performed research; S.C.H., J.K.L., and J.M.C. analyzed data; N.W. provided some pathology specimens; S.C.H., J.K.L., and J.M.C. wrote the paper. All authors approved the final version of the article.
dc.contributor.author | Huang, Sherry C. | en_US |
dc.contributor.author | Lee, Jeffrey K. | en_US |
dc.contributor.author | Smith, E. Julieta | en_US |
dc.contributor.author | Doctolero, Ryan T. | en_US |
dc.contributor.author | Tajima, Akihiro | en_US |
dc.contributor.author | Beck, Stayce E. | en_US |
dc.contributor.author | Weidner, Noel | en_US |
dc.contributor.author | Carethers, John M. | en_US |
dc.date.accessioned | 2011-02-02T17:57:40Z | |
dc.date.available | 2012-03-05T15:30:01Z | en_US |
dc.date.issued | 2011-02-01 | en_US |
dc.identifier.citation | Huang, Sherry C.; Lee, Jeffrey K.; Smith, E. Julieta; Doctolero, Ryan T.; Tajima, Akihiro; Beck, Stayce E.; Weidner, Noel; Carethers, John M. (2011). "Evidence for an hMSH3 defect in familial hamartomatous polyps S.C.H. and J.M.C. designed research; S.C.H., J.K.L., E.J.S., R.T.D., A.T., S.E.B., and J.M.C. performed research; S.C.H., J.K.L., and J.M.C. analyzed data; N.W. provided some pathology specimens; S.C.H., J.K.L., and J.M.C. wrote the paper. All authors approved the final version of the article. ." Cancer 117(3): 492-500. <http://hdl.handle.net/2027.42/79407> | en_US |
dc.identifier.issn | 0008-543X | en_US |
dc.identifier.issn | 1097-0142 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/79407 | |
dc.description.abstract | BACKGROUND: Patients with hamartomatous polyposis syndromes have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. The authors examined whether familial hamartomatous polyps harbor defects in DNA mismatch repair (MMR), and assayed for somatic mutation of PTEN , a gene inactivated in the germline of some hamartomatous polyposis syndrome patients. METHODS: Ten hamartomatous polyposis syndrome patients were genotyped for germline mutations. Epithelial and nonepithelial polyp DNA were assayed for microsatellite instability (MSI) and PTEN frameshift mutation. DNA MMR and PTEN protein expression were assessed in all polyps by immunohistochemistry. In addition, 99 MSI-high sporadic CRCs and 50 each of hMLH1 −/− and hMSH3 −/− cell clones were examined for PTEN frameshifts. RESULTS: Twenty-five (58%) of 43 hamartomatous polyposis syndrome polyps demonstrated dinucleotide or greater MSI in polyp epithelium, consistent with hMSH3 deficiency. MSI domains lost hMSH3 expression, and PTEN expression was lost in polyps from germline PTEN patients; sporadic hamartomatous polyps did not show any of these findings. PTEN analysis revealed wild type exon 7 and 8 sequences suggestive of nonexistent or rare events for PTEN frameshifts; however, MSI-high sporadic CRC showed 11 (11%) of 99 frameshifts within PTEN , with 4 tumors having complete loss of PTEN expression. Subcloning hMLH1 −/− and hMSH3 −/− cells revealed somatic PTEN frameshifts in 4% and 12% of clones, respectively. CONCLUSIONS: Nondysplastic epithelium from hamartomatous polyposis syndrome polyps harbors hMSH3 defects, which may prime neoplastic transformation. Polyps from PTEN +/− patients lose PTEN expression, but loss is not a universal early feature of all hamartomatous polyposis syndrome. However, PTEN frameshifts can occur in hMSH3-deficient cells, suggesting that hMSH3 deficiency could drive hamartomatous polyposis syndrome tumorigenesis. Cancer 2011. © 2010 American Cancer Society. | en_US |
dc.format.extent | 360675 bytes | |
dc.format.extent | 3118 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.publisher | Wiley Subscription Services, Inc., A Wiley Company | en_US |
dc.subject.other | Life and Medical Sciences | en_US |
dc.subject.other | Cancer Research, Oncology and Pathology | en_US |
dc.title | Evidence for an hMSH3 defect in familial hamartomatous polyps S.C.H. and J.M.C. designed research; S.C.H., J.K.L., E.J.S., R.T.D., A.T., S.E.B., and J.M.C. performed research; S.C.H., J.K.L., and J.M.C. analyzed data; N.W. provided some pathology specimens; S.C.H., J.K.L., and J.M.C. wrote the paper. All authors approved the final version of the article. | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Oncology and Hematology | en_US |
dc.subject.hlbsecondlevel | Public Health | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Department of Medicine, University of California at San Diego, San Diego, California ; Biomedical Sciences Program, University of California at San Diego, San Diego, California ; Moores Comprehensive Cancer Center, University of California at San Diego, San Diego, California ; Veterans Administration Research Service, San Diego, California ; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan ; Fax: (734) 232-3838 ; Professor of Internal Medicine, University of Michigan, 3101 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109 | en_US |
dc.contributor.affiliationother | Department of Pediatrics, University of California at San Diego, San Diego, California ; Rady Children's Hospital, San Diego, California | en_US |
dc.contributor.affiliationother | Department of Medicine, University of California at San Diego, San Diego, California | en_US |
dc.contributor.affiliationother | Department of Medicine, University of California at San Diego, San Diego, California | en_US |
dc.contributor.affiliationother | Department of Medicine, University of California at San Diego, San Diego, California | en_US |
dc.contributor.affiliationother | Department of Medicine, University of California at San Diego, San Diego, California | en_US |
dc.contributor.affiliationother | Biomedical Sciences Program, University of California at San Diego, San Diego, California | en_US |
dc.contributor.affiliationother | Department of Pathology, University of California at San Diego, San Diego, California | en_US |
dc.identifier.pmid | 20845481 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/79407/1/25445_ftp.pdf | |
dc.identifier.doi | 10.1002/cncr.25445 | en_US |
dc.identifier.source | Cancer | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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