Evidence for an hMSH3 defect in familial hamartomatous polyps.
Evidence for an hMSH3 defect in familial hamartomatous polyps.
复制标题
家族性错构瘤性息肉中 hMSH3 缺陷的证据。
DOI：
10.1002/cncr.25445
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发表时间：
2011-02-01
期刊：
影响因子：
6.2
通讯作者：
Carethers, John M.
中科院分区：
文献类型：
--
作者：
Huang, Sherry C.;Lee, Jeffrey K.;Smith, E. Julieta;Doctolero, Ryan T.;Tajima, Akihiro;Beck, Stayce E.;Weidner, Noel;Carethers, John M.
关键词：
Patients with hamartomatous polyposis syndromes (HPS) have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. We 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 HPS patients. Ten HPS patients were genotyped for germline mutations. Epithelial and non-epithelial polyp DNA was assayed for microsatellite instability (MSI) and PTEN frameshift mutation. DNA MMR and PTEN protein expression were assessed in all polyps by immunohistochemistry. Additionally, 99 MSI-High (MSI-H) sporadic CRCs and 50 each of hMLH1−/− and hMSH3−/− cell clones were examined for PTEN frameshifts. Twenty-five of 43 (58%) HPS polyps demonstrated dinucleotide or greater MSI in polyp epithelium, consistent with hMSH3-deficiency. MSI domains lost hMSH3 expression, while PTEN expression was lost in polyps from germline PTEN patients; sporadic hamartomatous polyps did not show any of these findings. PTEN analysis revealed wildtype exon 7 and 8 sequences suggestive of nonexistent or rare events for PTEN frameshifts; however MSI-H sporadic CRC showed 11/99 (11%) 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. Non-dysplastic epithelium from HPS polyps harbor hMSH3 defects, which may prime neoplastic transformation. Polyps from PTEN+/− patients lose PTEN expression but loss is not a universal early feature of all HPS. However, PTEN frameshifts can occur in hMSH3-deficient cells suggesting that hMSH3-deficiency could drive HPS tumorigenesis.
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通讯作者：
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Boland, CR