Department of Pediatrics, University of California at San Diego, San Diego, California, USA.
Cancer. 2011 Feb 1;117(3):492-500. doi: 10.1002/cncr.25445. Epub 2010 Sep 15.
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.
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.
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.
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.
具有错构瘤性息肉综合征的患者结直肠癌（CRC）的风险增加。尽管观察到息肉向癌的进展，但发病机制尚不清楚。作者研究了家族性错构瘤性息肉是否存在 DNA 错配修复（MMR）缺陷，并检测了一些错构瘤性息肉综合征患者中种系失活的 PTEN 的体细胞突变。
对 10 名错构瘤性息肉综合征患者进行种系突变检测。上皮和非上皮息肉 DNA 检测微卫星不稳定性（MSI）和 PTEN 移码突变。通过免疫组织化学法评估所有息肉的 DNA MMR 和 PTEN 蛋白表达。此外，还检测了 99 例 MSI 高的散发性 CRC 和 50 例 hMLH1（-/-）和 hMSH3（-/-）细胞克隆中的 PTEN 移码突变。
43 个错构瘤性息肉综合征息肉中的 25 个（58%）显示二核苷酸或更大的 MSI 在上皮息肉中，提示 hMSH3 缺乏。MSI 缺失的区域失去了 hMSH3 的表达，并且来自种系 PTEN 患者的息肉中失去了 PTEN 的表达；散发性错构瘤性息肉没有表现出这些发现中的任何一种。PTEN 分析显示外显子 7 和 8 的野生型序列，提示不存在或罕见的 PTEN 移码突变；然而，MSI 高的散发性 CRC 中有 11 个（99 个中的 11%）PTEN 发生移码突变，其中 4 个肿瘤完全失去了 PTEN 的表达。hMLH1（-/-）和 hMSH3（-/-）细胞的亚克隆显示出分别有 4%和 12%的克隆发生体细胞 PTEN 移码突变。
错构瘤性息肉的非发育不良上皮存在 hMSH3 缺陷，这可能导致肿瘤转化。来自 PTEN（+/-）患者的息肉失去了 PTEN 的表达，但这不是所有错构瘤性息肉综合征的普遍早期特征。然而，PTEN 移码突变可以发生在 hMSH3 缺陷的细胞中，这表明 hMSH3 缺陷可能驱动错构瘤性息肉综合征的肿瘤发生。
