Evidence for an hMSH3 defect in familial hamartomatous polyps

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 À/À and hMSH3 À/À 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 À/À and hMSH3 À/À 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 þ/À 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;117:492

Interleukin 6 Alters Localization of hMSH3, Leading to DNA Mismatch Repair Defects in Colorectal Cancer Cells

“…EMAST has been observed in a number of cancers, including small cell cancer of the lung (10), bladder cancer (11), ovarian cancers (9), and colorectal cancers (12–15), and among benign familial hamartomatous polyps in the colon (25). EMAST is strongly associated with inflammation, and its presence is a biomarker for poor prognosis in patients with colorectal cancers (15,16,19).…”

Microsatellite Instability Pathway and EMAST in Colorectal Cancer

“…Inactivation of MSH2 and MLH1, the most common proteins affected in Lynch Syndrome, causes complete loss of MMR function; MLH1 is also the principal protein affected in sporadic MSI colorectal cancers [1–3]. When between 0% and 20% of markers show frameshifts, this is termed MSI-Low, and the frameshift is almost exclusively in the dinucleotide markers and not mononucleotide markers [1,10,11]. Although MSH6 dysfunction can generate mono- and di-nucleotide frameshifts, the absence of any mononucleotide frameshifts characteristic of MSI-Low is most likely associated with isolated MSH3 dysfunction [10,11].…”

“…When between 0% and 20% of markers show frameshifts, this is termed MSI-Low, and the frameshift is almost exclusively in the dinucleotide markers and not mononucleotide markers [1,10,11]. Although MSH6 dysfunction can generate mono- and di-nucleotide frameshifts, the absence of any mononucleotide frameshifts characteristic of MSI-Low is most likely associated with isolated MSH3 dysfunction [10,11]. Lack of any mono- or di-nucleotide markers with frameshifts defines microsatellite stable (MSS) CRCs, equating to no observable defect in MMR function [1,10,12].…”

PTEN hamartoma tumor syndrome: Clinical risk assessment and management protocol

“…Along a similar vein, others have found that a defect in DNA MMR, namely hMSH3 function can be associated with frameshift mutation of PTEN [46]. Loss of hMSH3 could occur in the setting of inflammation, a common finding within hamartomatous polyps, and inflammation has been associated with acquired DNA MMR defects [35,36].…”