4.7 Article

Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions

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CLINICAL CANCER RESEARCH
卷 26, 期 6, 页码 1277-1287

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-2898

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  1. NIH [U54-CA163109, R01 CA211184, R01 CA034992]
  2. MIT Ludwig Center for Molecular Oncology
  3. Howard Hughes Medical Institute
  4. Pew Foundation
  5. Sidney Kimmel Foundation
  6. MIT Center for Stem Cell Research
  7. Koch Institute Swanson Biotechnology Center (Cancer Center Support Grant) [NIH-P30CA014051]
  8. Deutsche Forschungsgemeinschaft (DFG) [RI2408/1-1]
  9. MGH ECOR Tosteson
  10. Fund for Medical Discovery Fellowship
  11. NIH/NCI [1K08CA198002-01]

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Purpose: Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma-associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. Experimental Design: Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC. Results: Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normalmucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in themuscularismucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs. Conclusions: Muscularis mucosae-based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.

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