TY - JOUR
T1 - Agrin in the Muscularis mucosa serves as a biomarker distinguishing hyperplastic polyps from sessile serrated lesions
AU - Rickelt, Steffen
AU - Condon, Charlene
AU - Mana, Miyeko
AU - Whittaker, Charlie
AU - Pfirschke, Christina
AU - Roper, Jatin
AU - Patil, Deepa T.
AU - Brown, Ian
AU - Mattia, Anthony R.
AU - Zukerberg, Lawrence
AU - Zhao, Qing
AU - Chetty, Runjan
AU - Lauwers, Gregory Y.
AU - Neyaz, Azfar
AU - Leijssen, Lieve G.J.
AU - Boylan, Katherine
AU - Yilmaz, Omer H.
AU - Deshpande, Vikram
AU - Hynes, Richard O.
N1 - Funding Information:
The authors thank Chenxi Tian for assistance in using the confocal laser-scanning microscope, and all members of the Hynes laboratory for advice and discussions. They thank the Swanson Biotechnology Center at the Koch Institute/MIT, especially Mike S. Brown and Kathleen S. Cormier from the Hope Babette Tang (1983) Histology Facility and Jeff Wykoff in the Microscopy Facility for exceptional technical support, Duanduan Ma from the Barbara K. Ostrom Bioinformatics & Computing Facility for assistance with bioinformatic analyses and power calculations, and Sven Holder for sample sectioning. They also thank Lucia Suarez-Lopez (Koch Institute); Roderick T. Bronson (Harvard Medical School); and Mari Mino-Kenudson, Jeck Williams, and Martin S. Taylor (Massachusetts General Hospital) for discussion, data collection, and advice. The authors also thank Eric R. Fearon (Department of Internal Medicine, University of Michigan, Ann Arbor, MI) for kindly providing slides of colon sections from control and CDX2P-CreERT2 CDX2fl/fl;BrafLSL-V600E/+mice and Mary Bronner (Department of Pathology, University of Utah, Salt Lake City, UT) for critically reading the manuscript and providing samples previously described by Kanth and colleagues (2016, ref. 29). This work was supported by NIH grants U54-CA163109 (Tumor Microenvironment Network to R.O. Hynes) and R01 CA211184, R01 CA034992 (to O.H. Yilmaz), the MIT Ludwig Center for Molecular Oncology and the Howard Hughes Medical Institute, of which R.O. Hynes is an investigator. O.H. Yilmaz was supported by the Pew Foundation, Sidney Kimmel Foundation, and MIT Center for Stem Cell Research. Facility support was provided by the Koch Institute Swanson Biotechnology Center (Cancer Center Support Grant NIH-P30CA014051). S. Rickelt was supported by postdoctoral fellowships from the Deutsche Forschungs-gemeinschaft (DFG) RI2408/1-1 and the MIT Ludwig Center for Molecular Oncology. C. Pfirschke was supported by the MGH ECOR Tosteson and Fund for Medical Discovery Fellowship, and J. Roper by NIH/NCI (1K08CA198002-01).
Funding Information:
O.H. Yilmaz is an employee/paid consultant for Merck and reports receiving commercial research grants from Exelixis. V. Deshpande is an employee/paid
Funding Information:
The authors thank Chenxi Tian for assistance in using the confocal laser-scanning microscope, and all members of the Hynes laboratory for advice and discussions. They thank the Swanson Biotechnology Center at the Koch Institute/MIT, especially Mike S. Brown and Kathleen S. Cormier from the Hope Babette Tang (1983) Histology Facility and Jeff Wykoff in the Microscopy Facility for exceptional technical support, Duanduan Ma from the Barbara K. Ostrom Bioinformatics & Computing Facility for assistance with bioinformatic analyses and power calculations, and Sven Holder for sample sectioning. They also thank Lucia Suarez-Lopez (Koch Institute); Roderick T. Bronson (Harvard Medical School); and Mari Mino-Kenudson, Jeck Williams, and Martin S. Taylor (Massachusetts General Hospital) for discussion, data collection, and advice. The authors also thank Eric R. Fearon (Department of Internal Medicine, University of Michigan, Ann Arbor, MI) for kindly providing slides of colon sections from control and CDX2P-CreERT2 CDX2fl/fl;BrafLSL-V600E/? mice and Mary Bronner (Department of Pathology, University of Utah, Salt Lake City, UT) for critically reading the manuscript and providing samples previously described by Kanth and colleagues (2016, ref. 29). This work was supported by NIH grants U54-CA163109 (Tumor Microenvironment Network to R.O. Hynes) and R01 CA211184, R01 CA034992 (to O.H. Yilmaz), the MIT Ludwig Center for Molecular Oncology and the Howard Hughes Medical Institute, of which R.O. Hynes is an investigator. O.H. Yilmaz was supported by the Pew Foundation, Sidney Kimmel Foundation, and MIT Center for Stem Cell Research. Facility support was provided by the Koch Institute Swanson Biotechnology Center (Cancer Center Support Grant NIH-P30CA014051). S. Rickelt was supported by postdoctoral fellowships from the Deutsche Forschungsgemeinschaft (DFG) RI2408/1-1 and the MIT Ludwig Center for Molecular Oncology. C. Pfirschke was supported by the MGH ECOR Tosteson and Fund for Medical Discovery Fellowship, and J. Roper by NIH/NCI (1K08CA198002-01).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - 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 normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value ¼ 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.
AB - 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 normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value ¼ 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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U2 - 10.1158/1078-0432.CCR-19-2898
DO - 10.1158/1078-0432.CCR-19-2898
M3 - Article
C2 - 31852835
AN - SCOPUS:85081945914
SN - 1078-0432
VL - 26
SP - 1277
EP - 1287
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -