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Agrin in the Muscularis Mucosa Serves As a Biomarker Published OnlineFirst December 18, 2019; DOI: 10.1158/1078-0432.CCR-19-2898 CLINICAL CANCER RESEARCH | PRECISION MEDICINE AND IMAGING Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions Steffen Rickelt1, Charlene Condon1,2, Miyeko Mana1, Charlie Whittaker1,2, Christina Pfirschke3, Jatin Roper1, Deepa T. Patil4, Ian Brown5, Anthony R. Mattia6, Lawrence Zukerberg7, Qing Zhao8, Runjan Chetty9, Gregory Y. Lauwers10, Azfar Neyaz7, Lieve G.J. Leijssen11,12, Katherine Boylan13, Omer H. Yilmaz1,7, Vikram Deshpande7, and Richard O. Hynes1,14,15 ABSTRACT ◥ Purpose: Sessile serrated lesions (SSL) are precursors to colon Results: Differential gene expression analysis and IHC identi- carcinoma, and their distinction from other polyps, in particular fied AGRN, serine peptidase inhibitor (SERPINE2), and TIMP hyperplastic polyps (HP), presents significant diagnostic chal- metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs lenges. We evaluated expression patterns in colonic polyps of but decreased in TAs and absent in normal colon. AGRN-positive previously identified colon carcinoma–associated extracellular basal laminae were noted in all TA, TSA, HP, and SSL in matrix (ECM) proteins to identify markers distinguishing SSLs distinguishable patterns, whereas other polyps and normal muco- from other polyps. sa were negative. SSL with or without dysplasia consistently Experimental Design: Gene-expression analyses of ECM pro- showed IHC staining for AGRN in the muscularis mucosae, which teins were performed using publicly available data on preneo- was absent in HP, TSA, TA, and other polyps. In contrast, plastic colonic polyps. In parallel, we evaluated by IHC the histologic evaluation showed only weak interobserver agreement expression of agrin (AGRN) in over 400 colonic polyps, including (kappa value ¼ 0.493) in distinguishing SSLs. HP, SSL with and without dysplasia, traditional serrated adeno- Conclusions: Muscularis mucosae–based AGRN immunos- mas (TSA), and tubular adenomas (TA), and compared the taining is a novel biomarker to distinguish SSL from HP, TSA, consistency of standard histologic diagnosis of SSLs by experi- and TA, with a specificity of 97.1% and sensitivity of 98.9% and can enced gastrointestinal pathologists with that of AGRN IHC. assist in diagnosis of morphologically challenging colonic polyps. Introduction and sigmoid colon, lack malignant potential and are by far the most Colonic polyps differ in their risk for progression to cancer; common colonic polyps, accounting for approximately 80% of all consequently, recommendations for removal and further management serrated polyps (6). In contrast, SSLs, which do have malignant are dependent on polyp classification (1). Although tubular adenomas potential, are estimated to represent up to 20% of serrated polyps (TA) were traditionally considered to be the sole precursor lesions of with a predilection for the right colon (9, 10). TSAs also have malignant colorectal carcinoma, the recognition of the serrated polyp route to potential but represent only 1% of all serrated lesions (11). carcinoma has been an important milestone (2, 3). Although SSLs show abnormal basal crypt architecture, HPs lack The WHO recognizes three categories of serrated polyps: traditional these specific features (9). However, uncertainty exists regarding serrated adenomas (TSA), hyperplastic polyps (HP), and sessile the minimum criteria for diagnosis of SSL and their distinction from serrated lesions (SSL; refs. 4–8). HPs, predominantly arising in rectum HP. The number of abnormal crypts required has varied among 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Note: Supplementary data for this article are available at Clinical Cancer Institute of Technology, Cambridge, Massachusetts. 2Swanson Biotech- Research Online (http://clincancerres.aacrjournals.org/). nology Center, David H. Koch Institute for Integrative Cancer Research, Current address for Jatin Roper: Department of Medicine, Division of Gastro- Massachusetts Institute of Technology, Cambridge, Massachusetts. enterology, Duke University, Durham, North Carolina. 3Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts. 4Cleveland V. Deshpande and R.O. Hynes share senior authorship for this article. Clinic, Department of Pathology, Cleveland, Ohio. 5Envoi Pathology, Corresponding Authors: Richard O. Hynes, David H. Koch Institute for Integra- Kelvin Grove, Queensland, Australia. 6Department of Pathology, North tive Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Shore Medical Center, Salem, Massachusetts. 7Department of Pathology, Avenue, 76-361D, Cambridge, MA 02139. Phone: 617-253-6422; Fax: 617-253- Massachusetts General Hospital, Boston, Massachusetts. 8Department of 8357; E-mail: [email protected]; Vikram Deshpande, Massachusetts General Pathology and Laboratory Medicine, Boston University Medical Center, Hospital, Boston, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-2967; Boston, Massachusetts. 9Department of Pathology, Toronto General Hos- E-mail: [email protected]; and Steffen Rickelt, David H. Koch pital, Toronto, Ontario, Canada. 10Department of Pathology, Moffitt Can- Institute for Integrative Cancer Research, Massachusetts Institute of Technol- cer Center, Tampa, Florida. 11Department of General and Gastrointestinal ogy, 77 Massachusetts Avenue, 76-343, Cambridge, MA 02139. Phone: 617-253- Surgery, Massachusetts General Hospital, Boston, Massachusetts. 12Har- 4225; E-mail: [email protected] vard Medical School, Boston, Massachusetts. 13Department of Pathology, University of Utah, Huntsman Cancer Institute, Salt Lake City, Clin Cancer Res 2020;XX:XX–XX Utah. 14Howard Hughes Medical Institute, Chevy Chase, Maryland. doi: 10.1158/1078-0432.CCR-19-2898 15Department of Biology, Massachusetts Institute of Technology, Cam- bridge, Massachusetts. Ó2020 American Association for Cancer Research. AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst December 18, 2019; DOI: 10.1158/1078-0432.CCR-19-2898 Rickelt et al. mentary Fig. S2; Supplementary Table S2). The SSL samples (n ¼ 189) Translational Relevance included 132 (69.9%) polyps from the right colon, 49 (25.9%) from the Sessile serrated lesions (SSL) are precursors of colon carcinoma. left colon, and 8 (4.2%) rectal polyps. Among the 71 HP cases, 9 Their distinction from other polyps with better prognoses, most (12.7%) polyps were from the right colon, 32 (45.1%) from the left notably hyperplastic polyps (HP), often presents a significant colon, and 30 (42.2%) from the rectum. HPs were further characterized diagnostic challenge, and histologic evaluation shows only weak as microvesicular HPs (MVHP; n ¼ 38) and goblet cell HPs (GCHP; interobserver agreement among experts. We identified the extra- n ¼ 33) by two pathologists (AN, VD; Supplementary Table S2; cellular matrix protein agrin in the muscularis mucosae (MM) of ref. 27). SSL biopsies but not in other polyps or normal colonic tissue. IHC To define the serrated polyposis syndrome (SPS), we used criteria staining of the MM for agrin presents a novel biomarker with high proposed by Syngal and colleagues (28). Briefly, diagnosis was based on specificity and sensitivity and markedly improves the discrimina- the following criteria: (i) at least five serrated polyps proximal to the tion among polyp subtypes. Immunostaining for agrin in the MM sigmoid colon with 2 of these being >10 mm; (ii) any number of enables pathologists towards more accurate diagnoses of patients serrated polyps proximal to the sigmoid colon in an individual who has with SSLs, can assist with morphologically challenging cases, and a first-degree relative with serrated polyposis; or (iii) >20 serrated may allow evidence-based surveillance of serrated polyps. polyps of any size, distributed throughout the large intestine. Addi- tional SPS patient samples were provided by the Department of Pathology, University of Utah (Salt Lake City, UT; ref. 29). guidelines from one to three SSL-like crypts (5–7). Furthermore, there Ethics is significant interobserver variability as to what constitutes an abnor- The study was approved by the Partners Institutional Review mal crypt and poor specimen orientation and other biopsy artifacts Board protocol (IRB #2017P000061) and the MIT IRB (Protocol accentuate the challenge (12–14). Indeed, substantial interobserver #1408006568). variation among gastrointestinal (GI) pathologists remains and agree- ment among experts is moderate at best (13, 15–20). These uncer- Majority-based pathology classification approach tainties often result in the inability to definitively distinguish SSL Approach for majority agreement on 50 diagnostically challenging from HP. The diagnosis of SSL prompts more aggressive surveillance, serrated polyps generally 1 to 3 years, whereas a diagnosis of HP and small TAs (<10 We used a majority approach for the diagnosis of SSL. From our mm) indicates less aggressive surveillance, every 5 to 10 years (5, 18). cohort of 408 colonic polyps and within the 100 cases validated by the 4 Collectively, the evidence suggests a need to identify biomarkers for nonpathologists (see Supplementary Materials and Methods), 2 GI SSLs to guide appropriate management. Suggested biomarkers eval- pathologists identified 50 diagnostically challenging
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