Improved Detection of Microsatellite Instability in Early Colorectal Lesions

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Abstract

Microsatellite instability (MSI) occurs in over 90% of Lynch syndrome cancers and is considered a hallmark of the disease. MSI is an early event in colon tumor development, but screening polyps for MSI remains controversial because of reduced sensitivity compared to more advanced neoplasms. To increase sensitivity, we investigated the use of a novel type of marker consisting of long mononucleotide repeat (LMR) tracts. Adenomas from 160 patients, ranging in age from 29–55 years old, were screened for MSI using the new markers and compared with current marker panels and immunohistochemistry standards. Overall, 15 tumors were scored as MSI-High using the LMRs compared to 9 for the NCI panel and 8 for the MSI Analysis System (Promega). This difference represents at least a 1.7-fold increase in detection of MSI-High lesions over currently available markers. Moreover, the number of MSI-positive markers per sample and the size of allelic changes were significantly greater with the LMRs (p = 0.001), which increased confidence in MSI classification. The overall sensitivity and specificity of the LMR panel for detection of mismatch repair deficient lesions were 100% and 96%, respectively. In comparison, the sensitivity and specificity of the MSI Analysis System were 67% and 100%; and for the NCI panel, 75% and 97%. The difference in sensitivity between the LMR panel and the other panels was statistically significant (p<0.001). The increased sensitivity for detection of MSI-High phenotype in early colorectal lesions with the new LMR markers indicates that MSI screening for the early detection of Lynch syndrome might be feasible.

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Most cited references 44

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A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

C R Boland, S Thibodeau, S Hamilton … (1998)

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

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Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.

Asad Umar, C. Boland, Jonathan Terdiman … (2004)

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

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A dynamic and intricate regulatory network determines Pseudomonas aeruginosa virulence

Deepak Balasubramanian, Lisa Schneper, Hansi Kumari … (2012)

Pseudomonas aeruginosa is a metabolically versatile bacterium that is found in a wide range of biotic and abiotic habitats. It is a major human opportunistic pathogen causing numerous acute and chronic infections. The critical traits contributing to the pathogenic potential of P. aeruginosa are the production of a myriad of virulence factors, formation of biofilms and antibiotic resistance. Expression of these traits is under stringent regulation, and it responds to largely unidentified environmental signals. This review is focused on providing a global picture of virulence gene regulation in P. aeruginosa. In addition to key regulatory pathways that control the transition from acute to chronic infection phenotypes, some regulators have been identified that modulate multiple virulence mechanisms. Despite of a propensity for chaotic behaviour, no chaotic motifs were readily observed in the P. aeruginosa virulence regulatory network. Having a ‘birds-eye’ view of the regulatory cascades provides the forum opportunities to pose questions, formulate hypotheses and evaluate theories in elucidating P. aeruginosa pathogenesis. Understanding the mechanisms involved in making P. aeruginosa a successful pathogen is essential in helping devise control strategies.

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Author and article information

Contributors

Michela Grosso: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 7 August 2015

Publication date Collection: 2015

Volume: 10

Issue: 8

Electronic Location Identifier: e0132727

Affiliations

[1 ]Genetic Analysis Group, Promega Corporation, Madison, Wisconsin, United States of America

[2 ]Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America

[3 ]Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America

[4 ]Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America

[5 ]Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America

University of Naples Federico II, ITALY

Author notes

Competing Interests: JWB, IV, and DRS are employees of the Promega Corporation and DRS owns stock, whose company partly funded this study. RBH received funds from the Promega Corporation to collect human samples, prepare genomic DNA for microsatellite testing, and perform immunohistochemistry for MLH1, MSH2, MSH6, and PMS2. The long mononucleotide markers were compared to current standards – the Promega MSI Analysis System which is widely used for microsatellite testing and immunohistochemistry. The purpose of this study was to determine whether the long mononucleotides were more sensitive to microsatellite instability than the current standards. The long mononcleotides are not part of any product marketed by the Promega Corporation or any of its competitors. There are no patents, products in development or marketed products to declare. The authors adhere to the PLOS ONE policies on sharing data and materials; long mononucleotide primers will be freely available to investigators through a Material Transfer Agreement with Promega.

Conceived and designed the experiments: JWB ICG JMW DRS ATT RBH. Performed the experiments: JWB CKS DMA ICG JMW KAM IV DRS ATT RBH. Analyzed the data: JWB CKS DMA ICG JMW KAM RMA IV LC DRS ATT RBH. Wrote the paper: JWB CKS DMA ICG JMW KAM RMA IV LC DRS ATT RBH.

* E-mail: rbhalberg@ 123456medicine.wisc.edu

Article

Publisher ID: PONE-D-14-55226

DOI: 10.1371/journal.pone.0132727

PMC ID: 4529134

PubMed ID: 26252492

SO-VID: 20288c00-c52c-4960-b3f9-53c9c98b288a

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 15 December 2014

Date accepted : 17 June 2015

Page count

Figures: 6, Tables: 2, Pages: 17

Funding

This work was a collaboration between investigators at the Promega Corporation and the University of Wisconsin. Support was provided to JWB and RBH from the Promega Corporation and to RBH from the School of Public Health and Medicine, the Department of Medicine, Division of Gastroenterology and Hepatology, as well as Carbone Cancer Center (P30 CA014520) at University of Wisconsin. JMW was supported by a Mentored Research Scholar Grant in Applied and Clinical Research, MRSG-13-144-01-CPHPS from the American Cancer Society and by the University of Wisconsin Institute for Clinical and Translational Research through the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427. The funder, Promega Corporation, provided support in the form of salaries for authors JWB, IV, and DRS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

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Data Availability All relevant data are within the paper and its Supporting Information files. Primers will be made available upon request under a Material Transfer Agreement with Promega Corporation. Requests should be directed to Dr. Bacher ( jeff.bacher@ 123456promega.com ).

Improved Detection of Microsatellite Instability in Early Colorectal Lesions

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Abstract

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Most cited references 44

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.

A dynamic and intricate regulatory network determines Pseudomonas aeruginosa virulence

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