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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2015; 21(31): 9253-9261
Published online Aug 21, 2015. doi: 10.3748/wjg.v21.i31.9253
Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer
John M Carethers, Elena M Stoffel
John M Carethers, Elena M Stoffel, Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-5368, United States
John M Carethers, Elena M Stoffel, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5368, United States
Author contributions: Both authors contributed to this manuscript.
Supported by The United States Public Health Service (DK067287 and CA162147); and the A. Alfred Taubman Medical Research Institute of the University of Michigan.
Conflict-of-interest statement: No potential conflicts of interest are disclosed. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: John M Carethers, MD, Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5368, United States. jcarethe@umich.edu
Telephone: +1-734-6151717 Fax: +1-734-6152645
Received: May 9, 2015
Peer-review started: May 12, 2015
First decision: June 2, 2015
Revised: June 13, 2015
Accepted: July 8, 2015
Article in press: July 8, 2015
Published online: August 21, 2015
Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

Keywords: Hereditary non-polyposis colorectal cancer, Lynch syndrome, Lynch-like syndrome, Familial colorectal cancer, DNA mismatch repair, Microsatellite instability, Familial colorectal cancer type X, Constitutional mismatch repair deficiency syndrome, Hereditary colorectal cancer

Core tip: Clinical criteria and phenotypic presentation of patients and families with hereditary non-polyposis colorectal cancer (HNPCC) do not adequately differentiate the several genetic diseases now classified under HNPCC. Tumor analysis for microsatellite instability (MSI) can dichotomize for the clinician conditions with MSI or without MSI, allowing a focused differential diagnosis. Individual or panel germline genetic testing can further differentiate HNPCC into its genetically defined syndromes or its phenocopies.