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ISSN: 2161-069X
Journal of Gastrointestinal & Digestive System
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An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms

Aaron R. Huber*, D.O., Christa L. Whitney-Miller, Jennifer and J. Findeis-Hosey

Surgical Pathology Unit, University of Rochester Medical Center, USA

*Corresponding Author:
Aaron Ryan Huber
University of Rochester Medical Center
Surgical Pathology Unit 601 Elmwood Avenue
Rochester, NY 14618, USA
Tel: (585) 275-1702
Fax: (585) 276-2802
E-mail: [email protected]

Received date: November 06, 2013; Accepted date: November 18, 2013; Published date: November 26, 2013

Citation: Huber AR, Whitney-Miller DOCL, Jennifer, Findeis-Hosey J (2013) An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms. J Gastroint Dig Syst 3:151. doi: 10.4172/2161-069X.1000151

Copyright: © 2013 Whitney-Miller CL, et al. 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.

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Lynch syndrome, originally described in 1913 and previously known as hereditary nonpolyposis colorectal
carcinoma syndrome, is the most common hereditary cancer syndrome. This syndrome is classically due to germline
mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. The cancer risk for patients with Lynch
syndrome is not limited to the colorectum; women with Lynch syndrome are at risk for endometrial cancer, and Lynch
patients of both genders are at risk for other cancers as well. There are cases of cancers in families that meet the
clinical criteria (Amsterdam and Bethesda criteria) for Lynch syndrome but do not have a mutation in the one of the
four classic mismatch repair genes. For some time, there has been speculation that other mutations or mechanisms
were responsible for a subset of Lynch syndrome patients; much research has gone into identifying those alternative
mutations and mechanisms. Recently, EPCAM deletion, CHEK2 mutations, and germline MLH1 hypermethylation
have been identified as alternative mutations that cause Lynch syndrome in mismatch repair-negative patients. This
article reviews these novel mechanisms and mutations, their clinical significance, and the pathogenesis of these Lynch
causing mutations.


Lynch syndrome; Pathogenesis; Cancers; Muttions


In 1913 Warthin described a family in Michigan with a propensity to develop gastrointestinal and gynecologic cancers without colorectal polyps [1,2]. In 1966, Lynch et al. published data on two other Midwestern families with a clustering of similar types of cancer [1,2]. This syndrome, Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer), is the most common hereditary cancer syndrome and is inherited in an autosomal dominant fashion [1-3]. Typically, Lynch syndrome is the result of germline mutations in the mismatch repair (MMR) genes MSH2, MSH6, PMS2, or MLH1 with subsequent heterozygous loss of function [1-5]. While Lynch syndrome accounts for approximately 1-7% of all colorectal carcinomas [2-9], there is also an elevated risk of extracolonic malignancies including carcinomas of the small bowel, upper genitourinary tract, stomach, pancreas, ovary, and endometrium [1-3,5-14]. In women, endometrial cancer and colon cancer are equally likely to be the sentinel tumor event [5].

The MMR proteins are responsible for the repair of DNA basepair errors or “mismatches” that develop during DNA replication [1]. When these errors occur, they are most commonly in long, repetitive DNA sequences commonly seen in microsatellites [1]. Microsatellites are short mono, di, or trinucleotide repeats in noncoding regions throughout the human genome [1]. When there is a mutation in one of these MMR genes the abnormal protein is unable to correct the transcriptional errors or “mismatches,” and the length of the microsatellite regions (which are usually fixed in a given individual) become variable, leading to microsatellite instability [1]. Abnormal MMR proteins can be detected using immunohistochemistry and microsatellite instability can be assessed for using molecular methods, though definitive diagnosis of Lynch syndrome requires germline sequencing of MMR genes. Historically patients with Lynch syndrome have been identified based on family history, first by the Amsterdam criteria and more recently by the modified Bethesda criteria [4-6]. A subset of approximately 40% of patients with Lynch syndrome that meet clinical criteria and have a microsatellite instability-high colorectal cancer do not have an identifiable mutation in one of the four mismatch repair genes [2,3,5,6,7,13]. Recently, several novel genetic abnormalities have been identified which lead to the Lynch syndrome phenotype and may explain differences in the rates and risk of extracolonic malignancies [1-3,5-18]. We subsequently outline newly identified abnormalities, including EPCAM deletions, germline promoter hypermethylation of the MLH1 gene, and CHEK2 mutations, and their role in Lynch syndrome.

Epithelial Cellular Adhesion Molecule (EPCAM) Mutations

The EPCAM gene, formerly known as TACSTD1 (tumor associated calcium signal transducer 1), codes for epithelial cellular adhesion molecule CD326 and is located on the short arm of chromosome 2 [1,6-9]. EPCAM is expressed in nearly all epithelial cells as well as some epithelial malignancies, including colorectal carcinomas [1,6,8,9]. Fairly recently, a germline deletion in the 3’ exon of EPCAM, which is directly upstream from MSH2, was discovered in Dutch, German, and Chinese populations that results in MSH2 promoter hypermethylation, inactivation of the MSH2 gene, and development of Lynch syndrome [1,3,5-12]. It is estimated that this deletion may be present in up to1- 2.8% of those with Lynch syndrome [6,14]. Concomitant lack of MSH2 and EPCAM expression, as determined by immunohistochemistry, is characteristic of these tumors; however, EPCAM expression can be retained in some cancers and may not be expressed by all cells limiting the utility of immunohistochemistry in diagnosis [1,6]. The cumulative risk of colorectal cancer at age 70 years for carriers of an EPCAM deletion is similar to those that are carriers of EPCAM-MSH2, MSH2, or MLH1 mutations; however, it is higher than carriers of MSH6 mutations [10].

Germline Promoter Hypermethylation of MLH1

Approximately 10% of sporadic colorectal cancers demonstrate the microsatellite instability-high (MSI-H) phenotype with loss of MLH1 protein expression by immunohistochemistry as a consequence of somatic hypermethylation of the promoter region of the MLH1 gene and transcriptional silencing [1-3,9,13,14]. Another novel mechanism leading to a Lynch syndrome phenotype is germline promoter hypermethylation of the MLH1 gene [1,13,14]. Both germline and somatic hypermethylation result in loss of expression of the MLH1 protein by immunohistochemistry and a microsatellite instabilityhigh phenotype. The presence of hypermethylation of the MLH1 promoter does not exclude Lynch syndrome [1,13,14]. The main factor differentiating the two is that sporadic tumors demonstrate somatic hypermethylation and tumors of Lynch syndrome show germline hypermethylation [1,13,14]. In one study, 9.4% of patients with Lynch syndrome (MMR mutation negative; fulfilled Amsterdam criteria) were due to germline hypermethylation of MLH1 [1,13]. Methylation analysis can be carried out by extracting DNA from peripheral blood lymphocytes, treating the DNA with bisulfite, amplifying the MLH1 promoter region by polymerase chain reaction, and separating the methylated and unmethylated products by gel electrophoresis [13]. Currently, the exact phenotype regarding cancer risk, cancer types, and cancer incidence in this group is still being studied [1].

Cell Cycle Checkpoint Kinase 2 (CHEK2) Mutations

Mutation in cell cycle checkpoint kinase 2 (CHEK2) is a recently described mechanism for the development of Lynch syndrome [1,2,15-19]. CHEK2 is a multiorgan cancer susceptibility gene that codes for a serine/threonine kinase that serves a regulatory function in processes such as cell cycle progression, apoptosis, DNA damage repair, and may be a genetic modifier for other susceptibility genes [1,15,17,18]. CHEK2 mutations have been associated with elevated risk of breast cancer in some northern and central/eastern European populations (Poland, Finland, Germany, and the Czech republic) and are second only to BRCA mutations in hereditary breast cancer gene incidence [1,2,15-19]. There are four known Ck2 mutations; two of them, I157T and 1100delC, may be associated with increased risk of multiple malignancies including breast, colon, kidney, prostate, and thyroid cancer [1,2,15-19]. Initial studies demonstrated that carriers of the 1100delC mutation had significantly higher rates of breast cancer, colon cancer, ovarian cancer, and other malignancies seen in Lynch syndrome; it was identified in approximately 3% of families with clinically diagnosed Lynch syndrome [1,16,19]. CHEK2 mutations may be responsible for some cases of Lynch syndrome without a MMR mutation, though the possibility that the 1100delC is modifying an unidentified susceptibility gene that causes a syndrome similar to Lynch cannot be excluded [1,16].

Studies of the I157T mutation found that this mutation is strongly associated with Lynch-related malignancies, both colorectal and extracolonic, in Finnish and Polish populations [1,2,15,17,18]. The missense I157T allele seems to be the mutation most associated with colorectal cancer and was seen in 7.7% of Lynch syndrome families and 4.8% of control subjects [17]. All of these studies are limited by the small number of cases but there is evidence to suggest that the 1100delC and I157T CHEK2 mutations may be responsible for the Lynch phenotype.


Lynch syndrome is a common hereditary cancer syndrome which is most classically due to germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Now, 100 years after Lynch syndrome was first described, several novel mechanisms involved in the pathogenesis of this syndrome, other than mismatch repair gene mutations, are being discovered. Among these novel mechanisms, EPCAM deletions, CHEK2 mutations, and germline promoter hypermethylation of MLH1 have been described with evidence that these are responsible for some of the MMR-negative cases (Table 1). Other genetic pathways that are linked to the Lynch syndrome phenotype maybe discovered, helping to identify those individuals with Lynch syndrome, allowing for appropriate preventative screening in these patients and their family members.

Gene (s) Mutation (s) Mechanism Phenotype
Mismatch Repair (MLH1, MSH6, PMS2, MSH2) Germline deletions, point, truncation, missense, or frame shift Abnormal MMR protein expression leading to faulty repair of DNA replication errors Early-onset colorectal cancer; increased risk of endometrial, ovarian, gastric, urinary tract, renal, biliary tract, brain, and small bowel cancers
Epithelial Cellular Adhesion Molecule (EPCAM) Germline deletion involving 3΄ exon Epigenetic silencing of neighboring MSH2 Early-onset colorectal cancer; increased risk of endometrial, bladder, small bowel, and appendiceal cancers
MLH1 Germline promoter hypermethylation Loss of MLH1 expression Tumor spectrum, phenotype, and incidence are under investigation
Cell Cycle Check Point Kinase 2 (CHEK2) 1100delC and I157T Inactivation of CHEK2: a serine/threonine kinase with mutliple regulatory functions (cell cycle progression, apoptosis, DNA damage repair) 1100delC: increased risk of breast, colon, and ovarian cancers; and various other Lynch-related malignancies I157T: increased risk of breast, colon, kidney, prostate, and thyroid cancers

Table 1: Molecular Mechanisms Responsible for Lynch Syndrome.


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