mardi 10 juillet 2012

Mutated genes in cancer (75) – MLH1, MSH2 and MSH6

MLH1, MSH2 and MSH6


In databases:

● Entrez ( 4292 or MLH1
● Ensembl ( ENSG00000076242
● UniProt ( P40692
● GeneCards ( MLH1
● HGNC ( 7127 or MLH1

Gene locus:


Protein name:

MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)

Protein Size:

756 amino acids; about 85 kDa


In databases:

● Entrez ( 4436 or MSH2
● Ensembl ( ENSG00000095002
● UniProt ( P43246
● GeneCards ( MSH2
● HGNC ( 7325 or MSH2

Gene locus:


Protein name:

MutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)

Protein Size:

934 amino acids; about 105 kDa


In databases:

Ensembl ( ENSG00000116062
UniProt ( P52701
GeneCards ( MSH6
HGNC ( 7329 or MSH6

Gene locus:


Protein name:

MutS homolog 6 (E. coli)

Protein Size:

1360 amino acids; about 153 kDa


MLH1 forms heterodimer with PMS2 (MutL alpha), PMS1 (MutL beta) or MLH3 (MutL gamma). MutL alpha is a component of the post-replicative DNA mismatch repair system (MMR).  DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6), which recognize and bind to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. While MutS alpha complex binds to base-base and insertion-deletion mismatches, MutS beta only binds to insertion-deletion mismatches. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC (replication factor C) and PCNA (Proliferating Cell Nuclear Antigen) is sufficient to activate endonuclease activity of PMS2 (it seems that MLH1 itself has no enzymatic activity). It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III,  suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. In fact, MutL alpha is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages.

MLH1, MSH2 and MSH6 are part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains.

Cancer-related alterations

Germinal mutations: there are over 300 MLH1 and 300 MSH2 germline mutations described all along the gene that cause HNPCC. These mutations are not present in any particular hot spot or zone of the gene and include either nucleotide substitutions (missense, nonsense or splicing errors) or insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. There are also founding mutations which account for a high proportion of the HNPCC tumors in some specific populations (for example there are two Finnish mutations that delete the exons 16 or 6). Regarding MSH6, its germline mutations have variable penetration and are relatively rare in HNPCC and HNPCC-like families.

Somatic ML1, MSH2 and MSH6 mutations have been observed mainly in tumors of large intestine, stomach, ovary and endometrium. These mutations are not present in any particular hot spot or zone of the gene and include either nucleotide substitutions (missense, nonsense or splicing errors) or insertions/deletions (gross or small). Somatic MLH1 and MSH2 mutation may cause microsatellite instability (MSI) in colorectal, gastric and endometrial cancer. The involvement of somatic or epigenetic inactivation of MSH6 is rare in colorectal cancer and missense mutations in MSH6 are often clinically innocuous or have a low penetrance. However, somatic mutations of MSH6 have been shown to confer resistance to alkylating agents such as temozolomide in malignant gliomas in vivo.

Defects in MLH1, MSH2 and MSH6 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2), HNPCC1 (and HNPCC8, see below) and HNPCC5, respectively. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes (25% of cases each). HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas.
Clinically, HNPCC is often divided into two subgroups.
Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon.
Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria:
3 or more relatives affected by colorectal cancer, one a first degree relative of the other two;
2 or more generation affected;
1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes.
MSH6 mutations (10% of HNPCC cases) appear to be associated with atypical HNPCC and in particular with development of endometrial carcinoma or atypical endometrial hyperplasia, the presumed precursor of endometrial cancer. Defects in MSH6 are also found in familial colorectal cancers (suspected or incomplete HNPCC) that do not fulfill the Amsterdam criteria for HNPCC.
Defects in MSH2 are a cause of a particular type of HNPCC named HNPCC8, resulting from heterozygous deletion of 3-prime exons of EPCAM and intergenic regions directly upstream of MSH2; the consequence is a read-through and epigenetic silencing of MSH2 in tissues expressing EPCAM.

MicroSatellite Instability (MSI) is a characteristic of tumors in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system. This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and with lower incidence in some other tissues.
MSI may be due to sporadic or germline (in HNPCC) mutations in MLH1 or MSH2.

Germline alterations in MLH1 or MSH2 are a cause of Muir-Torre syndrome (MuToS); also abbreviated MTS. MuToS is a rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.

Defects in MLH1 or MSH6 are a cause of mismatch repair cancer syndrome (MMRCS) MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots. MSH2 mutations may predispose to hematological malignancies and multiple cafe-au-laity spots.

References (open access):

Lynch Syndrome. Kohlmann W, Gruber SB. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of Washington,  Seattle; 1993-2004 Feb 05 [updated 2011 Aug 11].

An optimized pentaplex PCR for detecting DNA mismatch repair-deficient colorectal cancers. Goel A, Nagasaka T, Hamelin R, Boland CR. PLoS One. 2010 Feb 24;5(2):e9393.

Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Ramsoekh D, Wagner A, van Leerdam ME, Dooijes D, Tops CM, Steyerberg EW, Kuipers EJ. Hered Cancer Clin Pract. 2009 Dec 23;7(1):17.

A comparison of models used to predict MLH1, MSH2 and MSH6 mutation carriers. Pouchet CJ, Wong N, Chong G, Sheehan MJ, Schneider G, Rosen-Sheidley B, Foulkes W, Tischkowitz M. Ann Oncol. 2009 Apr;20(4):681-8.

The frequency of Muir-Torre syndrome among Lynch syndrome families. South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A. J Natl Cancer Inst. 2008 Feb 20;100(4):277-81.

Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein B, Peltomäki P, Kolodner RD, Nilbert M, Lindblom A. J Natl Cancer Inst. 2007 Feb 21;99(4):291-9.

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