- Human pathology

Home > A. Molecular pathology > mismatch repair diseases

mismatch repair diseases

Monday 15 December 2003

microsatellite instability, MSI-H, DNA microsatellite instability, MSI, mismatch-repair deficiency; MMR diseases; DNA Mismatch Repair Protein Deficiency

Definition: A cause for genetic instability is the frequent appearance of mismatches on the double helix of DNA. (DNA mismatch repair)

Base-base mismatches

Base-base mismatches and small loops may occur during most of the main mechanism that process DNA, that is, replication, recombination and repair itself. From bacteria to eukaryotes, there are special enzymatic machineries that correct these mismatches, restoring the original DNA sequence, which are generally called DNA mismatch repair.


- HNPCCs (Lynch syndrome) (HPA:980)
- MMR-associated Turcot syndrome (MSI-associated Turcot syndrome) (HPA:15145)
- DNA mismatch repair-associated leukemias (HPA:13680)
- mismatch repair cancer syndrome (HPA:13677)
- Muir-Torre syndrome (HPA:3252)

Mutator phenotype

Defects on DNA repair in bacteria have long been known as a cause for a mutator phenotype. Thus, such a phenotype would be also expected in human cells, and it could also be related to hereditary cancer.

In fact, one of the most interesting recent findings in the field was the discovery that mutations in mismatch repair genes (such as hMSH2, hMLH1, hPMS1 and hPMS2) are responsible for the hereditary nonpolyposis colorectal cancer (HNPCC), which affects as many as 1 in 200 individuals, and also a subset of sporadic colorectal cancers.

Individuals are normally heterozygous for the mismatch genes, but the loss of heterozygosity, that may occur spontaneously, leads to genetic instability, originating tumor cells.

In fact, cells from tumors of HNPCC patients show increased microsatellite instability and are normally defective for DNA mismatch repair.

As for the ATM gene, the availability of the DNA mismatch repair gene sequences will aid the screening of HNPCC families for the most frequent mutated alleles.

Moreover, other types of sporadic cancers are found to be associated with the instability of microsatellite DNA sequences, probably due to a deficient mismatch repair.

By removing biosynthetic errors from newly synthesized DNA, mismatch repair (MMR) improves the fidelity of DNA replication by several orders of magnitude.

Loss of MMR brings about a mutator phenotype, which causes a predisposition to cancer. But MMR status also affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes such as class-switch recombination, somatic hypermutation and triplet-repeat expansion.


- in gastric carcinoma
- in colonic carcinoma

Defects in the mismatch repair (MMR) genes hMLH1 and hMSH2 have been found in 10% to 20% of sporadic colorectal carcinomas and also many cases of hereditary nonpolyposis colorectal cancer syndrome. Patients with these tumors have an improved prognosis and may show greater sensitivity to chemotherapy.

Mucinous tumors were common in hMLH1 tumors (36.3%) but not in hMSH2 tumors (11.1%). hMLH1 tumors were most likely to be poorly differentiated (70%), which was uncommon with hMSH2 tumors (22.2%). hMSH2 tumors were more likely to be confined to the wall (66.7%) than hMLH1 (20%) or intact tumors (23%). (14576472)

Although the significance of immunohistochemical detection of DNA mismatch repair proteins and/or microsatellite instability testing in identifying patients at risk for germline deficiency in DNA mismatch repair genes is well established in colorectal carcinomas, the proper use of such techniques in sebaceous neoplasms, another tumor type that has been implicated in patients with hereditary DNA mismatch repair deficiency, has not been clearly defined. (19342947)


- DNA mismatch repair

@<@object width="425" height="350">@<@param name="movie" value="">@<@/param>@<@param name="wmode" value="transparent">@<@/param>@<@embed src="" type="application/x-shockwave-flash" wmode="transparent" width="425" height="350">@<@/embed>@<@/object>


- Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels.
Stadler ZK, Battaglin F, Middha S, Hechtman JF, Tran C, Cercek A, Yaeger R, Segal NH, Varghese AM, Reidy-Lagunes DL, Kemeny NE, Salo-Mullen EE, Ashraf A, Weiser MR, Garcia-Aguilar J, Robson ME, Offit K, Arcila ME, Berger MF, Shia J, Solit DB, Saltz LB. J Clin Oncol. 2016 Mar 28. pii: JCO651067. PMID: 27022117


- Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006 May;7(5):335-46. PMID: 16612326

- Stojic L, Brun R, Jiricny J. Mismatch repair and DNA damage signalling. DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1091-101. PMID: 15279797

- Kruse R, Ruzicka T. DNA mismatch repair and the significance of a sebaceous skin tumor for visceral cancer prevention. Trends Mol Med. 2004 Mar;10(3):136-41. PMID: 15102357

- Duval A, Hamelin R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res. 2002 May 1;62(9):2447-54. PMID: 11980631

- Wei K, Kucherlapati R, Edelmann W. Mouse models for human DNA mismatch-repair gene defects. Trends Mol Med. 2002 Jul;8(7):346-53. PMID: 12114115

- Fishel R. The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. Cancer Res. 2001 Oct 15;61(20):7369-74. PMID: 11606363

- Peltomaki P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet. 2001 Apr;10(7):735-40. PMID: 11257106

- Simpson AJ, Caballero OL, Pena SD. Microsatellite instability as a tool for the classification of gastric cancer. Trends Mol Med. 2001 Feb;7(2):76-80. PMID: 11286759

- Eshleman JR, Markowitz SD. Mismatch repair defects in human carcinogenesis. Hum Mol Genet. 1996;5 Spec No:1489-94. PMID: 8875255

References in pathology

- Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel. Shia J, Tang LH, Vakiani E, Guillem JG, Stadler ZK, Soslow RA, Katabi N, Weiser MR, Paty PB, Temple LK, Nash GM, Wong WD, Offit K, Klimstra DS. Am J Surg Pathol. 2009 Nov;33(11):1639-45. PMID: 19701074

- Towards Identification of Hereditary DNA Mismatch Repair Deficiency: Sebaceous Neoplasm Warrants Routine Immunohistochemical Screening Regardless of Patient’s Age or Other Clinical Characteristics. Orta L, Klimstra DS, Qin J, Mecca P, Tang LH, Busam KJ, Shia J. Am J Surg Pathol. 2009 Apr 1. PMID: 19342947