General Biology of Cancer and Metastasis
Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George in The Scientific Basis of Urology, 2010
Patients with HNPCC have tumors in which there are a large number of microsatellites in the genome of the tumor. Microsatellites are short (two to four nucleotides; e.g., CACA on one strand and GTGT on the other), noncoding, tandem repeats of DNA, which are found throughout the genome and which show pronounced polymorphism. Abnormalities in microsatellites have been found in Huntington’s chorea, the fragile X syndrome, and spinobulbar atrophy, in which, over several generations, there is a progressive expansion of the nucleotide repeats in the genes of interest. This leads to disease, but it is found that with each succeeding generation there is an increased severity of the disease because the microsatellites become longer. This phenomenon is called genetic anticipation. In HNPCC, microsatellite instability is thought to be the result of failure to correct replication errors that occur during cell division. This failure is caused by hereditary defects in the enzymes responsible for the repair of these replication mismatch errors. These enzymes include MSH2, MLH1, GTBP, and PMS1.
Methods for Genetic Testing I
Peter G. Shields in Cancer Risk Assessment, 2005
The assessment of microsatellite instability is a marker for altered DNA repair. Analysis of tumors indicates that there are increased numbers of repeat DNA sequences that are not present in the patient’s nontumor tissues. Thus, there were errors during DNA replication. Mono-, di-, tri-, quadra-, and pentanucleotide repeats are ubiquitous in human genomes, probably due to replication errors through evolution, but then in tumors, these loci are possible sites for more slippage during replication. Microsatellite instability is one of the common genetical alterations in human tumors where the repeats might be more or less. They are caused by somatic changes, and also occur in people with genetical mismatch repair deficiencies in hereditary nonpolyposis colorectal cancer. The germline mutations of MLH1 and MSH2 (PMS1, PMS2, MSH6) have been most commonly documented in some, not all, families with high rates of colon cancer (55,56) . Target molecules can be surrogate markers for microsatellite instability (replication error type). These include TGF beta II receptor, MSH3, MSH6, IGF II receptor, and Bax gene (57). The alterations in repetitive sequences in the coding exon of these genes can be predictive of progress.
Adjuvant Therapy of Colon Cancer
Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams in Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
In stage II colon cancer, there is a small survival advantage with adjuvant chemotherapy of approximately 3%–5%. However, the majority of colorectal cancer patients in stage II do not benefit from adjuvant therapy. Where there is a treatment request in stage II, a microsatellite analysis should be performed. Patients with high microsatellite instability (approximately 15%–20% of patients in stage II), have an excellent prognosis which cannot be improved by a 5-FU-based therapy. Consequently, patients within this category do not need adjuvant therapy, but if there is a request to treat patients with microsatellite stable low-risk stage II tumours, six-month treatment preferably with capecitabine may be recommended. An oxaliplatin-containing therapy is not indicated.
Current and future molecular diagnostics of gastric cancer
Published in Expert Review of Molecular Diagnostics, 2019
Rachel Sin-Yu Choi, Wing Yin Xenia Lai, Lok Ting Claire Lee, Wing Lam Christa Wong, Xiao Meng Pei, Hin Fung Tsang, Joel Johnson Leung, William Chi Shing Cho, Man Kee Maggie Chu, Elaine Yue Ling Wong, Sze Chuen Cesar Wong
Genetic instability results in an accumulation of genetic abnormalities during early stages of gastric carcinogenesis [9]. Classification of genomic instability includes microsatellite instability (MSI) resulted from dysfunction of DNA mismatch pair [3,9]. High-frequency microsatellite instability (MSI-H) describes the condition in which at least two of the five microsatellite loci exhibit errors in replication whereas replication errors of a single locus are known as low-frequency MSI (MSI-L) [26]. MSI is thought to contribute to the pathogenesis of hereditary non-polyposis colorectal cancer (HNPCC) and sporadic GC. MSI-H is shown in only 4% of stomach carcinomas, especially in well-differentiated type in elderly patients. In contrast, MSI-L is observed in approximately 30% of primary GC which is often at the early stage [9] and precancerous lesions such as intestinal metaplasia and adenomas [27].
Immune checkpoint inhibitors: a new era for esophageal cancer
Published in Expert Review of Anticancer Therapy, 2019
Li-Qing Zou, Xi Yang, Yi-Da Li, Zheng-Fei Zhu
Normally, intrinsic errors in DNA replication are corrected by the mismatch – repair (MMR) machinery. Thus, mutations in MMR genes in tumor cells can cause a large number of mutations. Microsatellite instability (MSI) is inversely correlated with the ability to repair DNA errors, and has been demonstrated to have a strong association with response to ICIs [15]. Nevertheless, we still need to notice the frequency of microsatellite instability high(MSI-H)or mismatch repair deficiency (dMMR) is fairly low even though the exact frequency varies from study to study. Ning Lua et al. [16] examined alterations in microsatellite markers in laser capture microdissected (LCM) endoscopic biopsies in 22 ESCC patients and found 4 specimens with MSI-H. Araki K et al. [17] analyzed MSI in 50 Japanese and 50 Chinese ESCC patients and found the frequencies of MSI in the Chinese and Japanese patients were 4% and 8%, with all the alterations mild (within two base pairs) and observed in a limited number of markers. Hiroaki Shiraishi et al. [18] examined 26 ESCC and 12 EAC cases, while only one EAC was MSI-H. Jian-Chun Cai et al. [19] assessed 23 ESCC and 18 EAC cases and determined 6 ESCC and 3 EAC patients with MSI-H. In summary, the ability to predict ICIs treatment response and its low frequency of MSI/MMR should both be noted.
Experience of mismatch repair/microsatellite instability (MMR/MSI) testing among patients with advanced/metastatic colorectal cancer in the US
Published in Current Medical Research and Opinion, 2020
Jennifer Eriksson, Mayur Amonkar, Gemma Al-Jassar, Jeremy Lambert, Mia Malmenäs, Monica Chase, Lucy Sun, Linda Kollmar, Michelle Vichnin
CRC is caused by several genetic mutations and epigenetic changes in the epithelial cells found in the lining of the colon and rectum. Mismatch repair (MMR)/microsatellite instability (MSI) testing is one of the genetic testing tools that is used for characterizing CRC tumors at a molecular level. Microsatellite instability is used as a marker for the presence of deficient DNA mismatch repair activity (dMMR), which is caused by mutation in the MMR genes (MLH1, MSH2, MSH6, and PMS2) [3]. Approximately 15% of stage II/III CRC patients have MSI status whereas only 4–5% of stage IV CRC are dMMR [4,5]. CRC tumors that are associated with MSI have distinctive features. They tend to arise in the proximal colon [6], differentiate poorly and have abundant lymphocytic infiltrate [7]. In contrast to patients with microsatellite stable tumors, early stage patients with MSI tumors have a better stage-adjusted survival or prognosis [8] whereas patients with metastatic tumors have been shown to present with poorer survival rates [9–12]. It has been shown that 5-fluorouracil-based adjuvant chemotherapy is beneficial for patients with microsatellite stable tumors but not for patients with MSI tumors [13,14].
Related Knowledge Centers
- DNA Mismatch Repair
- DNA Replication
- Microsatellite
- Mutation
- Phenotype
- Polymerase
- Polymerase Chain Reaction
- Genetics
- Insertion
- Deletion