Microsatellite instability

Growth inhibition by TGF- 3, associated with inhibition of c-myc, cdks, reduction in cyclin D1 levels, and inhibition of cdk-4-associated Rb kinase activity, as well as induction of cdk inhibitors pi5 and p27, has been noted in intestinal epithelial cells. Loss of responsiveness to growth inhibition from TGF- 3 occurs in many cell types including breast, colorectal carcinoma, and pancreatic carcinoma cells. Mutational inactivation of T 3RH represents one mechanism of this process, which in many cases, leads to the development of gastrointestinal cancer. Thirteen percent of colorectal carcinomas are thought to be associated with a replication error (RER) or microsatellite instability phenotype. Subsequent inactivation of T 3RII and... 

Genetic Familial prostate cancer is inherited in an autosomal dominant manner. Mutations in p53, Rb, E-cahedrin, a-catenin, androgen receptor, KAII, microsatellite instability, loss of heterozygocity at 1, 2q, 12p, 15q, 16p, and 16q. Candidate prostate cancer gene locus identified on chromosome 1. 

Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nature Med 1998 4[11] 1276 1280. 

Ionov, Y, Nowak N, Perucho M, Markowitz S, Cowell JK (2004) Manipulation of nonsense mediated decay identifies gene mutations in colon cancer Cells with microsatellite instability. Oncogene 23 639-645 Ito A, Lai CH, Zhao X, Saito S, Hamilton MH, Appella E, Yao TP (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20 1331-1340... 

Anthoney DA, Mcllwrath AJ, Gallagher WM, Edlin ARM, Brown R. Microsatellite instability, apoptosis and loss of p53 function in drug resistant tumor cells. Cancer Res 1996 56 1374—1381. 

Anne PR, Edmonston TB, Rose D, et al. Microsatellite instability predicts for tumor response in a prospective trial of preoperative 5-FU, CPT-11, and radiation for locally advanced rectal cancer [Abstract]. Int J Radiat Oncol Biol Phys 2000 48(3 Suppl) 121. 

Microsatellite instability (MSI) in the tumor caused by defeetive DNA mismateh repair has been associated with outeome to ehemotherapy (34). For example, a study of 320 Dukes B2 and C colon cancers treated with 5-FU therapy showed that MSI status was eorrelated with improved survival (p = O.OI) (35). MSI is also associated with a mutator phenotype that may lead to mutations in pharmaeogenetic markers, which would not be pieked up by screening the germline genome. 

Sinicrope FA, Rego RL, Hailing KC et al. Thymidylate synthase expression in colon carcinomas with microsatellite instability. Clin Cawcer Rex 2006 12 2738-2744. 

Ahuja N, Mohan AL, Li Q, et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res 1997 57 3370-3374. 

Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 2005 23 609-18. 

Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 2003 349 247-257. 

The instability of simple repeat sequences is called microsatellite instability (MSI), and it is used as a tool for the diagnosis of HNPCC. It is thought to be caused by... 

Perucho, M. (1996). Microsatellite instability the mutator that mutates the other mutator. Nature Med. 2,630-631. 

Loeb LA (1994) Microsatellite instability marker of a mutator phenotype in cancer. Cancer Research 54 5059-5063. 

Microsatellite instability is found to be a common feature of nearly all tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) (4,16). The majority of HNPCC cases arise through germline mutations in two genes, hMSH2 and hMLHl on chromosomes 2 and 3, which encode the human homologs of bacterial mismatch repair genes, MutS and MutL (17,18). Cells which display microsatellite instability are termed as having an RER+ phenotype, which stands for replication error (5). Such RER+ tumor cells have been shown to have defects in mismatch repair and possess a mutator phenotype (19). 

Below is given a protocol for PCR amplification of microsatellite sequences using internal radiolabelling and a touchdown protocol which has been successfully used to analyze microsatellite instability in human, mouse and canine DNA. 

Fig 1. Example of microsatellite instability at the locus D17S796 in twenty subclones of the cisplatin resistant cell line A2780/cp70. The PCR products were fractionated on a 6% denaturing polyacrylamide gel and detected by autoradiography. The first four lanes show the M13 sequencing ladder used as a molecular-weight marker. Reproduced with authors permission. 

Patel, U., Grundfest-Broniatowski, S., Gupta, M., and Banerjee, S. (1994) Microsatellite instabilities at five chromosomes in primary breast tumors. Oncogene 9,3695-3700. 

Eshleman, J. R. and Markowitz, S. D. (1995) Microsatellite instability in inherited and sporadic neoplasms. Curr. Opin. Oncol. 7, 83-89. 

Hailing KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Nad Cancer Inst 1999 91 1295-303. 

Souza R, Appel R, Yin J, Wang S, Smolinski KN, Abraham JM, et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet 1996 14 255-7. 

Colon cancer is one of the main causes of cancer mortality in Western societies [150]. About 15-20% of colorectal tumors are causally determined by inheritance of genetic alterations such as the hereditary nonpolyposis colorectal cancer (HNPCC) and the syndrome familial adenomatous polyposis (FAP) [151,152]. Microsatellite instability, a characteristic of HNPCC, is caused by mutations in the genes essential for mismatch repair. The loss of mismatch repair has several consequences most crucially, the loss of proofreading and correction of small deletions and insertions. FAP is a rare autosomal dominant syndrome caused by an inherited mutation in the APC gene. The disease is characterized by the development of multiple colorectal adenomas, numbering from a few polyps to several thousands. 

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