title: Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients.
abstract: BACKGROUND
  The inevitable side effects of the currently used chemotherapy are associated with serious syndromes. Genotoxic effects and consequent genetic instability may play an important role in these syndromes. The aim of the study was to evaluate chemotherapy-related microsatellite instability (MSI), loss of heterozygosity (LOH), and loss of mismatch repair (MMR) expression in solid tumor patients.
  
  
  METHODS
  Samples were collected from 117 de novo patients with solid tumors of different origins. Specimens, taken pre- and post-treatment, were screened for MSI and LOH in 10 microsatellite sequences in blood, and expression of five MMR proteins were analyzed in cancer tissues using immunohistochemistry. Statistical analysis included the use of; Fisher's exact test, Chi Square, and an inter-rater reliability test using Cohen's kappa coefficient.
  
  
  RESULTS
  Microsatellite analysis showed that 66.7% of the patients had MSI, including 23.1% high-positive MSI and 43.6% low-positive MSI. A large portion (41%) of the patients exhibited LOH in addition to MSI. MSI and LOH were detected in seven loci in which incidence rates ranged from 3.8% positive for Bat-26 to 34.6% positive for Tp53-Alu. Immunohistochemistry revealed that human mutL homolog 1 (hMLH1) expression was deficient in 29.1% of the patients, whereas 18.8%, 23.9%, 13.4%, and 9.7% were deficient for human mutS homolog 2 (hMSH2), P53, human mutS homolog 6 (hMSH6) and human post-meiotic segregation increased 2 (hPMS2), respectively. There was a significant correlation between MSI and LOH incidence in Tp53-Alu, Mfd41, and APC with low or deficient expression of hMLH1, hMSH2, and P53. A significant association between MSI and LOH, and incidence of secondary tumors was also evident.
  
  
  CONCLUSIONS
  The negative correlation between MMR expression, MSI, and LOH and increased resistance to anti-cancer drugs and development of secondary cancers demonstrates a useful aid in early detection of potential chemotherapy-related side-effects. The diagnostic value demonstrated in our earlier study on breast cancer patients was confirmed for other solid tumors.
authors.affiliation: Department of Molecular Biosciences, the Wenner-Gren Institute (MBW), Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Nasir
authors.initials: N
authors.lastname: Kamat
authors.affiliation: Department of Genetics Research, Management of Natural Conservations, AlAin City, UAE.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Khidhir
authors.affiliation: Department of Oncology and Hematology, Tawam Hospital, AlAin City, UAE.
authors.forename: Sabir
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, Utah 84112 USA.
authors.forename: Mouied M
authors.initials: MM
authors.lastname: Alashari
authors.affiliation: Department of Molecular Biosciences, the Wenner-Gren Institute (MBW), Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Rannug
keywords: Chemotherapy; Genetic instability; Microsatellites; Mismatch repair; Secondary tumors