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Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0001-5790-8915
Management of Natural Conservation , UAE.
Oncology department, Tawam Hospital, UAE.
Pathology Department, Tawam hospital, UAE.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives: The aim of the studywas 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. 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, whereas18.8%, 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.

Keyword [en]
Chemotherapy, genetic instability, microsatellites, mismatch repair, secondary tumors
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-92696OAI: oai:DiVA.org:su-92696DiVA: diva2:640976
Projects
Genotoxic effects of systemic chemotherapy in cancer patients, with special focus on the relation between MSI, LOH and development of secondary cancers
Available from: 2013-08-15 Created: 2013-08-15 Last updated: 2013-08-23Bibliographically approved
In thesis
1. Genotoxic effects of systemic chemotherapy in cancer patients, with special focus on the relation between MSI, LOH and development of secondary cancers
Open this publication in new window or tab >>Genotoxic effects of systemic chemotherapy in cancer patients, with special focus on the relation between MSI, LOH and development of secondary cancers
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic chemotherapy results in both phenotypic and genotypic side effects. Genotoxicity posed by chemotherapy is a major concern since it induces DNA damage and instability in the patients’ genome. Chemotherapy-related genetic instability is thought to be the cause of some secondary tumors especially the acute myeloid leukemia and/or myelodysplasia, which affect 2-15% of patients receiving chemotherapy. Microsatellites are polymorphic repetitive DNA sequences that undergo changes in their length due to instability. Microsatellite instability (MSI) and loss of heterozygosity (LOH) are the main features of chemotherapy-related genotoxicity.

Using a panel of five and ten microsatellite markers, MSI and LOH were evident in blood specimens collected from patients with breast cancer or other solid tumors, respectively. In addition, the expression of mismatch repair (MMR) proteins was analyzed in tumor tissues using immunohistochemistry. The results showed a decreased expression of the following proteins, human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), human mutS homolog 6 (hMSH6), human post-meiotic segregation increased 2 (hPMS2), and p53 tumor suppressor protein (p53) after completion of chemotherapy. The clinical complications resistance to chemotherapy, recurrence of primary tumor, and development of secondary tumors were also studied. Incidence of MSI and LOH detected in Tp53-Alu, the marker related to the TP53 tumor suppressor gene, was noticeable compared to the other studied microsatellites. Statistical analysis showed a significant correlation between alterations in microsatellites in blood specimens (MSI and LOH) and MMR expression in tumor tissues. Another strong correlation observed was between MSI, LOH and MMR and the recurrence of primary tumor and/or development of secondary cancers.

The findings support the hypothesis that MSI and LOH play an important role in tumorigenesis of primary and secondary tumors, and that MSI and LOH may be used as screening tools for early prediction of chemotherapy-related side effects, especially resistance to treatment, recurrence of primary cancer and generation of secondary tumors.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 105 p.
Keyword
Chemotherapy, Genetic instability, Microsatellites instability, Loss of heterozygosity, Mismatch repair
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-92698 (URN)978-91-7447-737-5 (ISBN)
Public defence
2013-09-27, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
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Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Mansuscript. Paper 3: Accepted.

Available from: 2013-09-05 Created: 2013-08-15 Last updated: 2013-11-06Bibliographically approved

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