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High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
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2012 (English)In: BMC Cancer, ISSN 1471-2407, Vol. 12, 373- p.Article in journal (Refereed) Published
Abstract [en]

Background: The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. Methods: A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4-5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. Results: A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established. Conclusion: Our results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.

Place, publisher, year, edition, pages
2012. Vol. 12, 373- p.
Keyword [en]
Chemotherapy, Breast cancer, Genetic instability, Microsatellites, Mismatch repair, Loss of heterozygosity
National Category
URN: urn:nbn:se:su:diva-83981DOI: 10.1186/1471-2407-12-373ISI: 000311047500001OAI: diva2:578004


Available from: 2012-12-17 Created: 2012-12-17 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.
Chemotherapy, Genetic instability, Microsatellites instability, Loss of heterozygosity, Mismatch repair
National Category
Research subject
Molecular Genetics
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)

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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