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Genotoxic effects of systemic chemotherapy in cancer patients, with special focus on the relation between MSI, LOH and development of secondary cancers
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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 [en]
Chemotherapy, Genetic instability, Microsatellites instability, Loss of heterozygosity, Mismatch repair
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-92698ISBN: 978-91-7447-737-5 (print)OAI: oai:DiVA.org:su-92698DiVA: diva2:642619
Public defence
2013-09-27, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
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
List of papers
1. High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study
Open this publication in new window or tab >>High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-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.

Keyword
Chemotherapy, Breast cancer, Genetic instability, Microsatellites, Mismatch repair, Loss of heterozygosity
National Category
Genetics
Identifiers
urn:nbn:se:su:diva-83981 (URN)10.1186/1471-2407-12-373 (DOI)000311047500001 ()
Note

AuthorCount:7;

Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2017-12-06Bibliographically approved
2. Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients
Open this publication in new window or tab >>Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients
Show others...
(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
Chemotherapy, genetic instability, microsatellites, mismatch repair, secondary tumors
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-92696 (URN)
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
3. Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study
Open this publication in new window or tab >>Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study
2013 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 6, no 5, 1413-1420 p.Article in journal (Refereed) Published
Abstract [en]

Microsatellite instability (MSI) is a mutator phenotype that results from a defective mismatch repair (MMR) pathway. The present study examined the incidence of MSI and loss of heterozygosity (LOH) according to five markers from the panel of the National Cancer Institute (NCI) in 38 colorectal cancer (CRC) patients from the United Arab Emirates (UAE). MSI and LOH were analyzed using fragment analyses in a multiplex PCR setting on a capillary array electrophoresis platform. The expression of the MMR proteins, hMLH1 and hMSH2, was analyzed using immunohistochemistry. The cohort consisted of 17 females (44.7%) and 21 males (55.3%) with mean ages of 59.9 and 63.3 years, respectively. The overall MSI incidence was 31.3% (95% CI, 16.1-50.0), and included three patients with high MSI (MSI-H; 9.4%; 95% CI, 2.0-25.0) and seven patients with low MSI (MSI-L; 21.9%; 95% CI, 10.7-39). LOH was detected in three patients, while the remaining 25 patients (65.8%) showed no instability and were therefore classified as microsatellite stable (MSS). MSI was detected in the following screened markers: Bat25 in seven patients, Bat26 in three patients, adenomatous polyposis coli (APC; D5S346) in five patients, AFM093xh3 (D2S123) in two patients and Mfd15 (D17S250) in three patients. Of the five MSI-positive patients, four (80%) were evidently younger, aged 38, 48, 49 and 59 years, respectively. The MSI-H incidence (9.4%) was lower compared with that of other ethnic groups. In terms of the MMR proteins, hMLH1 expression was deficient in seven patients, of whom three were MSI-H patients, and hMSH2 was deficient in three patients. Fisher's exact test showed significant associations between hMLH1 and MSI when classified as MSS, MSI-L or MSI-H (P=0.0003). No such association was observed with abnormal MMR protein expression, age, cancer stage or gender.

Keyword
colorectal cancer, microsatellite instability, mismatch repair defects
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-95741 (URN)10.3892/ol.2013.1573 (DOI)000324858100046 ()
Note

AuthorCount:4;

Available from: 2013-11-06 Created: 2013-11-04 Last updated: 2017-12-06Bibliographically approved

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