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Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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.

Place, publisher, year, edition, pages
2013. Vol. 6, no 5, 1413-1420 p.
Keyword [en]
colorectal cancer, microsatellite instability, mismatch repair defects
National Category
Genetics
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-95741DOI: 10.3892/ol.2013.1573ISI: 000324858100046OAI: oai:DiVA.org:su-95741DiVA: diva2:662327
Note

AuthorCount:4;

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

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