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MTDH genetic variants in colorectal cancer patients
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Institute of Pathology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer (CRC) is the second most common cancer worldwide and accounts for around 8.5% of all cancer related death. The colorectal carcinogenesis is a complex process of genetic alterations. For better prognosis it is very important to understand the composition of genetic alterations in a tumor. Astrocyte elevated gene-1 (AEG-1) has been shown to be overexpressed in CRC and had prognostic significance. The aim of this study was to determine the frequency and the spectrum of MTDH variants, and their relationship to clinicopathological variables in CRC patients. The study included tumors from 356 unselected CRC patients. Mutation analysis of the MTDH gene, including coding region and adjacent intronic sequences, was performed by direct DNA sequencing. We detected 42 intronic variants, whereby 25 were novel. Furthermore, we found eight exonic variants of which four, one missense (c.977C>G) and three frameshift mutations (c.533delA, c.1731delA, c.1340dupA), were novel. In silico prediction analyses revealed that four variants c.232G>T, c.533delA, c.1340dupA and c.1731delA were deleterious. There were no correlations between the MTDH variants and tumor stage, differentiation or patient survival. The detection of pathogenic mutations and alterations in functional protein domains suggest their involvement in tumorigenesis, although none of the variants had prognostic potential.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016. Vol. 6
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-121865DOI: 10.1038/srep23163ISI: 000372164500001OAI: oai:DiVA.org:liu-121865DiVA: diva2:860235
Note

Funding agencies:  Swedish Cancer Foundation; Swedish Research Council, and the Health Research Council in South-East Sweden; Ministry of Health, Czech Republic [RVO 64165]

Vid tiden för disputation förelåg publikationen som manuskript

Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2016-04-13Bibliographically approved
In thesis
1. Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
Open this publication in new window or tab >>Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The incidence and death rate for colorectal cancer (CRC) decreased during the last decades as a result of improved diagnosis and treatment. However, CRC is still the third most common cancer in the world, and is responsible for about 700 000 deaths per year worldwide. Therefore, it is important to understand the mechanisms of the disease, and to find molecular markers in order to further improve prognosis, and to develop new treatment strategies. Astrocyte elevated gene-1 (AEG-1), encoded by the MTDH gene, is upregulated in a variety of cancers. AEG-1 is involved in cell survival, proliferation, migration, invasion, metastasis,  angiogenesis, and apoptosis.

The aim of this thesis was to investigate the role of AEG-1 in CRC development and the impact of AEG-1 on the response of radiation treatment. The AEG-1 expression, analysed in different CRC patient cohorts in paper I and III, was increased in the tumour tissue compared with the normal mucosa, and higher in the lymph node and liver metastases. Expression analyses in normal and cancer cell lines confirmed these results. In paper II, sequencing of the complete coding sequence of the MTDH gene in 356 patients revealed 50 single nucleotide variants of which 29 were novel. Eight exonic variants were detected, including three frameshift variants which were probably pathogenic, and two missense variants located in functional protein regions. There was no correlation of the MTDH variants or AEG-1 expression with the patient survival. In paper III, we also investigated the impact of AEG-1 on the response to radiation treatment. AEG-1 knockdown decreased the cellular survival upon radiation in several colon cancer cell lines. The AEG-1 expression was furthermore analysed in patients, which were randomised to either surgery alone or preoperative radiotherapy (RT), followed by surgery. The rectal cancer patients with high AEG-1 expression treated with RT had a significantly higher risk of developing distant recurrence and had a worse disease free survival, likely due to the metastasis promoting properties of AEG-1. In paper IV, the impact of AEG-1 knockdown and radiation on migration and invasion was analysed in colon cancer cell lines in vitro  and in a novel zebrafish model in vivo. AEG-1 knockdown decreased migration and invasion, and radiation-enhanced migration and invasion in the cell lines tested.

In conclusion, our data suggest that AEG-1 is involved in CRC development, while MTDH gene variants probably not have a high clinical importance in CRC. Furthermore, AEG-1 is a promising radiosensitising target and a valuable prognostic marker in CRC. We further showed that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced cell migration and invasion.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 84 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1476
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-121868 (URN)10.3384/diss.diva-121868 (DOI)978-91-7685-970-4 (print) (ISBN)
Public defence
2015-11-13, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2016-04-01Bibliographically approved

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Gnosa, SebastianTicha, IvanaHaapaniemi, StaffanSun, Xiao-Feng
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Division of Clinical SciencesFaculty of Medicine and Health SciencesDepartment of Surgery in NorrköpingDepartment of Oncology
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