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Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
2009 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 7, 2896-2901 p.Article in journal (Refereed) Published
Abstract [en]

Telomeres are repetitive structures located at chromosome ends. Previous studies have indicated that blood cell telomeres may serve as a biomarker for cancer risk. In addition, we recently reported that blood telomere length predicted survival in patients with breast cancer. In the present study, we examined whether blood telomere length may act as a predictor for survival in newly diagnosed patients with clear cell renal cell carcinoma. Furthermore, we analyzed telomere length in tumor samples and corresponding kidney cortex. Relative telomere length (RTL) was measured on extracted DNA using real-time PCR. Interestingly, and in line with our previous findings in breast cancer, patients with the longest blood telomeres (fourth quartile) had a significantly worse prognosis compared with patients with shorter blood RTL (P=0.005). A highly significant association was found between long blood telomeres and a poor outcome in patients with nonmetastatic disease (P<0.001), whereas patients with distant metastases had a poor survival regardless of blood RTL (P=0.432). No correlations were found between blood RTL and various clinical variables, such as erythrocyte sedimentation rate, hemoglobin, and thrombocyte count. Multivariate Cox regression analysis verified long blood RTL as an independent negative prognostic marker. In contrast, telomere length in kidney cortex and tumor tissue did not predict survival. In conclusion, our results indicate that blood RTL may predict kidney cancer survival, with implications for future treatment strategies.

Place, publisher, year, edition, pages
2009. Vol. 69, no 7, 2896-2901 p.
Keyword [en]
Renal cell carcinoma, telomere length, peripheral blood, prognosis
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-26482DOI: 10.1158/0008-5472.CAN-08-3513PubMedID: 19318563OAI: oai:DiVA.org:umu-26482DiVA: diva2:271435
Available from: 2009-10-12 Created: 2009-10-12 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Telomere length: dynamics and role as a biological marker in malignancy
Open this publication in new window or tab >>Telomere length: dynamics and role as a biological marker in malignancy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Telomeres are protective structures at the end of our chromosomes, composed of multiple repeats of the DNA sequence TTAGGG. They are essential for maintaining chromosomal stability by preventing damage and degradation of the chromosome ends. Telomeres are normally shortened with each cell division until a critical length is reached, at which stage cell cycle arrest is induced. Telomere shortening can be prevented in the presence of the telomere-­‐elongating enzyme telomerase. Telomerase is expressed during embryogenesis and in certain normal cell types, but most somatic cells exhibit undetectable levels of telomerase activity. In contrast, most cancer cells express telomerase enabling them to proliferate indefinitely.

There is a search for reliable molecular markers that can be used to help predict cancer risk and outcome. The interest of investigating telomere length as a potential biomarker in malignancy has grown rapidly, and both tumors and normal tissues have been in focus for telomere length measurements. In this thesis, telomere length was investigated in breast cancer patients and in patients with renal cell carcinoma (RCC). The breast cancer patients were found to have significantly longer mean telomere length in peripheral blood cells (i.e. immune cells) compared to a tumor-­‐free control group. Moreover, patients with the longest blood telomere length had a significantly worse outcome compared to patients with shorter blood telomeres. In a patient group with clear cell RCC, telomere length was investigated in peripheral blood cells, in tumors and in corresponding kidney cortex. Again, patients with the longest blood telomere length had a significantly worse prognosis compared to those with shorter blood telomeres. In contrast, telomere length in tumor and kidney cortex tissues did not predict outcome per se.

Immunological components may play a role in telomere length dynamics as well as in cancer development. We aimed to investigate a possible association between telomere length and certain immunological parameters, including various cytokines and peripheral levels of a blood cell type with suppressor function [regulatory T cells (Tregs)]. In our patients with clear cell RCC, three cytokines correlated significantly with tumor telomere length, but not with telomere length in peripheral blood cells. In a separate patient group with various RCC tumors, blood telomere length correlated positively with the amount of Tregs. It might be speculated that a subset of patients with long blood telomeres has a less efficient immune response due to high Treg levels, contributing to a worse prognosis.

Another aim of this thesis was to explore telomere length changes over time. Evaluation of blood samples collected at a 6-­‐month interval from 50 individuals, showed that half of the participants experienced a decline in mean telomere length during the time period. This group had longer telomere length at baseline compared to those who demonstrated increased/stable telomere length. In a separate group of five blood donors, a remarkable drop in telomere length was detected in one donor over a 6-­‐month period, whereas the other donors exhibited only small fluctuations in telomere length.

In conclusion, the results of this thesis indicate that blood telomere length has potential to act as an independent prognostic marker in malignancy. Adding to the complexity is the fact that changes in blood telomere length might occur within relatively short time spans, indicating that telomere length is a dynamic character. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2012. 53 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1522
Keyword
Telomere length, peripheral blood, immune cells, breast cancer, renal cell carcinoma, biological marker
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-61549 (URN)978-91-7459-481-2 (ISBN)
Public defence
2012-12-14, Sal B, 9tr, By 1D - Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-11-23 Created: 2012-11-19 Last updated: 2012-12-16Bibliographically approved

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