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Telomere length: dynamics and role as a biological marker in malignancy
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. (Göran Roos)
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 [en]
Telomere length, peripheral blood, immune cells, breast cancer, renal cell carcinoma, biological marker
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-61549ISBN: 978-91-7459-481-2 (print)OAI: oai:DiVA.org:umu-61549DiVA: diva2:570563
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
List of papers
1. Breast cancer survival is associated with telomere length in peripheral blood cells
Open this publication in new window or tab >>Breast cancer survival is associated with telomere length in peripheral blood cells
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2008 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 10, 3618-3623 p.Article in journal (Refereed) Published
Abstract [en]

Telomeres are essential for maintaining chromosomal stability. Previous studies have indicated that individuals with shorter blood telomeres may be at higher risk of developing various types of cancer, such as in lung, bladder, and kidney. We have analyzed relative telomere length (RTL) of peripheral blood cells in relation to breast cancer incidence and prognosis. The study included 265 newly diagnosed breast cancer patients and 446 female controls. RTL was measured by real-time PCR, and our results show that the patient group displayed significantly longer telomeres compared with controls (P < 0.001). Age-adjusted odds ratios (OR) for breast cancer risk increased with increasing telomere length, with a maximal OR of 5.17 [95% confidence interval (95% CI), 3.09-8.64] for the quartile with the longest telomeres. Furthermore, RTL carried prognostic information for patients with advanced disease. Node positive (N+) patients with short telomeres (</=median) showed an increased survival compared with N+ patients with long telomeres (P = 0.001). For patients with ages <50 years with tumors >16 mm (median tumor diameter), short telomeres were associated with a significantly better outcome than longer telomeres (P = 0.006). Cox regression analysis showed that long RTL was a significant independent negative prognostic factor (hazards ratio, 2.92; 95% CI, 1.33-6.39; P = 0.007). Our results indicate that blood RTL may serve as a prognostic indicator in breast cancer patients with advanced disease.

Keyword
Age Factors, Aged, Breast Neoplasms/*blood/*mortality, Chromosomal Instability, Female, Humans, Middle Aged, Odds Ratio, Prognosis, Proportional Hazards Models, Reverse Transcriptase Polymerase Chain Reaction, Risk, Telomere/*ultrastructure, Treatment Outcome, Tumor Markers; Biological/*metabolism
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-9691 (URN)10.1158/0008-5472.CAN-07-6497 (DOI)18483243 (PubMedID)
Available from: 2008-05-20 Created: 2008-05-20 Last updated: 2012-11-23Bibliographically approved
2. Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma
Open this publication in new window or tab >>Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma
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.

Keyword
Renal cell carcinoma, telomere length, peripheral blood, prognosis
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-26482 (URN)10.1158/0008-5472.CAN-08-3513 (DOI)19318563 (PubMedID)
Available from: 2009-10-12 Created: 2009-10-12 Last updated: 2012-11-23Bibliographically approved
3. Telomere length in relation to immunological parameters in patients with renal cell carcinoma
Open this publication in new window or tab >>Telomere length in relation to immunological parameters in patients with renal cell carcinoma
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, e55543- p.Article in journal (Refereed) Published
Abstract [en]

Over the last decade, telomere length (TL) has gained attention as a potential biomarker in cancer disease. We previously reported that long blood TL was associated with a poorer outcome in patients with breast cancer and renal cell carcinoma. Based on these findings, we hypothesized that certain immunological components may have an impact on TL dynamics in cancer patients. One aim of the present study was to investigate a possible association between serum cytokines and TL of peripheral blood cells, tumors and corresponding kidney cortex, in patients with clear cell renal cell carcinoma. For this purpose, a multiplex cytokine assay was used. Correlation analysis revealed significant positive correlations between tumor TL and peripheral levels of three cytokines (IL-7, IL-8 and IL-10). In a parallel patient group with various kidney tumors, TL was investigated in whole blood and in immune cell subsets in relation to peripheral levels of regulatory T cells (Tregs). A significant positive association was found between whole blood TL and Treg levels. However, the strongest correlation was found between Tregs and TL of the T lymphocyte fraction. Thus, patients with higher Treg levels displayed longer T cell telomeres, which might reflect a suppressed immune system with fewer cell divisions and hence less telomere shortening. These results are in line with our earlier observation that long blood TL is an unfavorable prognostic factor for cancer-specific survival. In summary, we here show that immunological components are associated with TL in patients with renal cell carcinoma, providing further insight into the field of telomere biology in cancer. 

Place, publisher, year, edition, pages
Public Library Science, 2013
Keyword
Telomere length, peripheral blood, immune cells, cytokines, renal cell carcinoma
National Category
Immunology in the medical area Other Basic Medicine Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-61388 (URN)10.1371/journal.pone.0055543 (DOI)23383336 (PubMedID)
Note

Originally included in thesis in manuscript form

Available from: 2012-11-12 Created: 2012-11-12 Last updated: 2017-12-07Bibliographically approved
4. Blood cell telomere length is a dynamic feature
Open this publication in new window or tab >>Blood cell telomere length is a dynamic feature
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, e21485- p.Article in journal (Refereed) Published
Abstract [en]

There is a considerable heterogeneity in blood cell telomere length (TL) for individuals of similar age and recent studies have revealed that TL changes by time are dependent on TL at baseline. TL is partly inherited, but results from several studies indicate that e.g. life style and/or environmental factors can affect TL during life. Collectively, these studies imply that blood cell TL might fluctuate during a life time and that the actual TL at a defined time point is the result of potential regulatory mechanism(s) and environmental factors. We analyzed relative TL (RTL) in subsequent blood samples taken six months apart from 50 individuals and found significant associations between RTL changes and RTL at baseline. Individual RTL changes per month were more pronounced than the changes recorded in a previously studied population analyzed after 10 years' follow up. The data argues for an oscillating TL pattern which levels out at longer follow up times. In a separate group of five blood donors, a marked telomere loss was demonstrated within a six month period for one donor where after TL was stabilized. PCR determined RTL changes were verified by Southern blotting and STELA (single telomere elongation length analysis). The STELA demonstrated that for the donor with a marked telomere loss, the heterogeneity of the telomere distribution decreased considerably, with a noteworthy loss of the largest telomeres. In summary, the collected data support the concept that individual blood cell telomere length is a dynamic feature and this will be important to recognize in future studies of human telomere biology.

Place, publisher, year, edition, pages
San Francisco: Public Library of Science, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-57221 (URN)10.1371/journal.pone.0021485 (DOI)21720548 (PubMedID)
Available from: 2012-07-10 Created: 2012-07-10 Last updated: 2017-12-07Bibliographically approved

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