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Breast cancer survival is associated with telomere length in peripheral blood cells
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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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.

Place, publisher, year, edition, pages
2008. Vol. 68, no 10, 3618-3623 p.
Keyword [en]
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: urn:nbn:se:umu:diva-9691DOI: 10.1158/0008-5472.CAN-07-6497PubMedID: 18483243OAI: oai:DiVA.org:umu-9691DiVA: diva2:149362
Available from: 2008-05-20 Created: 2008-05-20 Last updated: 2012-11-23Bibliographically approved
In thesis
1. Telomere length - inheritance pattern and role as a biomarker
Open this publication in new window or tab >>Telomere length - inheritance pattern and role as a biomarker
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Telomeres are repetitive TTAGGG structures ending each chromosome and thereby protecting its integrity. Due to the end-replication problem, telomeres shorten with each cell division. When reaching a critical telomere length (TL), the cells stop dividing and enter replicative senescence. It has been speculated that telomeres might regulate lifespan at the organism level but this hypothesis is controversial. However, telomeres in human blood cells do shorten with increasing age.

Telomerase is an enzyme capable of lengthen telomeres. It consists of a catalytic subunit, hTERT, and a RNA template, hTR. Telomerase is active in germ cells, stem cells, activated lymphocytes and highly proliferating epithelial cells while no activity is found in other somatic cells. One step in order to produce a tumour mass is that cancer cells need to have a limitless replicative potential and this can be achieved by activating telomerase. Most tumour cells express telomerase activity and hence, the enzyme is an interesting target for cancer therapy.

Telomere length is in part inherited. Two separate family cohorts were investigated to elucidate the inheritance pattern and a strong paternal inheritance was observed. In the larger, multifamily cohort spanning up to four generations, a weak correlation between the TL of the mother and the child was also found, as well as a significant correlation between grandparent-grandchild pairs. Interestingly, the heritable impact diminished with increasing age, indicating than non-heritable factors might influence TL during life.

A functional T to C transition polymorphism in the hTERT promoter was previously reported, showing that the -1327C/C genotype was correlated with shorter TL compared to the alternative genotypes in healthy individuals and in coronary artery disease patients. When investigating 226 myocardial infarction patients and 444 controls separately, no differences were observed regarding mean TL or increased attrition rate between the different genotypes.

TL in blood cells is shown to be altered in patients with certain types of solid tumours. In our breast cancer cohort, TL was a strong prognostic marker. Short telomeres were associated with increased survival, especially in young patients and in those with advanced tumours. It has been speculated that cancer patients might have a faster telomere attrition rate than controls but this has not been experimentally proven. Two blood samples from the same individual taken with 9-11 years interval was investigated. Some were diagnosed with a malignancy after the second blood draw. When comparing patients with controls, telomere attrition rate was not correlated to future tumour development. About one third of the individuals elongated their telomeres over a decade and the individual telomere attrition rate was telomere length dependent, showing an inverse correlation to TL at a highly significant level. This strongly suggests that the TL maintenance mechanism shown to provide protection for short telomeres in vitro is important also in human cells in vivo.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2008. 59 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1200
Keyword
telomere length, peripheral blood, inheritance, breast cancer, survival, polymorphism
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-1844 (URN)978-7264-620-9 (ISBN)
Public defence
2008-10-10, Betula, 6M, NUS, By 6M, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-09-19 Created: 2008-09-19 Last updated: 2009-05-06Bibliographically approved
2. 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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Svenson, UlrikaStegmayr, BirgittaTavelin, BjörnHenriksson, RogerLenner, PerRoos, Göran

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