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Telomere length - inheritance pattern and role as a biomarker
Umeå University, Faculty of Medicine, Medical Biosciences.
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 [en]
telomere length, peripheral blood, inheritance, breast cancer, survival, polymorphism
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1844ISBN: 978-7264-620-9 OAI: oai:DiVA.org:umu-1844DiVA: diva2:142181
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
List of papers
1. Telomere length and heredity: Indications of paternal inheritance.
Open this publication in new window or tab >>Telomere length and heredity: Indications of paternal inheritance.
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2005 (English)In: Proceedings of the National Academy of Science of the United States of America, ISSN 0027-8424, Vol. 102, no 45, 16374-16378 p.Article in journal (Refereed) Published
Keyword
Adult, Age Factors, Aged, Aged; 80 and over, DNA-Binding Proteins/genetics, Female, Heredity, Humans, Male, Middle Aged, Sex Characteristics, Telomerase/genetics, Telomere
Identifiers
urn:nbn:se:umu:diva-15227 (URN)10.1073/pnas.0501724102 (DOI)16258070 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11Bibliographically approved
2. The paternal influence on telomere length is stronger than the maternal and the heritable impact diminishes with age
Open this publication in new window or tab >>The paternal influence on telomere length is stronger than the maternal and the heritable impact diminishes with age
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3466 (URN)
Available from: 2008-09-19 Created: 2008-09-19 Last updated: 2011-05-17Bibliographically approved
3. hTERT (-1327)T/C polymorphism is not associated with age-related telomere attrition in peripheral blood.
Open this publication in new window or tab >>hTERT (-1327)T/C polymorphism is not associated with age-related telomere attrition in peripheral blood.
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2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, Vol. 358, no 1, 215-218 p.Article in journal (Refereed) Published
Keyword
Aged, Aging/*genetics, Female, Genomic Instability, Genotype, Humans, Male, Middle Aged, Myocardial Infarction/blood/*genetics, Polymorphism; Genetic, Sweden, Telomerase/blood/*genetics, Telomere/*genetics/ultrastructure
Identifiers
urn:nbn:se:umu:diva-7567 (URN)10.1016/j.bbrc.2007.04.099 (DOI)17481586 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11Bibliographically approved
4. 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
5. Human blood cell telomere attrition rate is telomere length dependent but not associated to tumour development.
Open this publication in new window or tab >>Human blood cell telomere attrition rate is telomere length dependent but not associated to tumour development.
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3469 (URN)
Available from: 2008-09-19 Created: 2008-09-19 Last updated: 2011-05-17Bibliographically approved

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