☆ 4.4 Review

Telomere length and cancer risk: finding Goldilocks

BIOGERONTOLOGY (2023)

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Article Genetics & Heredity

Clinical genetic counseling and translation considerations for polygenic scores in personalized risk assessments: A Practice Resource from the National Society of Genetic Counselors

Hannah Wand et al.

Summary: Polygenic scores (PGS) have potential for personalized risk assessments and population health screening, but there is no consensus on best practices and clinical utility. Despite this, individuals can access their PGS information through various sources. Therefore, educational resources are needed for clinicians encountering PGS information.

JOURNAL OF GENETIC COUNSELING (2023)

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Article Multidisciplinary Sciences

Heritable defects in telomere and mitotic function selectively predispose to sarcomas

Mandy L. Ballinger et al.

Summary: Cancer genetics has focused on epithelial malignancies, but this study explores specific pathways related to sarcomas, rare malignancies derived from embryonic mesoderm. Germline sequencing of sporadic cases and healthy controls reveals two sarcoma-specific pathways involved in mitotic and telomere functions. Centrosome gene variants are linked to specific tumors, while heritable defects in the shelterin complex increase susceptibility to sarcomas, melanomas, and thyroid cancers. These findings highlight the role of heritable defects in mitotic and telomere biology in sarcoma risk.

SCIENCE (2023)

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Article Multidisciplinary Sciences

High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform

Cheng-Yong Tham et al.

Summary: The authors developed a method using single-molecule real-time (SMRT) sequencing to capture and accurately analyze the length of telomeres, addressing challenges in quantifying telomere length at the nucleotide level. Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes, and their progressive shortening is a promising biomarker for age-associated diseases. The workflow involved capturing telomeres using new telobaits and measuring their length accurately with high resolution using SMRT sequencing. Results showed the heterogeneity of telomeric variant sequences (TVSs), which disrupt the continuity of the canonical telomere repeats and affect telomere protection.

NATURE COMMUNICATIONS (2023)

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Review Cell Biology

Does oxidative stress shorten telomeres in vivo? A meta-analysis

Emma Armstrong et al.

Summary: Telomere attrition, a hallmark of ageing, is not consistently affected by oxidative stress in living organisms, according to a meta-analysis of 37 studies. However, a subset of studies using a specific telomere measurement method showed a significant correlation between oxidative stress and telomere attrition. Additionally, intervention studies manipulating oxidative stress had a significant effect on telomere dynamics.

AGEING RESEARCH REVIEWS (2023)

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Review Cell Biology

Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies

Boran Chen et al.

Summary: This systematic review and meta-analysis of Mendelian randomization studies found that leukocyte telomere length (LTL) is associated with various health-related outcomes. Longer LTL is causally related to increased risk of neoplasms, excessive or abnormal growth outcomes, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Conversely, shorter LTL is causally related to coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Genetically determined LTL is also associated with specific neoplastic and non-neoplastic diseases. Further research is needed to understand the underlying mechanisms and explore the potential applications of telomere length in prediction, prevention, and treatment.

AGING CELL (2023)

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Article Hematology

The distribution and accumulation of the shortest telomeres in telomere biology disorders

Hannah A. Raj et al.

Summary: Individuals with telomere biology disorders (TBDs) have significantly shortened telomeres in blood cells, which is associated with increased risk of bone marrow failure and reduced survival. The mean telomere length is estimated to be 5 kilobases, but it is the shortest telomeres that indicate cellular senescence. By using the Telomere Shortest Length Assay (TeSLA), it was found that TBD patients have much shorter mean telomere length and an increased number of telomeres less than 3 kilobases. In addition, TBD patients with severe bone marrow failure and multiple organ manifestations have even shorter telomeres.

BRITISH JOURNAL OF HAEMATOLOGY (2023)

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Article Oncology

Report T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers

Kristen E. Schratz et al.

Summary: Patients with short telomere syndromes (STS) have a predisposition to certain types of solid cancers, specifically squamous cell carcinomas of the head and neck, anus, or skin. This predisposition is not due to increased chromosome instability but rather acquisition of telomere maintenance mechanisms and T cell immunodeficiency. The findings suggest that the susceptibility to solid cancers in STS patients is driven by T cell exhaustion.

CANCER CELL (2023)

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Review Cell Biology

POT1 mutations cause differential effects on telomere length leading to opposing disease phenotypes

Nikita Harish Zade et al.

Summary: POT1 is a telomere-binding protein that prevents DNA damage response at telomeres, thus protecting against genomic instability. It is also involved in maintaining telomere length by regulating telomerase-mediated elongation. Mutations in POT1 result in different telomere phenotypes, leading to cancer or telomeropathies.

JOURNAL OF CELLULAR PHYSIOLOGY (2023)

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Review Genetics & Heredity

Genetics of human telomere biology disorders

Patrick Revy et al.

Summary: This article reviews the confirmed and potential genes causing telomere diseases and describes their main functions in telomere biology. The authors also discuss the genetic features underlying the complexity of these diseases.

NATURE REVIEWS GENETICS (2023)

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Article Medicine, General & Internal

Familial Clonal Hematopoiesis in a Long Telomere Syndrome

Emily A. DeBoy et al.

Summary: Persons with variant POT1 protein were found to have unusually long telomeres and susceptibility to familial clonal hematopoiesis and other neoplasms. The study suggests that long telomere length is associated with extended cellular longevity and the capacity to maintain telomeres over time.

NEW ENGLAND JOURNAL OF MEDICINE (2023)

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Article Genetics & Heredity

Characterization of POT1 tumor predisposition syndrome: Tumor prevalence in a clinically diverse hereditary cancer cohort

Jennifer Herrera-Mullar et al.

Summary: By conducting multigene panel testing, we determined the prevalence of cancer types associated with POT1 pathogenic variants. These findings have the potential to impact clinical management recommendations for patients and families at risk for melanoma and sarcoma.

GENETICS IN MEDICINE (2023)

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Review Cell Biology

Telomere length and chronological age across the human lifespan: A systematic review and meta-analysis of 414 study samples including 743,019 individuals

Qiaofeng Ye et al.

Summary: Telomere length decreases with chronological age in a non-linear trend. Methodological factors, such as TL measurement methods and tissue types, influence the correlation between TL and age, while sex or disease status does not have an impact.

AGEING RESEARCH REVIEWS (2023)

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Article Genetics & Heredity

Genetic and clinical determinants of telomere length

Patrick Allaire et al.

Summary: Many epidemiologic studies have found important connections between leukocyte telomere length (LTL) and genetics and health. This study used data from two large patient populations to identify genetic loci associated with LTL and to explore the relationship between LTL and various diseases. The study also found that age and genetics explain a significant portion of LTL variance. These findings highlight the need for further research on the relationship between TL biology and human health, with potential applications in medicine.

HUMAN GENETICS AND GENOMICS ADVANCES (2023)

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Article Cell Biology

Stress and telomere shortening: Insights from cellular mechanisms

Jue Lin et al.

Summary: Short telomeres may increase the risk of degenerative diseases, with stress-induced telomere damage being an important pathway. The initial setting point of telomere length at birth appears to be influential, possibly affected by stress. Intergenerational stress effects on telomeres include prenatal stress and direct inheritance of short telomeres.

AGEING RESEARCH REVIEWS (2022)

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Article Hematology

Telomeres, aging, and cancer: the big picture

Peter M. Lansdorp

Summary: This article summarizes the role of telomeres in human health and disease and discusses the antagonistic role of telomere loss in aging and cancer. It proposes the Telomere Erosion in Disposable Soma theory.

BLOOD (2022)

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Article Hematology

Disease progression and clinical outcomes in telomere biology disorders

Marena R. Niewisch et al.

Summary: This study examined the associations between mode of inheritance in Dyskeratosis congenita related telomere biology disorders (DC/TBDs) and the clinical manifestations and long-term outcomes. The results showed that different modes of inheritance were correlated with different clinical presentations, and they also had an impact on the survival of patients.

BLOOD (2022)

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Review Cell Biology

Telomere dysfunction in ageing and age-related diseases

Francesca Rossiello et al.

Summary: The article reviews the impact of telomere shortening and dysfunction on aging and a variety of age-related diseases in humans. Accumulation of senescent cells in aging organisms is believed to contribute to bodily dysfunction. Telomere shortening and damage are known causes of cellular senescence and aging. The authors argue that telomeric dysfunction plays a broad role in human pathologies associated with normal aging.

NATURE CELL BIOLOGY (2022)

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Review Medicine, General & Internal

Effect of Physical Activity, Smoking, and Sleep on Telomere Length: A Systematic Review of Observational and Intervention Studies

Rocio Barragan et al.

Summary: Reduced sedentary activities, optimal sleep habits, and non- or ex-smoker status have been associated with less telomere shortening.

JOURNAL OF CLINICAL MEDICINE (2022)

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Article Education, Scientific Disciplines

Dyskeratosis congenita and telomere biology disorders

Sharon A. Savage

Summary: New genetic discoveries and clinical telomere length testing have revealed a range of telomere biology disorders (TBDs) that go beyond the classic dyskeratosis congenita (DC) symptoms. TBDs patients have significantly shortened telomeres and are at high risk for various diseases.

HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM (2022)

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Review Hematology

The biology and management of dyskeratosis congenita and related disorders of telomeres

Hemanth Tummala et al.

Summary: This article discusses the clinical features, genetics, and biology of DC subtypes. Expert opinion includes diagnosis, treatment of hematological complications, and future prospects. Given the pleotropic nature of these disorders, a high index of suspicion is required for diagnosis.

EXPERT REVIEW OF HEMATOLOGY (2022)

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Review Medicine, Research & Experimental

Telomeres, Telomerase and Cancer

Peter M. Lansdorp

Summary: Telomeres and telomerase are crucial in human aging and cancer. The three drivers of human aging are the developmental program encoded in DNA, damage to the genome and epigenome, and the progressive loss of telomeric DNA. Malignant tumors arise when mutations and/or epimutations corrupt the developmental program and tumor suppression by telomere erosion.

ARCHIVES OF MEDICAL RESEARCH (2022)

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Article Multidisciplinary Sciences

Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis

Derek W. Brown et al.

Summary: The study identified 6 germline susceptibility loci and high frequencies of mosaic chromosomal alterations (mCAs) in myelofibrosis cases. The mCAs involving JAK2 were found to be strong promoters of clonal expansion in mutated clones of myelofibrosis cases.

NATURE COMMUNICATIONS (2022)

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Review Oncology

Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies

Jixuan Gao et al.

Summary: This review discusses the latest developments and strategies in targeting telomerase and ALT mechanisms for cancer treatment. It also introduces the methods for detecting these two mechanisms and their utility in clinical diagnosis. In addition to inhibiting telomere maintenance, exploiting the weaknesses of telomeres themselves can induce cell death.

NATURE REVIEWS CANCER (2022)

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Review Biochemistry & Molecular Biology

Telomeres: history, health, and hallmarks of aging

Deepavali Chakravarti et al.

Summary: The escalating social and economic burden of an aging world population has brought aging research into the spotlight. Through the lens of telomere biology, we can better understand the mechanisms of aging and the development of age-related diseases, providing insights for prevention and treatment.

CELL (2021)

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Article Multidisciplinary Sciences

Method comparison studies of telomere length measurement using qPCR approaches: A critical appraisal of the literature

Alyssa R. Lindrose et al.

Summary: The current literature on the relation between TL measurement methods lacks validity and scientific rigor, necessitating additional cross-laboratory studies with rigorous methodologic and statistical reporting.

PLOS ONE (2021)

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Article Oncology

Annual Report to the Nation on the Status of Cancer, Part 2: Patient Economic Burden Associated With Cancer Care

K. Robin Yabroff et al.

Summary: This study aims to quantify the patient economic burden associated with cancer care in the United States, providing comprehensive estimates of various costs linked to cancer treatment. The results reveal significant cost variations across different phases and cancer sites, with higher costs observed for patients diagnosed with later-stage diseases.

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE (2021)

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Article Genetics & Heredity

High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders

Kevin Norris et al.

Summary: Telomere biology disorders are complex clinical conditions caused by mutations in genes related to telomere maintenance. High-throughput STELA (HT-STELA) has been shown to accurately measure telomere lengths in unaffected individuals and mutation carriers, providing important diagnostic and prognostic information for telomeropathies.

HUMAN GENETICS (2021)

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Article Genetics & Heredity

Polygenic basis and biomedical consequences of telomere length variation

Veryan Codd et al.

Summary: This study characterized the genetic architecture of leukocyte telomere length in UK Biobank participants and identified 197 sentinel variants associated with LTL at 138 genomic loci. Genetically determined differences in LTL were found to be associated with various biological traits and diseases, and individuals with shorter LTL had a lower life expectancy compared to those with longer LTL. The findings provide insights into the genetic regulation of LTL, as well as its impact on physiological traits, diseases, and longevity.

NATURE GENETICS (2021)

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Article Biochemistry & Molecular Biology

Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps

Adebowale Adeyemo et al.

Summary: Polygenic risk scores (PRSs) aggregate multiple small effects of alleles in the human genome to estimate an individual's risk of disease or disease-related traits. By addressing key issues, PRSs can be used responsibly to improve human health.

NATURE MEDICINE (2021)

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Article Oncology

Telomeres and Cancer: Resolving the Paradox

Joe Nassour et al.

Summary: Decades of research on cell cycle regulation have shed light on the importance of telomeres in controlling cell lifespan and tumorigenesis. Telomeres act as both tumor suppressors and sources of genomic aberrations in cancer, playing a dual role in carcinogenesis.

ANNUAL REVIEW OF CANCER BIOLOGY, VOL 5, 2021 (2021)

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Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

Mariarosaria De Rosa et al.

Summary: Telomeres are protective nucleoprotein structures that cap linear chromosome ends, vital for genome stability. Shortening and dysfunction of telomeres may lead to cellular senescence, aging, or tumorigenesis. The enzyme telomerase is expressed in human reproductive cells, some stem cells, and most cancer cells to maintain telomere length by restoring telomeric DNA. Oxidative stress from excess reactive oxygen species is associated with accelerated telomere shortening and damage, which may contribute to degenerative diseases and cancer. The highly conserved guanine oxidation system involves specialized enzymes to mitigate the effects of mutagenic base lesions at telomeres.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Telomere Replication: Solving Multiple End Replication Problems

Erin Bonnell et al.

Summary: Telomeres, crucial for maintaining genomic stability, pose challenges for replication due to their repetitive nature and the formation of secondary structures, leading to replication fork stalling. Multiple mechanisms are involved in overcoming these obstacles to ensure efficient telomeric DNA duplication and preserve genome integrity.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof

Eloise Claude et al.

CURRENT OPINION IN GENETICS & DEVELOPMENT (2020)

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A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres

Huiling He et al.

THYROID (2020)

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The enigma of excessively long telomeres in cancer: lessons learned from rare human POT1 variants

Yi Gong et al.

CURRENT OPINION IN GENETICS & DEVELOPMENT (2020)

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Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction

Chongkui Sun et al.

EMBO JOURNAL (2020)

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Determinants of telomere length across human tissues

Kathryn Demanelis et al.

SCIENCE (2020)

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Telomeres and telomerase: three decades of progress

Jerry W. Shay et al.

NATURE REVIEWS GENETICS (2019)

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Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up

Blanche P. Alter et al.

HAEMATOLOGICA (2018)

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Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up

Blanche P. Alter et al.

HAEMATOLOGICA (2018)

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Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma

Mary L. McMaster et al.

BRITISH JOURNAL OF HAEMATOLOGY (2018)

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Review Biology

Comparison of telomere length measurement methods

Tsung-Po Lai et al.

PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES (2018)

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Reflections on telomere dynamics and ageing-related diseases in humans

Abraham Aviv et al.

PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES (2018)

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Diagnostic utility of telomere length testing in a hospital-based setting

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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

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EUROPEAN UROLOGY (2017)

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Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives

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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2017)

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Comparative analysis of whole genome sequencing-based telomere length measurement techniques

Michael Lee et al.

METHODS (2017)

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Systematic analysis of telomere length and somatic alterations in 31 cancer types

Floris P. Barthel et al.

NATURE GENETICS (2017)

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Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement

Casey L. Dagnall et al.

PLOS ONE (2017)

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A method for measuring the distribution of the shortest telomeres in cells and tissues

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NATURE COMMUNICATIONS (2017)

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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study

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JAMA ONCOLOGY (2017)

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Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Helen E. Speedy et al.

BLOOD (2016)

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Shorter telomere length in Europeans than in Africans due to polygenetic adaptation

Matthew E. B. Hansen et al.

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The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita

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DCAF4, a novel gene associated with leucocyte telomere length

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A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families

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Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma

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Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

Thet Thet Lin et al.

BRITISH JOURNAL OF HAEMATOLOGY (2014)

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Telomere Length in White Blood Cell DNA and Lung Cancer: A Pooled Analysis of Three Prospective Cohorts

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Genome-Wide Association Study Identifies Variants in Casein Kinase II (CSNK2A2) to be Associated With Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort

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Mutations in POT1 predispose to familial cutaneous malignant melanoma

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Michael Gardner et al.

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POT1 loss-of-function variants predispose to familial melanoma

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NATURE GENETICS (2014)

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Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Jianxin Shi et al.

NATURE GENETICS (2014)

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Article Multidisciplinary Sciences

Direct Comparison of Flow-FISH and qPCR as Diagnostic Tests for Telomere Length Measurement in Humans

Fernanda Gutierrez-Rodrigues et al.

PLOS ONE (2014)

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Telomeres in Molecular Epidemiology Studies

Clara Bodelon et al.

TELOMERES IN HEALTH AND DISEASE (2014)

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Identification of seven loci affecting mean telomere length and their association with disease

Veryan Codd et al.

NATURE GENETICS (2013)

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Epidemiologic evidence for a role of telomere dysfunction in cancer etiology

Jennifer Prescott et al.

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Telomere length measurement-Caveats and a critical assessment of the available technologies and tools

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The Association of Telomere Length and Cancer: a Meta-analysis

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Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR

Abraham Aviv et al.

NUCLEIC ACIDS RESEARCH (2011)

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Common variants near TERC are associated with mean telomere length

Veryan Codd et al.

NATURE GENETICS (2010)

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Article Cell Biology

Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study

Steven C. Hunt et al.

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Article Genetics & Heredity

TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita

Sharon A. Savage et al.

AMERICAN JOURNAL OF HUMAN GENETICS (2008)

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Meeting Abstract Hematology

Telomere length measurement by flow-FISH distinguishes Dyskeratosis congenita from other bone marrow failure syndromes.

Blanche P. Alter et al.

BLOOD (2006)

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Telomere measurement by quantitative PCR

RM Cawthon

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