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Simple Summary: Telomeres play an integral role in preventing genomic instability by protecting chromosomal ends using telomeric repeats, and their dysfunction may lead to premature aging disorders and age-related diseases. During cellular division, they undergo telomere attrition, resulting in the gradual shortening of those protective caps, leading to genomic instability and cellular aging. Critically short telomeres in normal cells trigger senescence, a major contributor to age-related diseases, and opens the door for genomic instability, which promotes carcinogenesis. This review aims to provide an updated overview of telomere biology and therapeutic strategies around telomere attrition. We emphasize the importance of understanding the complex balance between preserving telomere length in aging while inhibiting telomere maintenance in cancer by proposing Optimal Therapeutic Approaches based on the most updated literature. Background/Objectives: As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. Methods: We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. Results: Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson–Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. Conclusions: The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer affects millions worldwide, with gastrointestinal cancers being notably common. This review explores the potential of telomeres and telomerase as biomarkers for diagnosing and predicting these cancers. Telomeres are protective caps at chromosome ends that shorten with cell division, while telomerase helps extend them. Changes in these markers could indicate cancer risk and progression. Despite efforts to prevent cancer through lifestyle changes, gastrointestinal cancers such as colorectal and gastric cancer remain prevalent. Current detection methods like endoscopy are invasive, driving interest in non-invasive alternatives. By consolidating research on telomere length and telomerase activity, this review aims to highlight how these biomarkers could enhance early diagnosis and monitoring. Understanding these mechanisms better could lead to improved diagnostic tools and therapeutic strategies, potentially refining how gastrointestinal cancers are managed and improving patient outcomes. Gastrointestinal (GI) cancers, such as colorectal and gastric cancers, pose significant global health challenges due to their high rates of incidence and mortality. Even with advancements in treatment and early detection, many patients still face poor outcomes, highlighting the critical need for new biomarkers and therapeutic targets. Telomere length (TL) and telomerase activity (TA) have gained attention in this context. Telomeres, protective nucleotide sequences at chromosome ends, shorten with each cell division, leading to cellular aging. Telomerase, a ribonucleoprotein enzyme, counteracts this shortening by adding telomeric repeats, a process tightly regulated in normal cells but often dysregulated in cancer. This review critically evaluates the role of TL and TA in the pathogenesis of GI cancers, examining their potential as diagnostic, prognostic, and predictive biomarkers. It explores how alterations in telomere biology contribute to the initiation and progression of GI tumors and assesses the therapeutic implications of targeting telomerase. By integrating findings from diverse studies, this review aims to elucidate the intricate relationship between telomere dynamics and gastrointestinal carcinogenesis, offering insights into how TL and TA could be leveraged to enhance the early detection, treatment, and prognosis of GI cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomere length (TL) may influence the carcinogenesis process. Short telomeres lead to genomic instability, which is an important event in tumor initiation, while long telomeres may promote cell division and immortality influencing tumor promotion/progression. Despite the numerous observational epidemiological studies available, the association between TL in leukocytes (LTL) and lung cancer risk is currently still uncertain. Therefore, we conducted this systematic review and meta-analysis of prospective studies to summarize the evidence and derive a more accurate estimate of the effect of LTL on lung cancer occurrence. Longer LTL could be a marker to identify subjects at high risk of developing lung cancer. This may help to focus secondary prevention (screening) on specific groups of subjects. Although numerous epidemiological studies are available, the relationship between leukocyte telomere length (LTL) and lung cancer risk is still controversial. This systematic review and meta-analysis, performed according to the PRISMA statement and MOOSE guidelines, aims to summarize the evidence and calculate the risk of lung cancer associated with LTL. The literature search was performed on PubMed, Web of Science, and Scopus databases through May 2024. A random-effects model was used to calculate the pooled risk. Heterogeneity was assessed using I2 and Cochran's Q statistic. Begg's and Egger's tests were used to detect publication bias. Based on 8055 lung cancer cases and 854,653 controls (nine prospective studies), longer LTL was associated with a significant 42% increment in all types of lung cancer risk (OR 1.42, 95% CI 1.24–1.63). The effect was even more evident for adenocarcinomas (OR 1.98, 95% CI 1.69–2.31), while no association was observed for squamous cell carcinoma (OR 0.87, 95% CI 0.72–1.06). Significantly, no association was found for current smokers (OR 1.08, 95% CI 0.90–1.30), while it remained high for both never-smokers (OR 1.92, 95% CI 1.62–2.28) and former smokers (OR 1.34, 95% CI 1.11–1.62). No significant publication bias was evidenced. Longer LTL is associated with an increment in lung cancer risk particularly in never-smoker subjects. [ABSTRACT FROM AUTHOR]

Simple Summary: Three-dimensional (3D) telomere analysis using TeloView v 2.2 has shown promise in quantifying genomic instability and predicting therapy response. In a study of 156 Classic Hodgkin's lymphoma (cHL), we identified significant 3D telomere parameters that predict patient outcomes. A predictive model using four 3D telomere parameters, including the proportion of t-stumps (very short telomeres), achieved an area under curve (AUC) of 0.83, with a sensitivity and specificity of 0.82 and 0.78, respectively. Classic Hodgkin's lymphoma (cHL) is a curable cancer with a disease-free survival rate of over 10 years. Over 80% of diagnosed patients respond favorably to first-line chemotherapy, but few biomarkers exist that can predict the 15–20% of patients who experience refractory or early relapsed disease. To date, the identification of patients who will not respond to first-line therapy based on disease staging and traditional clinical risk factor analysis is still not possible. Three-dimensional (3D) telomere analysis using the TeloView® software platform has been shown to be a reliable tool to quantify genomic instability and to inform on disease progression and patients' response to therapy in several cancers. It also demonstrated telomere dysfunction in cHL elucidating biological mechanisms related to disease progression. Here, we report 3D telomere analysis on a multicenter cohort of 156 cHL patients. We used the cohort data as a training data set and identified significant 3D telomere parameters suitable to predict individual patient outcomes at the point of diagnosis. Multivariate analysis using logistic regression procedures allowed for developing a predictive scoring model using four 3D telomere parameters as predictors, including the proportion of t-stumps (very short telomeres), which has been a prominent predictor for cHL patient outcome in a previously published study using TeloView® analysis. The percentage of t-stumps was by far the most prominent predictor to identify refractory/relapsing (RR) cHL prior to initiation of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy. The model characteristics include an AUC of 0.83 in ROC analysis and a sensitivity and specificity of 0.82 and 0.78 respectively. [ABSTRACT FROM AUTHOR]

Simple Summary: Chemotoxicity in colorectal cancer (CRC) patients impacts treatment compliance, survival, and quality of life. While clinician-reported chemotoxicity predicts rehospitalization and survival, a comprehensive understanding is lacking. This systematic review and meta-analysis studied chemotoxicity in CRC patients. The study found that 45.7% of patients experienced overall moderate-to-severe toxicities, with gastrointestinal toxicity (22.9%) and neuropathy or neutropenia (17.9%) being the most common. Risk factors included malnutrition, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low quality of life. Age was linked to neutropenia and gastrointestinal toxicity. Older adults had higher overall and gastrointestinal toxicities but lower neutropenia than younger adults. The study underscores the need for close monitoring and management of chemotoxicity in CRC patients. Community contributions have been instrumental in raising awareness about these issues, advocating for patient support, and future research to improve treatment toxicities in CRC. Background: Colorectal cancer (CRC) patients experience multiple types of chemotoxicity affecting treatment compliance, survival, and quality of life (QOL). Prior research shows clinician-reported chemotoxicity (i.e., grading scales or diagnostic codes) predicts rehospitalization and cancer survival. However, a comprehensive synthesis of clinician-reported chemotoxicity is still lacking. Objectives: We conducted a systematic review and meta-analysis to determine chemotoxicity's prevalence and risk factors in CRC. Methods: A systematic search from 2009 to 2024 yielded 30 studies for review, with 25 included in the meta-analysis. Results: Pooled prevalences of overall, non-hematological, and hematological moderate-to-severe toxicities were 45.7%, 39.2%, and 25.3%, respectively. The most common clinician-reported chemotoxicities were gastrointestinal (GI) toxicity (22.9%) and neuropathy or neutropenia (17.9%). Significant risk factors at baseline were malnutritional status, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low QOL. Age was associated with neutropenia (β: −1.44) and GI toxicity (β:1.85) (p-values < 0.01). Older adults (>65 y.o.) had higher prevalences of overall (OR: 1.14) and GI (OR: 1.65) toxicities, but a lower prevalence of neutropenia (OR: 0.65) than younger adults (p-values < 0.05). Conclusions. Our findings highlight the importance of closely monitoring and managing chemotoxicity in CRC patients receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Leukocyte relative telomere length (RTL) has not been thoroughly studied among childhood cancer survivors, although survivors are believed to be at risk of telomere attrition due to exposure to cytotoxic cancer treatments. We examined the leukocyte relative telomere length (RTL) in 88 adolescent and young adult childhood cancer survivors. Overall, RTL was not significantly shorter than in age-matched references. However, among 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation had significantly shorter RTL, especially if they developed acute graft-versus-host disease ≥ grade II. Patients with severe or multiple chronic health conditions also had shorter RTL. We examined the leukocyte relative telomere length (RTL) in Korean adolescent and young adult (AYA) survivors of childhood cancer and evaluated the association of leukocyte RTL with multiple factors, including malignancy type, cancer treatment, age, and chronic health conditions (CHCs). Eighty-eight AYA survivors of childhood cancer with a median follow-up period of 73 months were recruited. RTL in pediatric cancer survivors was not significantly shorter than the predicted value for age-matched references. Neither age at diagnosis nor duration of therapy influenced the RTL. Among the 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation (HSCT) showed a significant shortening of the RTL compared with those who did not (p = 0.039). Among the 15 patients who underwent allogeneic HSCT, those who developed acute graft-versus-host disease (GVHD) of grade II or higher had significantly shorter RTL than those who did not (p = 0.012). Patients with grade II CHCs had significantly shorter RTL than those without CHCs or with grade I CHCs (p = 0.001). Survivors with ≥2 CHCs also exhibited shorter RTL (p = 0.027). Overall, pediatric cancer survivors had similar telomere lengths compared to age-matched references. HSCT recipients and patients with severe or multiple CHCs had shorter telomeres. GVHD augmented telomere attrition in HSCT recipients. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) has become one of the leading causes of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT) have been recently added to the clinical armamentarium of stage II/III diseases. Moreover, the improvement of a patient's telomere status may have a synergistic effect along with ICIs/ACT. This can be achieved either via lifestyle modifications with increased physical activity or with new promising treatments such as those acting on telomerase. Therefore, this review aims to comprehensively summarize the current data on immunotherapy in order to facilitate clinicians' familiarity with this relatively new therapeutic approach. Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other's efficacy, paving the way for promising future therapeutic advancements. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is the most common cancer in men. The pursuit of novel biomarkers for early detection of prostate cancer poses a contemporary challenge given the age-associated escalation in prostate cancer risk and severity. Our focus was directed towards evaluating leukocyte telomere length (LTL) and myeloid-derived suppressor cells (MDSC) in prostate cancer patients, considering their potential as adjunctive diagnostic markers. In a study of 102 patients who underwent prostate biopsy, those diagnosed with prostate cancer demonstrated significantly shorter LTL and an increased proportion of M-MDSC prior to diagnosis, along with elevated PSA levels and age, in comparison to controls. Furthermore, a significant negative correlation was observed between LTL and MDSC levels. This initial report of those findings could potentially contribute to a deeper understanding of the molecular, biological, and immunological factors involved in cancer development. Background: Leukocyte telomere length (LTL) and myeloid-derived suppressor cells (MDSC) are associated with aging and the development and progression of cancer. However, the exact nature of this relationship remains unclear. Our study aimed to investigate the potential of LTL and MDSC as diagnostic biomarkers for prostate cancer while also seeking to deepen our understanding of the relationship of these potential biomarkers to each other. Methods: Our study involved patients undergoing a prostate biopsy. We analyzed the relative LTL in genomic DNA obtained from peripheral blood leukocytes as well as the percentage of MDSC and their subtypes in peripheral blood mononuclear cells (PBMC). Our evaluation focused on examining the relationship between LTL and MDSC and pathological diagnoses as well as investigating the correlation between LTL and MDSC levels. Results: In our study of 102 participants, 56 were pathologically diagnosed with localized prostate cancer (cancer group), while 46 tested negative (control group). The cancer group exhibited significantly shorter LTL in comparison to the control group (p = 0.024). Additionally, the cancer group showed a tendency towards a higher percentage of monocytic MDSC (M-MDSC), although this difference did not reach statistical significance (p = 0.056). Our multivariate logistic regression analysis revealed that patients with shorter LTL and higher percentages of M-MDSC had a 2.98-fold (95% CI = 1.001–8.869, p = 0.049) and 3.03-fold (95% CI = 1.152–7.977, p = 0.025) increased risk of prostate cancer diagnosis, respectively. There was also a significant negative correlation between LTL and M-MDSC. (r = −0.347, p < 0.001). Conclusions: Our research has established a correlation between LTL and MDSC in patients undergoing biopsy for prostate cancer. Notably, we observed that individuals with localized prostate cancer tend to have shorter LTL and a higher percentage of M-MDSC prior to their diagnosis. These findings suggest that LTL and M-MDSC could potentially serve as adjunctive biomarkers for the early diagnosis of prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Leiomyosarcoma is a subtype of soft tissue sarcoma with poor outcomes and response to currently available treatments. The goal of this review is to assess the current landscape of targeted therapies and explore how our current understanding of the biology of leiomyosarcoma may inform the development of new targeted therapies to improve the treatment of leiomyosarcoma. Leiomyosarcoma (LMS) is an aggressive subtype of soft tissue sarcoma that arises from smooth muscle cells, most commonly in the uterus and retroperitoneum. LMS is a heterogeneous disease with diverse clinical and molecular characteristics that have yet to be fully understood. Molecular profiling has uncovered possible targets amenable to treatment, though this has yet to translate into approved targeted therapies in LMS. This review will explore historic and recent findings from molecular profiling, highlight promising avenues of current investigation, and suggest possible future strategies to move toward the goal of molecularly matched treatment of LMS. We focus on targeting the DNA damage response, the macrophage-rich micro-environment, the PI3K/mTOR pathway, epigenetic regulators, and telomere biology. [ABSTRACT FROM AUTHOR]

Simple Summary: In our glioblastoma patients treated with standard therapy, the TERTp C250T mutation occurred less frequently than the C228T mutation. Patients with the C250T mutation had better prognosis than those with either TERTp-wt or TERTp C228T mutations, even when adjusted for key glioblastoma prognostic factors. This may be due to the lesser involvement of the C250T mutation in telomere- and chromosome-related pathways, as evidenced by the results of a gene enrichment analysis adjusted for MGMTp methylation status: TERTp C250T was differentially enriched compared to TERTp-wt and C228T. There were no differences according to TERTp mutation status in the mutations or copy number variants of other genes commonly present in glioblastoma. The biological pathways by which TERTp and MGMTp exert their effects are independent. The aim of this study was to determine how TERTp mutations impact glioblastoma prognosis. Materials and Methods: TERTp mutations were assessed in a retrospective cohort of 258 uniformly treated glioblastoma patients. RNA-sequencing and whole exome sequencing results were available in a subset of patients. Results: Overall, there were no differences in outcomes between patients with mutated TERTp-wt or TERTp. However, we found significant differences according to the type of TERTp mutation. Progression-free survival (mPFS) was 9.1 months for those with the C250T mutation and 7 months for those with either the C228T mutation or TERTp-wt (p = 0.016). Overall survival (mOS) was 21.9 and 15 months, respectively (p = 0.026). This differential effect was more pronounced in patients with MGMTp methylation (mPFS: p = 0.008; mOS: p = 0.021). Multivariate analysis identified the C250T mutation as an independent prognostic factor for longer mOS (HR 0.69; p = 0.044). We found no differences according to TERTp mutation status in molecular alterations common in glioblastoma, nor in copy number variants in genes related to alternative lengthening of telomeres. Nevertheless, in the gene enrichment analysis adjusted for MGMTp methylation status, some Reactome gene sets were differentially enriched, suggesting that the C250T mutation may exert a lesser effect on telomeres or chromosomes. Conclusions: In our series, patients exhibiting the C250T mutation had a more favorable prognosis compared to those with either TERPp-wt or TERTp C228T mutations. Additionally, our findings suggest a reduced involvement of the C250T mutation in the underlying biological mechanisms related to telomeres. [ABSTRACT FROM AUTHOR]

Simple Summary: The study examined 130 pituitary adenoma (PA) patients and 320 healthy individuals, analyzing DNA samples. Real-time PCR and ELISA assessed genetic variations, telomere lengths, and serum proteins. Significant associations were found: TERF1 rs1545827 CT + TT genotypes decreased PA occurrence odds, while TNKS2 rs10509637 GG genotype increased the odds. Gender-specific patterns emerged: females with TERF1 rs1545827 CC + TT had lower odds; also males with TERF1 rs1545827 T allele showed decreased odds. TNKS2 rs10509637 AA genotype increased odds in both genders and in PA recurrence. PA patients had elevated TERF2 and decreased TERF1 serum levels, longer telomeres, and TERF1 rs1545827 T allele associated with reduced telomere shortening odds. Gender-specific genetic effects were observed, implicating TERF1 and TNKS2 in telomere regulation and PA susceptibility. In this study, we examined 130 patients with pituitary adenomas (PAs) and 320 healthy subjects, using DNA samples from peripheral blood leukocytes purified through the DNA salting-out method. Real-time polymerase chain reaction (RT-PCR) was used to assess single nucleotide polymorphisms (SNPs) and relative leukocyte telomere lengths (RLTLs), while enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of TERF1, TERF2, TNKS2, CTC1, and ZNF676 in blood serum. Our findings reveal several significant associations. Genetic associations with pituitary adenoma occurrence: the TERF1 rs1545827 CT + TT genotypes were linked to 2.9-fold decreased odds of PA occurrence. Conversely, the TNKS2 rs10509637 GG genotype showed 6.5-fold increased odds of PA occurrence. Gender-specific genetic associations with PA occurrence: in females, the TERF1 rs1545827 CC + TT genotypes indicated 3.1-fold decreased odds of PA occurrence, while the TNKS2 rs10509637 AA genotype was associated with 4.6-fold increased odds. In males, the presence of the TERF1 rs1545827 T allele was associated with 2.2-fold decreased odds of PA occurrence, while the TNKS2 rs10509637 AA genotype was linked to a substantial 10.6-fold increase in odds. Associations with pituitary adenoma recurrence: the TNKS2 rs10509637 AA genotype was associated with 4.2-fold increased odds of PA recurrence. On the other hand, the TERF1 rs1545827 CT + TT genotypes were linked to 3.5-fold decreased odds of PA without recurrence, while the TNKS2 rs10509637 AA genotype was associated with 6.4-fold increased odds of PA without recurrence. Serum TERF2 and TERF1 levels: patients with PA exhibited elevated serum TERF2 levels compared to the reference group. Conversely, patients with PA had decreased TERF1 serum levels compared to the reference group. Relative leukocyte telomere length (RLTL): a significant difference in RLTL between the PA group and the reference group was observed, with PA patients having longer telomeres. Genetic associations with telomere shortening: the TERF1 rs1545827 T allele was associated with 1.4-fold decreased odds of telomere shortening. In contrast, the CTC1 rs3027234 TT genotype was linked to 4.8-fold increased odds of telomere shortening. These findings suggest a complex interplay between genetic factors, telomere length, and pituitary adenoma occurrence and recurrence, with potential gender-specific effects. Furthermore, variations in TERF1 and TNKS2 genes may play crucial roles in telomere length regulation and disease susceptibility. [ABSTRACT FROM AUTHOR]

Simple Summary: Following infection with HIV, individuals are immunocompromised. Their weakened immune system puts them at a higher risk of certain cancers like Kaposi sarcoma and lymphoma. Even with antiretroviral therapy for HIV infection, these cancers remain common in developing countries, while in developed countries, there is a decline in some cancers but an increase in deaths from others. This review explores why these cancers happen in people with HIV and finds that the current treatment is not enough to prevent them. Understanding these reasons is crucial to improving the diagnosis and treatment of both HIV and its associated cancers, highlighting the need for more research to tackle this ongoing health issue. The immune deficiency associated with human immunodeficiency virus (HIV) infection causes a distinct increased risk of developing certain cancer types. Kaposi sarcoma (KS), invasive cervical cancer and non-Hodgkin's lymphoma (NHL) are the prominent malignancies that manifest as a result of opportunistic viral infections in patients with advanced HIV infection. Despite the implementation of antiretroviral therapy (ART), the prevalence of these acquired immunodeficiency syndrome (AIDS)-defining malignancies (ADMs) remains high in developing countries. In contrast, developed countries have experienced a steady decline in the occurrence of these cancer types. However, there has been an increased mortality rate attributed to non-ADMs. Here, we provide a review of the molecular mechanisms that are responsible for the development of ADMs and non-ADMs which occur in HIV-infected individuals. It is evident that ART alone is not sufficient to fully mitigate the potential for ADMs and non-ADMs in HIV-infected individuals. To enhance the diagnosis and treatment of both HIV and malignancies, a thorough comprehension of the mechanisms driving the development of such cancers is imperative. [ABSTRACT FROM AUTHOR]

Simple Summary: Immortalization is a hallmark of malignant tumors, including in pediatric cancer neuroblastoma, where it is associated with an adverse prognosis. In this study, we characterized a Swedish neuroblastoma cohort with the focus on telomere maintenance mechanisms (TMMs), i.e., MYCN amplification and the juxtapositioning of TERT and ATRX aberrations. We show a strong correlation between ATRX aberrations and ALT and that aberrations affecting ATRX or TERT are enriched in high-risk cases with 11q deletion. This study, thereby, supports the need for further advancement of TMM-targeted therapies for this subgroup of neuroblastoma patients. Tumor cells are hallmarked by their capacity to undergo unlimited cell divisions, commonly accomplished either by mechanisms that activate TERT or through the alternative lengthening of telomeres pathway. Neuroblastoma is a heterogeneous pediatric cancer, and the aim of this study was to characterize telomere maintenance mechanisms in a high-risk neuroblastoma cohort. All tumor samples were profiled with SNP microarrays and, when material was available, subjected to whole genome sequencing (WGS). Telomere length was estimated from WGS data, samples were assayed for the ALT biomarker c-circles, and selected samples were subjected to methylation array analysis. Samples with ATRX aberration in this study were positive for c-circles, whereas samples with either MYCN amplification or TERT re-arrangement were negative for c-circles. Both ATRX aberrations and TERT re-arrangement were enriched in 11q-deleted samples. An association between older age at diagnosis and 1q-deletion was found in the ALT-positive group. TERT was frequently placed in juxtaposition to a previously established gene in neuroblastoma tumorigenesis or cancer in general. Given the importance of high-risk neuroblastoma, means for mitigating active telomere maintenance must be therapeutically explored. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is an aggressive cancer of the bone that can present in children or adults. It has historically been thought that adults have worse clinical outcomes than children. However, current treatment strategies for adults are largely extrapolated from pediatric studies since the majority of clinical trials for osteosarcoma treatments are based on younger patient populations. We summarize the current understanding of the molecular etiology of osteosarcoma and how it may differ between age groups, hypothesizing why adult patients have worse outcomes compared to children. Malignant bone tumors are commonly classified as pediatric or adolescent malignancies, and clinical trials for these diseases have generally focused on these populations. Of primary bone cancers, osteosarcoma is among the most common. Osteosarcoma has a bimodal age distribution, with the first peak occurring in patients from 10 to 14 years old, and the second peak occurring in patients older than 65, with about 25% of cases occurring in adults between 20 and 59 years old. Notably, adult osteosarcoma patients have worse outcomes than their pediatric counterparts. It remains unclear whether age itself is a poor prognostic factor, or if inherent differences in tumor biology exist between age groups. Despite these unknowns, current treatment strategies for adults are largely extrapolated from pediatric studies since the majority of clinical trials for osteosarcoma treatments are based on younger patient populations. In light of the different prognoses observed in pediatric and adult osteosarcoma, we summarize the current understanding of the molecular etiology of osteosarcoma and how it may differ between age groups, hypothesizing why adult patients have worse outcomes compared to children. [ABSTRACT FROM AUTHOR]

Simple Summary: Knowledge of telomere maintenance mechanisms (TMMs) in different tumor types is crucial for the development of TMM-specific diagnostics and therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is used more frequently in human sarcoma subtypes than other cancers. However, ALT's prevalence in the aggressive hematopoietic and orphan tumor type termed histiocytic sarcoma (HS) is unknown. The aim of our retrospective study was to assess the ALT activity in canine HS as a surrogate for rare human HS cases. Bernese mountain dogs (BMDs) have a breed predisposition for HS. We show in cohorts of a total of 63 dog patients from two centers, including a homogeneous population of 47 BMDs, that ALT was used only infrequently in the BMDs and not at all in the non-BMD patients here. We conclude that ALT is useful for a few cases only to target HS but can play a role as a resistance mechanism after targeting telomerase. Cancer cells activate telomere maintenance mechanisms (TMMs) to overcome senescence and thus are targets for TMM-specific therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is frequently utilized as a TMM in human sarcoma subtypes. Histiocytic sarcoma (HS) is a rare but aggressive tumor of hematopoietic origin with unknown ALT incidence in humans. ALT has been identified in canine HS, a tumor type comparable to human HS that occurs with high rates in certain canine breeds such as Bernese mountain dogs (BMDs). This retrospective study characterized the frequency of ALT in BMD and non-BMD patients diagnosed with HS as surrogates for humans. Formalin-fixed paraffin-embedded tumor samples from 63 dogs at two centers, including 47 BMDs, were evaluated for their ALT activity and relative telomere content (TC) using a radiolabel C-circle assay (CCA). Known ALT-positive samples served as controls. CCA-positive cases were validated via FISH. Two BMD samples showed ALT activity of 1–14% compared to controls. All other samples were ALT-negative. The TC did not correlate with the CCA results. ALT positivity was validated by the appearance of ultrabright telomere foci. Low ALT activity was present in 4% of BMDs with HS and therefore does not appear to be a common target for therapeutic approaches but can have diagnostic value. [ABSTRACT FROM AUTHOR]

Simple Summary: G-quadruplexes (G4s) are guanine-rich, four-stranded nucleic acid structures that are abundantly found in the promoter region of various oncogenes (cMYC, cKIT, KRAS, etc.) and in the telomeric region. The ligand-induced stabilization of G4s is shown to be efficient in targeted cancer therapy, and simultaneously targeting multiple G4s is beneficial. Thus, this study aimed to achieve the 'stabilization of G4s with multi-target directed ligands (MTDL)'. We have developed different multi-tasking QSAR models to predict G4 interaction, G4 stabilization, G4 selectivity, and cytotoxicity and we have implemented them in the first computational tool, 'G4-QuadScreen', derived from this robust methodology with the functionality to screen-out a library of small-ligand molecules against G4 DNAs. A virtual screening using this 'G4-QuadScreen' server and a posterior experimental validation has allowed us to identify a total of three compounds with strong inhibitory effect on various human cancer cell lines, demonstrating the usefulness of computational tools to accelerate the discovery of novel anticancer therapies. The study presents 'G4-QuadScreen', a user-friendly computational tool for identifying MTDLs against G4s. Also, it offers a few hit MTDLs based on in silico and in vitro approaches. Multi-tasking QSAR models were developed using linear discriminant analysis and random forest machine learning techniques for predicting the responses of interest (G4 interaction, G4 stabilization, G4 selectivity, and cytotoxicity) considering the variations in the experimental conditions (e.g., G4 sequences, endpoints, cell lines, buffers, and assays). A virtual screening with G4-QuadScreen and molecular docking using YASARA (AutoDock-Vina) was performed. G4 activities were confirmed via FRET melting, FID, and cell viability assays. Validation metrics demonstrated the high discriminatory power and robustness of the models (the accuracy of all models is ~>90% for the training sets and ~>80% for the external sets). The experimental evaluations showed that ten screened MTDLs have the capacity to selectively stabilize multiple G4s. Three screened MTDLs induced a strong inhibitory effect on various human cancer cell lines. This pioneering computational study serves a tool to accelerate the search for new leads against G4s, reducing false positive outcomes in the early stages of drug discovery. The G4-QuadScreen tool is accessible on the ChemoPredictionSuite website. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomeres are essential to prevent telomere end fusions that cause the formation of dicentric chromosomes and nucleoplasmic bridges (NPBs) which in turn induce chromosomal instability, cancer initiation and progression. In this study, we show that telomere length (TL) is reduced and NPBs are increased in prostate cancer (PC) cases and the incidence of these adverse genomic insults is further elevated with increased severity of disease. NPBs and TL in white blood cells may have clinical utility to identify and triage PC cases who may be at risk of serious disease. More studies are required to confirm our observations and to explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to healthy controls. Telomeres are repetitive nucleotide (TTAGGG) sequences that stabilize the chromosome ends and play an important role in the prevention of cancer initiation and progression. Nucleoplasmic bridges (NPBs) are formed when chromatids remain joined together during mitotic anaphase either due to mis-repair of DNA breaks or due to chromatid end fusion as a result of telomere loss or telomere dysfunction. We tested the hypotheses that (i) telomere length (TL) is shorter in prostate cancer (PC) patients relative to healthy age-matched individuals, (ii) TL differs in different stages of PC and (iii) shorter TL is significantly correlated with NPBs formation in PC cases. TL was measured in whole blood by well-established quantitative PCR method and the frequency of NPBs was measured in lymphocytes using cytokinesis-block micronucleus cytome (CBMNcyt) assay. Our results indicate that TL is shorter and NPBs are increased in PC patients relative to age-matched healthy controls. Furthermore, TL was significantly shorter (p = 0.03) in patients with a Gleason score more than 7 and there was also a significant trend of decreasing TL across all three stages (p trend = 0.01; Gleason score <7, 7 and >7). Furthermore, TL was significantly inversely correlated with NPB frequency in PC patients (r = −0.316; p = 0.001) but not in controls (r = 0.163; p = 0.06) and their relationships became stronger with higher Gleason scores. More studies are required that can confirm our observations and explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to non-cancer cases. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric high-grade gliomas (pHGGs) are highly aggressive tumors with a dismal prognosis despite multimodal therapy including surgery, radiation therapy and chemotherapy, underscoring the urgent need to develop novel therapeutic strategies. During tumor development, cells achieve immortality by activating telomere maintenance mechanisms. Alternative lengthening of telomere (ALT) is an important mechanism for maintaining telomere length and cell proliferation in tumor cells. However, the molecular pathway and prognostic significance of ALT activation in pHGGs are poorly understood. Here, we report the heterogeneity of telomere maintenance mechanisms and their association with genetic alterations with the presence of both ALT and telomerase activation in some tumors. These findings are particularly important for the future development of novel therapeutic strategies targeting ALT and telomerase in pHGGs. Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG), are highly aggressive tumors with dismal prognoses despite multimodal therapy including surgery, radiation therapy, and chemotherapy. To achieve cellular immortality cancer cells must overcome replicative senescence and apoptosis by activating telomere maintenance mechanisms (TMMs) through the reactivation of telomerase activity or using alternative lengthening of telomere (ALT) pathways. Although the ALT phenotype is more prevalent in pHGGs compared to adult HGGs, the molecular pathway and the prognostic significance of ALT activation are not well understood in pHGGs. Here, we report the heterogeneity of TMM in pHGGs and their association with genetic alterations. Additionally, we show that sensitivity to the protein kinase ataxia telangiectasia- and RAD3-related protein (ATR) inhibitor and the ATR downstream target CHK1 is not specific to pHGG ALT-positive cells. Together, these findings underscore the need for novel therapeutic strategies to target ALT in pHGG tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: R-loops, also referred to as RNA: DNA hybrids, are tripartite structures formed when a single-stranded RNA molecule forms a complex with a double-stranded DNA duplex via homology-directed base pairing. Many cellular functions are thought to be mediated by R-loops, including gene regulation, DNA replication, chromatin patterning, and DNA repair. R-loops are common and dynamic structures that account for up to 5% of mammalian genomes. In this review, we present an updated review of R-loops at a specific locus, telomeres. We summarize recent advances in the protein factors that regulate the formation and resolution of R-loops at telomeres. We also discuss the role of persistent or unscheduled R-loops in promoting genome and telomere instability and their links to human diseases. Telomeric repeat containing RNA (TERRA) is transcribed from subtelomeric regions to telomeres. TERRA RNA can invade telomeric dsDNA and form telomeric R-loop structures. A growing body of evidence suggests that TERRA-mediated R-loops are critical players in telomere length homeostasis. Here, we will review current knowledge on the regulation of R-loop levels at telomeres. In particular, we will discuss how the central player TERRA and its binding proteins modulate R-loop levels through various mechanisms. We will further provide an overview of the consequences of TERRA-mediated persistent or unscheduled R-loops at telomeres in human ALT cancers and other organisms, with a focus on telomere length regulation after replication interference-induced damage and DNA homologous recombination-mediated repair. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarizes the current understanding of the telomere maintenance mechanism known as the Alternative Lengthening of Telomeres (ALT). The role, recognizable indicators, and proposed mechanism of the ALT pathway in sustaining cancer cells are reviewed. Potential molecular targets for future therapeutic development are proposed with the goal of synthesizing the current understanding of the ALT pathway that will be required to make future advances in ALT cancer treatments. As detailed by the end replication problem, the linear ends of a cell's chromosomes, known as telomeres, shorten with each successive round of replication until a cell enters into a state of growth arrest referred to as senescence. To maintain their immortal proliferation capacity, cancer cells must employ a telomere maintenance mechanism, such as telomerase activation or the Alternative Lengthening of Telomeres pathway (ALT). With only 10–15% of cancers utilizing the ALT mechanism, progress towards understanding its molecular components and associated hallmarks has only recently been made. This review analyzes the advances towards understanding the ALT pathway by: (1) detailing the mechanisms associated with engaging the ALT pathway as well as (2) identifying potential therapeutic targets of ALT that may lead to novel cancer therapeutic treatments. Collectively, these studies indicate that the ALT molecular mechanisms involve at least two distinct pathways induced by replication stress and damage at telomeres. We suggest exploiting tumor dependency on ALT is a promising field of study because it suggests new approaches to ALT-specific therapies for cancers with poorer prognosis. While substantial progress has been made in the ALT research field, additional progress will be required to realize these advances into clinical practices to treat ALT cancers and improve patient prognoses. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissues. We quantitatively assessed these associations through a systematic review and meta-analysis. Following PRISMA guidelines, we identified relevant studies through database searches, and performed meta-analyses using random effects models. We found no association between telomere length in circulating leukocytes and the risk of developing colorectal cancer, however, shorter leukocyte telomeres were associated with a worse survival in patients with colorectal cancer. Therefore, telomere length may serve as a potential biomarker especially for colorectal cancer prognosis. Larger prospective cohort studies are needed to further confirm this potential association. (1) Background: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissue. A systematic review and meta-analysis of the literature was conducted. The PubMed, Embase, and Web of Science databases were searched through March 2022. (2) Methods: Relevant studies were identified through database searching following PRISMA guidelines. Risk estimates were extracted from identified studies; meta-analyses were conducted using random effects models. (3) Results: Fourteen studies were identified (eight on risk; six on survival) through systematic review. While no association was observed between circulating leukocyte telomere length and the risk of colorectal cancer [overall OR (95% CI) = 1.01 (0.82–1.24)], a worse survival for those with shorter telomeres in leukocytes and longer telomeres in tumor tissues was observed [Quartile1/Quartile2–4 overall HR (95% CI) = 1.41 (0.26–7.59) and 0.82 (0.69–0.98), respectively]. (4) Conclusions: Although there was no association with colorectal cancer risk, a poorer survival was observed among those with shorter leukocyte telomere length. Future larger studies evaluating a potentially non-linear relationship between telomeres and colorectal cancer are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Mesothelioma is a rare cancer that originates in mesothelial surfaces of the peritoneum, pleura, and other sites. Diffuse malignant peritoneal mesothelioma (DMPM) corresponds to approximately 15% of all mesotheliomas. Cytoreductive surgery and HIPEC is the current standard of care, allowing the achievement of a median OS of at least 4 years. However, patient selection and perioperative management remain challenging. This paper outlines the diagnostic and therapeutic pathways of DMPM. Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of mesothelioma that carries a very poor prognosis. The 5-year overall survival is about 20% (±5.9). Survival is optimal for patients suitable for cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), with a median OS ranging from 34 to 92 months. However, selecting patients for surgery remains a complex task and requires a careful preoperative workup, rational analysis of prognostic profiles, and risk prediction models. Systemic chemotherapy could be offered: (1) in the adjuvant setting for high-risk patients; (2) for patients not eligible for CRS; and (3) for those with recurrent disease. It mainly includes the combination of Platin compound with Pemetrexed or immunotherapy. The biology of DMPM is still largely unknown. However, progress has been made on some fronts, such as telomere maintenance mechanisms, deregulation of apoptosis, tyrosine kinase pathways, and mutation of BRCA1-associated protein 1 (BAP1). Future perspectives should include translational research to improve our understanding of the disease biology to identify druggable targets. We should also clear the role of immune checkpoint inhibitors and investigate new locoregional technologies, such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) or normothermic intraperitoneal chemotherapy (NIPEC). [ABSTRACT FROM AUTHOR]

Simple Summary: The risk associated with obesity for the development of colorectal cancer seems to be well established. However, no biomarkers have been defined that allow the degree of obesity to be related to the clinical evolution of individuals affected by colorectal cancer. With the aim of contributing to the development of this correlation, we carried out a prospective study investigating parameters related to telomere function in the subcutaneous and visceral adipose tissues of a total of 147 subjects affected and not affected by colorectal cancer. Both the relative telomere length and the activity of telomerase in the adipose tissues seem to constitute parameters of interest in the clinical evaluation of individuals with colorectal cancer, which could be also related to the body mass index. To investigate the molecular mechanisms that link obesity and colorectal cancer (CRC), we analyzed parameters related to telomere function in subcutaneous and visceral adipose tissues (SAT and VAT), including subjects with and without CRC, who were classified according to their body mass index (BMI). Adipose tissues were obtained from 147 patients who had undergone surgery. A total of 66 cases corresponded to CRC patients, and 81 subjects were not affected by cancer. Relative telomere length was established by qPCR, and telomerase activity was determined by a method based on the telomeric repeat amplification protocol. Our results indicated longer telomeres in patients affected by CRC, both in SAT and VAT, when compared to the group of subjects without CRC. Tumor local invasion was associated with telomere length (TL) in SAT. Considering the BMI values, significant differences were found in the TL of both adipose tissues between subjects affected by CRC and those without cancer. Overweight subjects showed the greatest differences, with longer telomeres in the group of CRC patients, and a higher number of cases with telomerase reactivation in the VAT of subjects without cancer. In conclusion, parameters related to telomere function in adipose tissue could be considered as potential biomarkers in the evaluation of CRC and obesity. [ABSTRACT FROM AUTHOR]

Simple Summary: Short, dysfunctional telomeres represent the genetic biomarkers of cancer. Studies in early-stage non-small-cell lung cancer (NSCLC) have shown that telomere length and telomerase levels are correlated with survival. In patients with advanced NSCLC, telomere status has not yet been investigated, and its clinical significance remains unknown. We studied telomere length and the expression of telomerase and shelterin genes in a cohort of 79 patients with advanced NSCLC, and evaluated these parameters as potential prognostic and predictive factors. Telomere shortening, high levels of telomerase and aberrant expression of shelterin genes TRF2, RAP1 and TIN2 were significantly correlated with shorter survival. Furthermore, a worse response to immunotherapy was observed in patients with shorter telomeres. The determination of telomere parameters in advanced NSCLC could be useful for individualized treatment decisions. Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Human Papilloma Virus (HPV) is known to affect thousands globally. HPV infection can act carcinogenically on host cells with expression of the virus's E6 and E7 oncoproteins. Within the United States, roughly 70% of oropharyngeal cancers are thought to be HPV induced. Viral genome integration has been well studied, yet genomic effects of the E6 and E7 proteins on other genetic regions remain relatively unidentified. This study characterizes genomic mutation in HPV-infected HNSCC patients with specific regard to host E6 and E7 expression. Individuals with greater presence of these oncoproteins were found to exhibit a greater average of point mutations, particularly on chromosomes 1, 11, and 17. Greater expression of E6 and E7 also correlates to a lesser number of clustered variation events and fewer repeats of copy number segments. Analysis of the genomic effects of HPV may provide additional insight into the pathogenesis of HNSCC. Human Papilloma Virus (HPV) is highly prevalent within the U.S., with studies estimating that over 80% of individuals will contract the virus in their lifetime. HPV is considered a primary risk factor for the development and progression of oropharyngeal cancers. The impact of the HPV virus's E6 and E7 oncoproteins on cellular signaling pathways and genomic integration has been extensively characterized. Indirect genomic effects; however, remain relatively unidentified. In this study, we analyzed 83 HPV+ Head and Neck Squamous Cell Carcinoma (HNSCC) patients of varying HPV types. Expression counts of the HPV E6 and E7 oncogenes were estimated across samples and correlated with genomic mutational classes. High expression of E6 and E7 oncoproteins was associated with a greater number of total point mutations, especially on chromosomes 1, 11, and 17, which have been implicated in HPV-mediated cancers in previous studies. Samples with high E6 and E7 expression also exhibited more frequent non-clustered structural variation and a lack of clustered variation altogether. Copy number segments were present with fewer number of repeats in high E6 and E7 expression samples, which is known to correlate with decreased expression of affected genes. E6 and E7 expression was associated with increased activity of several cellular pathways associated in oncogenesis and telomere maintenance. In comprehensively characterizing the effects of the HPV oncoproteins on the human genome, potential mechanisms of HNSCC pathogenesis may be further elucidated. [ABSTRACT FROM AUTHOR]

Simple Summary: Under the continuous stimulation of oxidizing substances, DNA bases undergo oxidative damage and excision repair alternately at all times. Once this process becomes abnormal, many pathological diseases will appear one after another. NEIL3 is an important DNA glycosylase in the base excision repair pathway and is involved in oxidative DNA base damage repair. In recent years, several studies have confirmed that abnormal expression of NEIL3 is closely associated with cancers and cardiovascular and neurological diseases, and it may be a potential prognostic molecule and therapeutic target. circNEIL3, a circular RNA of exon-encoded origin by NEIL3, also promotes the development of multiple cancers. In this review, we not only describe the structural specificity and functional specificity of NEIL3, but also focus on NEIL3 and circNEIL3 in cancer progression and prognosis. In addition, we also discuss the link between NEIL3 and the progression of cardiovascular and neurological diseases. The accumulation of oxidative DNA base damage can severely disrupt the integrity of the genome and is strongly associated with the development of cancer. DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. The Nei endonuclease VIII-like 3 (NEIL3) is an emerging DNA glycosylase essential in maintaining genome stability. With an in-depth study of the structure and function of NEIL3, we found that it has properties related to the process of base damage repair. For example, it not only prefers the base damage of single-stranded DNA (ssDNA), G-quadruplex and DNA interstrand crosslinks (ICLs), but also participates in the maintenance of replication fork stability and telomere integrity. In addition, NEIL3 is strongly associated with the progression of cancers and cardiovascular and neurological diseases, is incredibly significantly overexpressed in cancers, and may become an independent prognostic marker for cancer patients. Interestingly, circNEIL3, a circular RNA of exon-encoded origin by NEIL3, also promotes the development of multiple cancers. In this review, we have summarized the structure and the characteristics of NEIL3 to repair base damage. We have focused on NEIL3 and circNEIL3 in cancer development, progression and prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The expression of the telomerase reverse transcriptase (TERT) gene is commonly repressed in terminally differentiated somatic cells and becomes reactivated in the large majority of tumors. Oncogenic viruses have evolved multiple strategies to subvert the telomerase function in the host cells. Viruses may promote TERT transcription through the binding of their oncoproteins to cis-regulatory elements in the gene promoter or by integrating their genomes nearby TERT locus. Other viruses cause telomerase activation via epigenetic mechanisms that contribute to the maintenance of long telomeres and cellular immortality. This review will outline recent findings on the strategies employed by viruses to deregulate telomerase activity and telomere length and to promote cancer development. Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is universally enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein–Barr virus (EBV) LMP1, Kaposi's sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) Tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate on recent findings on virus–telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer-causing viruses. [ABSTRACT FROM AUTHOR]

Simple Summary: Cells infected with high-risk human papillomaviruses (HPV) can accumulate DNA damage and eventually transform into HPV-driven cancers. Genome instability, or the progressive accumulation of DNA alterations (e.g., mutations), in HPV-infected cells is directly induced by the HPV genes and indirectly promoted by HPV infection through the consequences of chronic infection maintenance, increased cell growth, and accumulation of damaging mutations in genes that themselves affect genome instability. While the HPV genome typically exists as a separate entity within cells, genome instability increases the chances of HPV integrating within the host (human) genome, which is common in HPV-induced cancers. The DNA regions surrounding HPV integrations are unstable and can undergo complex alterations that affect both human and HPV genes. This review discusses HPV-dependent and -independent drivers and mechanisms of genome instability in HPV-driven cancers, both globally and around sites of HPV integration, and describes the changes induced in the tumour genome. Human papillomavirus (HPV) is the causative driver of cervical cancer and a contributing risk factor of head and neck cancer and several anogenital cancers. HPV's ability to induce genome instability contributes to its oncogenicity. HPV genes can induce genome instability in several ways, including modulating the cell cycle to favour proliferation, interacting with DNA damage repair pathways to bring high-fidelity repair pathways to viral episomes and away from the host genome, inducing DNA-damaging oxidative stress, and altering the length of telomeres. In addition, the presence of a chronic viral infection can lead to immune responses that also cause genome instability of the infected tissue. The HPV genome can become integrated into the host genome during HPV-induced tumorigenesis. Viral integration requires double-stranded breaks on the DNA; therefore, regions around the integration event are prone to structural alterations and themselves are targets of genome instability. In this review, we present the mechanisms by which HPV-dependent and -independent genome instability is initiated and maintained in HPV-driven cancers, both across the genome and at regions of HPV integration. [ABSTRACT FROM AUTHOR]

Simple Summary: ATRX and DAXX mutations occur in 30–40% of pancreatic neuroendocrine tumours (PanNETs), and there are no reports in the literature of any genetically engineered mouse model (GEMM) evaluating the effect of Atrx disruption as a putative driver event on PanNET initiation. We created a novel GEMM with Atrx conditional disruption in β cells. We observed that this genetic alteration, per se, was not tumourigenic, but we reported novel roles of Atrx on endocrine function, which resulted in dysglycaemia and the exacerbation of inflammageing (increased pancreatic inflammation and hepatic steatosis). ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events. [ABSTRACT FROM AUTHOR]

Simple Summary: Genome complexity, detected by chromosome banding analysis or chromosomal microarray analysis, is a poor prognostic factor for chronic lymphocytic leukemia (CLL). Herein, we aimed to assess the performance of optical genome mapping (OGM) for the cytogenomic characterization of CLL patients, with a special focus on risk stratification based on genomic complexity. A cohort of 42 patients enriched in complex karyotypes was assessed by OGM, and the results were compared with those obtained from current methods. Moreover, clinical–biological characteristics and time to first treatment were analyzed according to the OGM-defined complexity. Globally, OGM identified 90% of the known alterations and provided novel structural information about these aberrations in 55% of patients. Regarding genomic complexity, OGM allowed us to identify a complex group (≥10 alterations) displaying enrichment of TP53 abnormalities and poorer evolution. Altogether, we confirmed that OGM is a valuable tool for the cytogenomic assessment and prognostic stratification of CLL patients. Novel treatments in chronic lymphocytic leukemia (CLL) have generated interest regarding the clinical impact of genomic complexity, currently assessed by chromosome banding analysis (CBA) and chromosomal microarray analysis (CMA). Optical genome mapping (OGM), a novel technique based on imaging of long DNA molecules labeled at specific sites, allows the identification of multiple cytogenetic abnormalities in a single test. We aimed to determine whether OGM is a suitable alternative to cytogenomic assessment in CLL, especially focused on genomic complexity. Cytogenomic OGM aberrations from 42 patients were compared with CBA, FISH, and CMA information. Clinical–biological characteristics and time to first treatment (TTFT) were analyzed according to the complexity detected by OGM. Globally, OGM identified 90.3% of the known alterations (279/309). Discordances were mainly found in (peri-)centromeric or telomeric regions or subclonal aberrations (<15–20%). OGM underscored additional abnormalities, providing novel structural information on known aberrations in 55% of patients. Regarding genomic complexity, the number of OGM abnormalities had better accuracy in predicting TTFT than current methods (C-index: 0.696, 0.602, 0.661 by OGM, CBA, and CMA, respectively). A cut-off of ≥10 alterations defined a complex OGM group (C-OGM, n = 12), which included 11/14 patients with ≥5 abnormalities by CBA/CMA and one patient with chromothripsis (Kappa index = 0.778; p < 0.001). Moreover, C-OGM displayed enrichment of TP53 abnormalities (58.3% vs. 3.3%, p < 0.001) and a significantly shorter TTFT (median: 2 vs. 43 months, p = 0.014). OGM is a robust technology for implementation in the routine management of CLL patients, although further studies are required to define standard genomic complexity criteria. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumors of the brain and nerves develop frequently in patients with neurofibromatosis type 1. Many are benign growths, such as pilocytic astrocytomas in the brain and neurofibromas in the nerves. However, in some patients, the tumors become malignant and may cause local damage, disseminate to distant sites and result in death. We studied changes in the levels of chromatin proteins and changes in telomeres, in cells obtained from mouse gliomas that are deficient in neurofibromin as well as excess brain and nerve tumor tissue from patients with neurofibromatosis type 1 or sporadic tumors lacking neurofibromin expression. A decrease in the levels of these proteins in experimental cell lines resulted in susceptibility to a class of specific drugs knowns as ATR inhibitors, which may represent a specific vulnerability of these tumor subgroups. We expect our data to provide the required rationale for the development of more accurate animal models to study neurofibromatosis, as well as specific molecularly based drugs for treatment as alternatives to the current, often devastating approaches of surgery, radiation, and chemotherapy. Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and the presence of alternative lengthening of telomeres (ALT). We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. Cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), an NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), an NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors, with or without a MEK inhibitor or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition, irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line demonstrated sensitivity to ATR inhibition, but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: DDLPS is a non-lipogenic tumor with aggressive clinical behavior. DDLPS patients have limited therapeutic options, especially those with retroperitoneal tumors, and their outcome remains largely unsatisfactory, highlighting the need for novel treatment strategies. Gene expression analysis carried out in clinical samples from primary retroperitoneal DDLPS indicated that these tumors highly express genes involved in telomere maintenance, the cellular process that guarantees immortality to tumor cells. In this study, we evaluated the effect of RHPS4, a molecule able to alter telomere by binding to telomeric structures called G-quadruplexes, in patient-derived DDLPS cell lines. Exposure to RHPS4 induced DNA damage and decreased cell proliferation and migration, thus suggesting telomere as a novel target and G-quadruplex binders as innovative therapeutic agents in DDLPS. Background: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS) accounts for ~60% of retroperitoneal sarcomas. WDLPS and DDLPS divergently evolve from a common precursor and are both marked by the amplification of the 12q13–q15 region, leading to the abnormal expression of MDM2, CDK4, and HMGA2 genes. DDLPS is a non-lipogenic disease associated with aggressive clinical behavior. Patients have limited therapeutic options, especially for advanced disease, and their outcome remains largely unsatisfactory. This evidence underlines the need for identifying and validating DDLPS-specific actionable targets to design novel biology-driven therapies. Methods: Following gene expression profiling of DDLPS clinical specimens, we observed the up-regulation of "telomere maintenance" (TMM) pathways in paired DD and WD components of DDLPS. Considering the relevance of TMM for LPS onset and progression, the activity of a telomeric G-quadruplex binder (RHPS4) was assessed in DDLPS patient-derived cell lines. Results: Equitoxic concentrations of RHPS4 in DDLPS cells altered telomeric c-circle levels, induced DNA damage, and resulted in the accumulation of γ-H2AX-stained micronuclei. This evidence was paralleled by an RHPS4-mediated reduction of in vitro cell migration and induction of apoptosis/autophagy. Conclusions: Our findings support telomere as an intriguing therapeutic target in DDLPS and suggest G-quadruplex binders as innovative therapeutic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Klinefelter syndrome (KS) is a rare congenital aneuploidy characterized by inherited gain of one X chromosome (XXY). KS is associated with higher susceptibility to the development of cancer. Somatic acquired chromosomal aberrations and chromosomal instability are hallmarks of cancer and leukemia but little is known about the cellular mechanisms involved. The conducted research aimed to identify genomic mechanisms involved in chromosomal evolution mechanisms important for leukemic development. In the leukemic blasts of a patient with KS and B-cell acute lymphoblastic leukemia (B-ALL), we identified additional acquired chromosomal aberration and a significant reduction in the length of the chromosomal ends, i.e., telomeres. A literature review of KS patients with B-ALL revealed that the majority of these patients had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. These data indicate that enhanced reduction in telomere length might be associated with chromosomal instability and may serve as a future target for therapy or prevention. Rare congenital aneuploid conditions such as trisomy 13, trisomy 18, trisomy 21 and Klinefelter syndrome (KS, 47,XXY) are associated with higher susceptibility to developing cancer compared with euploid genomes. Aneuploidy frequently co-exists with chromosomal instability, which can be viewed as a "vicious cycle" where aneuploidy potentiates chromosomal instability, leading to further karyotype diversity, and in turn, paving the adaptive evolution of cancer. However, the relationship between congenital aneuploidy per se and tumor initiation and/or progression is not well understood. We used G-banding analysis, array comparative genomic hybridization analysis and quantitative fluorescence in situ hybridization for telomere length analysis to characterize the leukemic blasts of a three-year-old boy with KS and B-cell acute lymphoblastic leukemia (B-ALL), to gain insight into genomic evolution mechanisms in congenital aneuploidy and leukemic development. We found chromosomal instability and a significant reduction in telomere length in leukemic blasts when compared with the non-leukemic aneuploid cells. Reviewing published cases with KS and B-ALL revealed 20 additional cases with B-ALL diagnostic cytogenetics. Including our present case, 67.7% (14/21) had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. The presented data indicate that congenital aneuploidy in B-ALL might be associated with chromosomal instability, which may be fueled by enhanced telomere attrition. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomeres are specialized repeat DNA sequences at the ends of each chromosome. The primary function of telomeres is to prevent genomic instability. Telomeres shorten with every cell division. The role of relative telomere length (RTL) change in colorectal cancer (CRC) is not fully understood. We studied RTL in CRC tissue and adjacent normal tissue from the same patients (n = 165). We found significant shortening of RTL in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. However, shortening was more pronounced in low-grade tumors and in the presence of MSI. Gene expression data suggested an association of telomere shortening with rapid cell division (upregulation of DNA replication and cyclin-dependent kinase genes), as well as downregulation of apoptosis genes. CRC tissue showed upregulation of some telomere maintenance genes. We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL in the CRC tissue compared to paired normal tissue (RTL 0.722 ± SD 0.277 vs. 0.809 ± SD 0.242, p = 0.00012). This magnitude of RTL shortening (by ~0.08) in tumor tissue is equivalent to RTL shortening seen in human leukocytes over 10 years of aging measured by the same assay. RTL was shorter in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. RTL shortening was more prominent in low-grade CRC and in the presence of microsatellite instability (MSI). In a subset of patients, we also examined differential gene expression of (a) telomere-related genes, (b) genes in selected cancer-related pathways and (c) genes at the genome-wide level in CRC tissues to determine the association between gene expression and RTL changes. RTL shortening in CRC was associated with (a) upregulation of DNA replication genes, cyclin dependent-kinase genes (anti-tumor suppressor) and (b) downregulation of "caspase executor", reducing apoptosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Alternative lengthing of telomere (ALT) is an important mechanism for maintaining telomere length and cell proliferation in telomerase-negative tumor cells. However, the molecular mechanism of ALT is still poorly understood. ALT occurs in a wide range of tumor types and usually associated with a worse clinical consequence. Here, we review the recent findings of ALT mechanisms, which promise ALT could be a valuable drug target for clinical telomerase-negative tumor treatment. Telomeres are DNA–protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The telomerase enzyme adds repetitive genetic sequences to the ends of chromosomes called telomeres to prevent cellular senescence. Gain of telomerase function is one of the hallmarks of human cancer. The telomerase protein is coded by the gene TERT and increased TERT RNA levels have been associated with disease relapse in Wilms tumor, the most common kidney cancer of childhood. This study aimed to determine the mechanisms of increased TERT expression in Wilms tumor. This study found mutations in the TERT promoter, increased methylation of the TERT promoter, and genomic copy number amplifications of TERT as potential mechanisms of TERT activation. Conversely, this study found that inactivating WT1 mutation was associated with low TERT RNA levels and telomerase activity. N-MYC overexpression in Wilms tumor cells resulted in increased TERT promoter activity and TERT transcription. TERT transcription is associated with molecular and histologic subgroups in Wilms tumor and telomere-targeted therapies warrant future investigation. Increased TERT mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased TERT expression by determining the association between TERT and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate TERT expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the TERT promoter. This study identified near ubiquitous hypermethylation of the TERT promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in WT1 (7/45, 15.6%) were found to have lower TERT expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher TERT expression and telomerase activity. In vitro shRNA knockdown of WT1 resulted in decreased expression of TERT, reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type WT1. CRISPR-Cas9-mediated knockout of WT1 resulted in decreased expression of telomere-related gene pathways. However, an inducible Wt1-knockout mouse model showed no relationship between Wt1 knockout and Tert expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased TERT promoter activity and TERT transcription. Thus, multiple mechanisms of TERT activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of TERT activation in Wilms tumor that could be of therapeutic interests. [ABSTRACT FROM AUTHOR]

Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is one of the most obvious differences between normal and cancer cells. There is, however, debate on how aneuploid cells arise and whether or not they are a cause or a consequence of tumorigenesis. Further, it is important to distinguish aneuploidy (the "state" of the karyotype) from chromosomal instability (CIN; the "rate" of karyotypic change). Although CIN leads to aneuploidy, not all aneuploid cells exhibit CIN. One proposed route to aneuploid cells is through an unstable tetraploid intermediate because tetraploidy promotes chromosomal aberrations and tumorigenesis. Tetraploidy or near-tetraploidy (T/NT) (81-103 chromosomes) karyotypes with or without additional structural abnormalities have been reported in acute leukemia, T-cell and B-cell lymphomas, and solid tumors. In solid tumors it has been shown that tetraploidization can occur in response to loss of telomere protection in the early stages of tumorigenesis in colon cancer, Barrett's esophagus, and breast and cervical cancers. In hematological malignancies T/NT karyotypes are rare and the role of telomere dysfunction for the induction of tetraploidization is less well characterized. To further our understanding of possible telomere dysfunction as a mechanism for tetrapolydization in hematological cancers we here characterized the chromosomal complement and measured the telomere content by interphase nuclei quantitative fluorescence in situ hybridization (iQFISH) in seven hematological cancer patients with T/NT karyotypes, and after cytogenetic remission. The patients were identified after a search in our local cytogenetic registry in the 5-year period between June 2012 and May 2017 among more than 12,000 analyzed adult patients in this period. One advantage of measuring telomere content by iQFISH is that it is a single-cell analysis so that the telomere content can be distinguished between normal karyotype cells and cells with T/NT karyotypes. We find that the telomeres are particularly short in cells with T/NT karyotypes as compared with normal cells, and in T/NT karyotypes harboring additional chromosomal aberrations as well. These findings suggest that telomere dysfunction in hematological malignancies may be a mechanism for tetraploidization and CIN. [ABSTRACT FROM AUTHOR]

Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Most prostate cancer is of an indolent form and is curable. However, some prostate cancer belongs to rather aggressive subtypes leading to metastasis and death, and immediate therapy is mandatory. However, for these, the therapeutic options are highly invasive, such as radical prostatectomy, radiation or brachytherapy. Hence, a precise diagnosis of these tumor subtypes is needed, and the thus far applied diagnostic means are insufficient for this. Besides this, for their endless cell divisions, prostate cancer cells need the enzyme telomerase to elongate their telomeres (chromatin endings). In this study, we developed a gene regulatory model based on large data from transcription profiles from prostate cancer and chromatin-immuno-precipitation studies. We identified the developmental regulator PITX1 regulating telomerase. Besides observing experimental evidence of PITX1′s functional role in telomerase regulation, we also found PITX1 serving as a prognostic marker, as concluded from an analysis of more than 15,000 prostate cancer samples. The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT, transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT, we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length. [ABSTRACT FROM AUTHOR]