TCGA Pan-Cancer genomic analysis of Alternative Lengthening of Telomeres (ALT) related genes

AbstractTelomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors have the ability to switch from a telomerase-dependent mechanism to ALT, in fact, the co-existence between telomerase and the ALT pathway have been observed in a variety of cancer types. Despite different elements in the ALT pathway have been uncovered, the molecular mechanism and other factors are still poorly understood, which difficult the detection and treatment of ALT-positive cells, which are known to present poor prognosis. Therefore, with the aim to identify potential molecular markers to be used in the study of ALT, we combined simplistic in silico approaches in 411 telomere maintenance (TM) genes which have been previously validated or predicted to be involved in the ALT pathway. In consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies (n=9,282) from The Cancer Genome Atlas in the cBioPortal and found 325,936 genomic alterations, being mRNA high and low the top alterations with 65,.8% and 10.7% respectively. Moreover, we analyzed the highest frequency means of genomics alterations, identified and proposed 20 genes, which are highly mutated and up and down regulated in the cancer studies and could be used for future analysis in the study of ALT. Finally, we made a protein-protein interaction network and enrichment analysis to obtain an insight into the main pathways these genes are involved. We could observe their role in main processes related to the ALT mechanism like homologous recombination, homology directed repair (HDR), HDR through homologous recombination and telomere maintenance and organization.. Overall, due to the lack of understanding of the molecular mechanisms and detection of ALT-positive cancers, we identified and proposed more molecular targets that can be used for expression analysis and additional ex vivo assays to validate them as new potential therapeutic markers in the study of the ALT mechanism.

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TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes

Genes ◽

10.3390/genes11070834 ◽

2020 ◽

Vol 11 (7) ◽

pp. 834

Author(s):

Isaac Armendáriz-Castillo ◽

Andrés López-Cortés ◽

Jennyfer García-Cárdenas ◽

Patricia Guevara-Ramírez ◽

Paola E. Leone ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ex Vivo ◽

Genomic Analysis ◽

Interaction Network ◽

Enrichment Analysis ◽

Telomere Maintenance ◽

The Cancer Genome Atlas ◽

Alternative Lengthening Of Telomeres ◽

Alternative Lengthening ◽

Pan Cancer

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85–90% reactivate telomerase, while 10–15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.

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Identification of Key Proteins in the Alternative Lengthening of Telomeres Associated Promyelocytic Leukemia Nuclear Bodies

10.20944/preprints202110.0001.v1 ◽

2021 ◽

Author(s):

Isaac Armendáriz-Castillo ◽

Katherine Hidalgo-Fernández ◽

Andy Pérez-Villa ◽

Jennyfer García-Cárdenas ◽

Andrés López-Cortés ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ex Vivo ◽

Promyelocytic Leukemia ◽

Nuclear Bodies ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Alternative Lengthening Of Telomeres ◽

Pml Nuclear Bodies ◽

Alternative Lengthening

One of the hallmarks of the Alternative Lengthening of Telomeres (ALT) is the association with Promyelocytic Leukemia (PML) Nuclear Bodies, known as APBs. In the last years, APBs have been described as the main place where telomeric extension occurs in ALT positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multi-omics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 PanCancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT positive cancers in the future.

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Alternative Lengthening of Telomeres is not synonymous with mutations in ATRX/DAXX

10.1101/2020.05.05.076125 ◽

2020 ◽

Author(s):

Alexandre de Nonneville ◽

Roger R. Reddel

Keyword(s):

Large Scale ◽

Telomere Maintenance ◽

Whole Genome Sequence ◽

Structural Variations ◽

Alternative Lengthening Of Telomeres ◽

Maintenance Mechanism ◽

Alternative Lengthening ◽

Different Types ◽

Promoter Mutations ◽

Pan Cancer

AbstractThe PCAWG Consortium has recently released an unprecedented set of tumor whole genome sequence (WGS) data from 2,658 cancer patients across 38 different primary tumor sites1. WGS is able to document the quantity and distribution of telomeric repeats2. In one of the papers analyzing the PCAWG dataset, Sieverling et al.3 confirmed previous data4 indicating that tumors with truncating ATRX or DAXX alterations, referred to as ATRX/DAXXtrunc, have an aberrant telomere variant repeat (TVR) distribution. By regarding these mutations, vs. TERT modifications (TERTmod; i.e. promoter mutations +/− amplifications +/− structural variations), as indicators of Alternative Lengthening of Telomeres (ALT) vs. telomerase, they built a random forest classifier for ALT-probability, and then associated genomic characteristics with the putative Telomere Maintenance Mechanism (TMM)3. However, we show here that equating ATRX/DAXXtrunc and TERTmod with ALT and telomerase, respectively, results in TMM predictions which correlate poorly with TMM assay data. ATRX/DAXXtrunc mutations are heterogeneously distributed in ALT-positive (ALT+) tumors of different types, as are TERTmod in telomerase-positive tumors4. Although these mutations are strongly associated with TMM, most tumors do not harbor them, making them an inadequate basis for building a classifier in a large-scale pan-cancer study4–7. Here, we provide a new analysis of the PCAWG data, based on C-circle assay (CCA)8 that is available for a subset of these tumors4,9,10. We show that the Sieverling et al. score overestimates the proportion of ALT associated with ATRX/DAXXtrunc and misclassifies ALT tumors when these mutations are absent. We also show some TVR correlate with ATRX/DAXXtrunc mutations, regardless of TMM. Finally, we propose a new classifier to identify ALT tumors in the PCAWG cohort.

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Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Nature Communications ◽

10.1038/s41467-021-21247-8 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Sabine A. Hartlieb ◽

Lina Sieverling ◽

Michal Nadler-Holly ◽

Matthias Ziehm ◽

Umut H. Toprak ◽

...

Keyword(s):

High Frequency ◽

Clinical Course ◽

Population Based ◽

Telomeric Repeat ◽

Telomere Maintenance ◽

Study Cohort ◽

Alternative Lengthening Of Telomeres ◽

Course Of Disease ◽

Low Protein ◽

Alternative Lengthening

AbstractTelomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.

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Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway

Science Advances ◽

10.1126/sciadv.aax6366 ◽

2019 ◽

Vol 5 (10) ◽

pp. eaax6366 ◽

Cited By ~ 8

Author(s):

Mafei Xu ◽

Jun Qin ◽

Leiming Wang ◽

Hui-Ju Lee ◽

Chung-Yang Kao ◽

...

Keyword(s):

Nuclear Receptors ◽

Direct Interaction ◽

Telomere Maintenance ◽

Telomeric Dna ◽

Core Complex ◽

Alternative Lengthening Of Telomeres ◽

Independent Manner ◽

Replication Complex ◽

Alternative Lengthening ◽

Key Steps

Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

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Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

Scientific Reports ◽

10.1038/s41598-020-76975-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Daniel R. Principe ◽

Matthew Narbutis ◽

Regina Koch ◽

Ajay Rana

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

The Cancer Genome Atlas ◽

Parp Inhibition ◽

Repair Pathway ◽

Wide Range ◽

Recombination Pathway ◽

Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

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Abstract 4767: Generating and characterizing novel prostate cancer cell lines that employ the alternative lengthening of telomeres (ALT) telomere maintenance mechanism

10.1158/1538-7445.am2016-4767 ◽

2016 ◽

Author(s):

Mindy K. Graham ◽

Jacqueline Brosnan-Cashman ◽

Anthony Rizzo ◽

Michael Haffner ◽

Alan Meeker ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Lines ◽

Telomere Maintenance ◽

Alternative Lengthening Of Telomeres ◽

Prostate Cancer Cell Lines ◽

Maintenance Mechanism ◽

Alternative Lengthening

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Alternative Lengthening of Telomeres and Chromatin Status

Genes ◽

10.3390/genes11010045 ◽

2019 ◽

Vol 11 (1) ◽

pp. 45 ◽

Cited By ~ 1

Author(s):

Ion Udroiu ◽

Antonella Sgura

Keyword(s):

Homologous Recombination ◽

Reverse Transcriptase ◽

Spatial Heterogeneity ◽

Telomere Length ◽

Epigenetic Modifications ◽

Alternative Lengthening Of Telomeres ◽

Telomere Elongation ◽

Alternative Lengthening ◽

Alt Activity

Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given.

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