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Evolution of telomere maintenance and tumour suppressor mechanisms across mammals.

ABSTRACT: Mammalian species differ dramatically in telomere biology. Species larger than 5-10 kg repress somatic telomerase activity and have shorter telomeres, leading to replicative senescence. It has been proposed that evolution of replicative senescence in large-bodied species is an anti-tumour mechanism counteracting increased risk of cancer due to increased cell numbers. By contrast, small-bodied species express high telomerase activity and have longer telomeres. To counteract cancer risk due to longer lifespan, long-lived small-bodied species evolved additional telomere-independent tumour suppressor mechanisms. Here, we tested the connection between telomere biology and tumorigenesis by analysing the propensity of fibroblasts from 18 rodent species to form tumours. We found a negative correlation between species lifespan and anchorage-independent growth. Small-bodied species required inactivation of Rb and/or p53 and expression of oncogenic H-Ras to form tumours. Large-bodied species displayed a continuum of phenotypes requiring additional genetic 'hits' for malignant transformation. Based on these data we refine the model of the evolution of tumour suppressor mechanisms and telomeres. We propose that two different strategies evolved in small and large species because small-bodied species cannot tolerate small tumours that form prior to activation of the telomere barrier, and must instead use telomere-independent strategies that act earlier, at the hyperplasia stage.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.

SUBMITTER: Tian X

PROVIDER: S-EPMC5784063 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Project description:Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay [a marker for alternative lengthening of telomeres (ALT)], TERT mRNA expression by RNA-sequencing, whole-genome/exome sequencing, and clinical covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines (n = 104) and patient-derived xenografts (n = 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in ATRX were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three subgroups (TERT-high, ALT+, and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT+, or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; P < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets. SIGNIFICANCE: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.

Project description:The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-?, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

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Evolution of telomere maintenance and tumour suppressor mechanisms across mammals.

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