Long telomere length predicts poor clinical outcome in esophageal cancer patients

Lv, Yunyun; Zhang, Yong; Li, Xinru; Ren, Xiaojuan; Wang, Meichen; Tian, Sijia; Hou, Peng; Shi, Bingyin; Yang, Qi

doi:10.1016/j.prp.2016.11.010

Cited by 6 publications

(4 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, telomerase-high CSCs are among the most energetically activated, migratory and proliferative cell sub-populations. These observations may provide a mechanistic explanation for why long telomere length [ 6 – 9 ] (a surrogate marker of increased telomerase activity) is specifically associated with metastasis and poor clinical outcome in NSC lung cancer and many other tumor types. Thus, high telomerase activity may drive poor clinical outcome by activating mitochondrial biogenesis, “fueling” the proliferation in lung CSCs [ 4 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial markers predict survival and progression in non-small cell lung cancer (NSCLC) patients: Use as companion diagnostics

Sotgia

Lisanti

2017

Oncotarget

View full text Add to dashboard Cite

Here, we used an informatics-based approach to identify novel biomarkers of overall survival and tumor progression in non-small cell lung cancer (NSCLC) patients. We determined whether nuclear-encoded genes associated with mitochondrial biogenesis and function can be used to effectively predict clinical outcome in lung cancer. This strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large, clinically-relevant, lung cancer patient populations. Towards this end, we used a group of 726 lung cancer patients, with negative surgical margins. Importantly, in this group of cancer patients, markers of cell proliferation (Ki67 and PCNA) were associated with poor overall survival, as would be expected. Similarly, key markers of inflammation (CD163 and CD68) also predicted poor clinical outcome in this patient population. Using this approach, we identified >180 new individual mitochondrial gene probes that effectively predicted significantly reduced overall survival, with hazard-ratios (HR) of up to 4.89 (p<1.0e-16). These nuclear-encoded mitochondrial genes included chaperones, membrane proteins as well as ribosomal proteins (MRPs) and components of the OXPHOS (I-V) complexes. In this analysis, HSPD1, a key marker of mitochondrial biogenesis, had the highest predictive value and was also effective in predicting tumor progression in both smokers and non-smokers alike. In fact, it had even higher predictive value in non-smokers (HR=5.9; p=3.9e-07). Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target, for the more effective treatment of human lung cancers. The mitochondrial biomarkers that we have identified could serve as new companion diagnostics to assist clinicians in more accurately predicting clinical outcomes in lung cancer patients, driving more personalized cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Mitochondrial markers predict survival and progression in non-small cell lung cancer (NSCLC) patients: Use as companion diagnostics

Sotgia

Lisanti

2017

Oncotarget

View full text Add to dashboard Cite

show abstract

“…The above examples are consistent with the idea of telomere length loss and subsequent dysfunction as being a precursor to tumour progression. Other studies indicate that the converse may be true, where for some cancers, longer telomere length predicts poor clinical outcome [ 131 , 132 , 133 , 134 , 135 , 136 , 137 ]. This has been demonstrated in oesophageal cancer where patients with a relative telomere length (RTL) greater than 1.22, as measured qPCR, have a shorter median survival time than patients with an RTL under this threshold [ 131 ].…”

Section: Telomere Length As a Prognostic Marker In Cancermentioning

confidence: 99%

“…These findings on leukocyte telomere length however, do not necessarily conflict with the model of short dysfunctional telomeres in the developing tumour clone, driving tumour progression through the generation of large scale genomic instability and subsequent clonal evolution. Instead an “immunohypothesis” has been put forward, suggesting that longer leukocyte telomere length may arise in patients with a suppressed immune system, leading to fewer cell divisions and reduced telomere shortening [ 131 ]. In support of this hypothesis, a significant correlation between leukocyte telomere length and peripheral levels of immunosuppressive regulatory T cells (Tregs) has been found in kidney cancer patients and hepatocellular carcinoma [ 136 , 138 ].…”

Section: Telomere Length As a Prognostic Marker In Cancermentioning

confidence: 99%

Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

Cleal

Norris

Baird

2018

IJMS

View full text Add to dashboard Cite

Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements.

show abstract

“…One might thus assume that short telomeres would always be detrimental. However in the case of esophageal cancer [140], prostate cancer [141], clear renal cell carcinoma [142], melanoma [143] and hepatocellular carcinoma [144], longer telomeres are associated with a poorer prognosis, possibly related to difficulties in replicating long telomeric tracts. As Rivera and colleagues showed, long telomeres might also be detrimental to cell fitness [145].…”

Section: Tert Expression and Telomere Length: Clinical Indicatorsmentioning

confidence: 99%

Tieing together loose ends: telomere instability in cancer and aging

2022

View full text Add to dashboard Cite

Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re‐addition of G‐rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.

show abstract

Long telomere length predicts poor clinical outcome in esophageal cancer patients

Cited by 6 publications

References 37 publications

Mitochondrial markers predict survival and progression in non-small cell lung cancer (NSCLC) patients: Use as companion diagnostics

Mitochondrial markers predict survival and progression in non-small cell lung cancer (NSCLC) patients: Use as companion diagnostics

Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

Tieing together loose ends: telomere instability in cancer and aging

Contact Info

Product

Resources

About