Evidence map›Paper›PMID 26053551›Full record

ArticlePLoS genetics2015

A Common Cancer Risk-Associated Allele in the hTERT Locus Encodes a Dominant Negative Inhibitor of Telomerase.

Anagha Killedar, Michael D Stutz, Alexander P Sobinoff, Christopher G Tomlinson, Tracy M Bryan, Jonathan Beesley, Georgia Chenevix-Trench, Roger R Reddel, Hilda A Pickett

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed, 3 pooled it
2.5field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 3 syntheses or guidelines pooled it, 45 citations in OpenAlex.

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  16. Genetic variations associated with telomere length confer risk of gastric cardia adenocarcinoma.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2019
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 1 country.

Anagha KilledarTelomere Length Regulation Group, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Michael D StutzTelomere Length Regulation Group, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Alexander P SobinoffTelomere Length Regulation Group, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Christopher G TomlinsonCell Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Tracy M BryanCell Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Jonathan BeesleyDepartment of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Georgia Chenevix-TrenchDepartment of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Roger R ReddelCancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Hilda A PickettTelomere Length Regulation Group, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
University of Sydney · AUChildren's Medical Research Institute · AUQIMR Berghofer Medical Research Institute · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The TERT-CLPTM1L region of chromosome 5p15.33 is a multi-cancer susceptibility locus that encodes the reverse transcriptase subunit, hTERT, of the telomerase enzyme. Numerous cancer-associated single-nucleotide polymorphisms (SNPs), including rs10069690, have been identified within the hTERT gene. The minor allele (A) at rs10069690 creates an additional splice donor site in intron 4 of hTERT, and is associated with an elevated risk of multiple cancers including breast and ovarian carcinomas. We previously demonstrated that the presence of this allele resulted in co-production of full length (FL)-hTERT and an alternatively spliced, INS1b, transcript. INS1b does not encode the reverse transcriptase domain required for telomerase enzyme activity, but we show here that INS1b protein retains its ability to bind to the telomerase RNA subunit, hTR. We also show that INS1b expression results in decreased telomerase activity, telomere shortening, and an increased telomere-specific DNA damage response (DDR). We employed antisense oligonucleotides to manipulate endogenous transcript expression in favor of INS1b, which resulted in a decrease in telomerase activity. These data provide the first detailed mechanistic insights into a cancer risk-associated SNP in the hTERT locus, which causes cell type-specific expression of INS1b transcript from the presence of an additional alternative splice site created in intron 4 by the risk allele. We predict that INS1b expression levels cause subtle inadequacies in telomerase-mediated telomere maintenance, resulting in an increased risk of genetic instability and therefore of tumorigenesis.

Indexed as

AllelesAlternative SplicingBreast NeoplasmsCarcinomaFemaleGenes, DominantHEK293 CellsHumansIsoenzymesMCF-7 CellsOvarian NeoplasmsPolymorphism, Single NucleotideTelomeraseTelomere ShorteningIsoenzymesTelomeraseTERT protein, human

Identifiers

PMID26053551
PMCPMC4459975
OpenAlexW642009597

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.