Evidence map›Paper›PMID 34348967›Full record

ArticleCancer research2021

Subclone Eradication Analysis Identifies Targets for Enhanced Cancer Therapy and Reveals L1 Retrotransposition as a Dynamic Source of Cancer Heterogeneity.

Kirsi Ketola, Heidi Kaljunen, Sinja Taavitsainen, Roosa Kaarijärvi, Emmi Järvelä, Bernardo Rodríguez-Martín, Kerstin Haase, Dan J Woodcock, Jose Tubio, David C Wedge and 2 more

Open access · hybridAbstract read
In one paragraph

Article in Cancer research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.6field-weighted citation impact, top 35% 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

7 citing papers in PubMed, 15 citations in OpenAlex.

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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

12 authors at 6 institutions in 4 countries.

Kirsi KetolaInstitute of Biomedicine, University of Eastern Finland, Kuopio, Finland. kirsi.ketola@uef.fi steve.bova@tuni.fi.
Heidi Kaljunen *Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Sinja Taavitsainen *Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland.
Roosa KaarijärviInstitute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Emmi JärveläInstitute of Biomedicine, University of Eastern Finland, Kuopio, Finland.ORCID 0000-0002-5249-2508
Bernardo Rodríguez-MartínGenomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
Kerstin HaaseExperimental and Clinical Research Center, Charité and the Max Delbrück Center for Molecular Medicine, Universitätsmedizin Berlin, Berlin, Germany.
Dan J WoodcockBig Data Institute, University of Oxford, Li Ka Shing Centre for Health Information and Discovery, Oxford, United Kingdom.
Jose TubioGenomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
David C WedgeManchester Cancer Research Centre, University of Manchester, Manchester, United Kingdom.ORCID 0000-0002-7572-3196
Matti NykterFaculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland.
G Steven BovaFaculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland. kirsi.ketola@uef.fi steve.bova@tuni.fi.ORCID 0000-0003-1639-3104
University of Eastern Finland · FITampere University of Applied Sciences · FIUniversidade de Santiago de Compostela · ESCancer Research UK Manchester Institute · GBHealth Data Research UK · GBMax Delbrück Center · DE

Funding

Modes of Prostate Ca Progression--role of p53 PathwayR01CA092234 · NCI · JOHNS HOPKINS UNIVERSITY · PI BOVA, GEORGE STEVEN · 2001 to 2005
$1.2M
Cancer Research UKNCI NIH HHS R01 CA092234
6 · The paper itself

Abstract

Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance. SIGNIFICANCE: Differential analysis of eradicated and resistant subclones following cancer treatment identifies that L1 activity associated with resistance is induced by current therapies and blocked by the antiretroviral drug azidothymidine.

Indexed as

Biomarkers, TumorGenetic HeterogeneityLong Interspersed Nucleotide ElementsAntineoplastic AgentsAutopsyBiopsyCell Line, TumorClonal EvolutionCpG IslandsDisease ManagementDisease SusceptibilityDNA MethylationDrug Resistance, NeoplasmEpigenesis, GeneticGene SilencingGenomicsAntineoplastic AgentsBiomarkers, TumorRetroelementsRNA, Small Interfering

Identifiers

PMID34348967
PMCPMC9397610
OpenAlexW3191178131

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.