Evidence map›Paper›PMID 26340530›Full record

ArticleInternational journal of cancer2016

NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas.

Lydia Meder, Katharina König, Luka Ozretić, Anne M Schultheis, Frank Ueckeroth, Carsten P Ade, Kerstin Albus, Diana Boehm, Ursula Rommerscheidt-Fuss, Alexandra Florin and 8 more

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

Article in International journal of cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers.

0numbers the graph read from it
0cells of the map it votes in
116citing papers in PubMed
10.3field-weighted citation impact, top 1% 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

116 citing papers in PubMed, 175 citations in OpenAlex.

  1. Esophageal neuroendocrine carcinoma: molecular insights, diagnostic advances, and emerging treatment strategies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Review
  2. Article
  3. Correlation of TP53 Mutations With p53 Expression and Ki-67 Index in Pulmonary Large Cell Neuroendocrine Carcinomas.APMIS : acta pathologica, microbiologica, et immunologica Scandinavica · 2026
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  19. Cancers · 2024
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56 more citing papers are in PubMed but not listed here.

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

18 authors at 3 institutions in 1 country.

Lydia MederInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Katharina KönigInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Luka OzretićInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Anne M SchultheisInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Frank UeckerothInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Carsten P AdeBiocenter, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
Kerstin AlbusInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Diana BoehmCenter for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Ursula Rommerscheidt-FussInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Alexandra FlorinInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Theresa BuhlInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Wolfgang HartmannInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Jürgen WolfCenter for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Sabine Merkelbach-BruseInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Martin EilersBiocenter, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
Sven PernerCenter for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Lukas C HeukampInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Reinhard BuettnerInstitute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
University Hospital Bonn · DEUniversity Hospital Cologne · DEUniversity of Würzburg · DE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionally, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.

Indexed as

Signal TransductionBasic Helix-Loop-Helix ProteinsCarcinoma, NeuroendocrineDNA Mutational AnalysisFlow CytometryFluorescent Antibody TechniqueHigh-Throughput Nucleotide SequencingHumansImmunohistochemistryIn Situ Hybridization, FluorescenceLung NeoplasmsReceptors, NotchRetinoblastoma ProteinSmall Cell Lung CarcinomaTransfectionTumor Suppressor Protein p53ASCL1 protein, humanBasic Helix-Loop-Helix ProteinsReceptors, NotchRetinoblastoma ProteinTP53 protein, humanTumor Suppressor Protein p53achaete-scute homolog 1Lung cancerneurogenic locus notch homologretinoblastoma proteinsmall cell lung cancer

Identifiers

PMID26340530
PMCPMC4832386
OpenAlexW2127327720

What OpenQuestion holds

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LicenceCC BY-NC-ND
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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.