Evidence map›Paper›PMID 27476653›Full record

ArticleAmerican journal of human genetics2016

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.

Ronja Adam, Isabel Spier, Bixiao Zhao, Michael Kloth, Jonathan Marquez, Inga Hinrichsen, Jutta Kirfel, Aylar Tafazzoli, Sukanya Horpaopan, Siegfried Uhlhaas and 18 more

Open access · bronzeAbstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
130citing papers in PubMed, 5 pooled it
22.6field-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

130 citing papers in PubMed, 5 syntheses or guidelines pooled it, 245 citations in OpenAlex.

  1. Guideline
  2. Genotype-phenotype correlations inOncology reviews · 2025
    Pooled it
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  4. Guideline
  5. Pooled it
  6. Trial
  7. [Hereditary colorectal cancer].Pathologie (Heidelberg, Germany) · 2026
    Review
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  10. Article
  11. Article
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  14. Article
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  18. Genetic predisposition to polyposis syndromes.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025
    Review
  19. Review
  20. Article

70 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

28 authors at 9 institutions in 4 countries.

Ronja AdamInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
Isabel SpierInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
Bixiao ZhaoDepartment of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
Michael KlothInstitute of Pathology, University of Cologne, 50937 Cologne, Germany.
Jonathan MarquezDepartment of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
Inga HinrichsenMedical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
Jutta KirfelInstitute of Pathology, University of Bonn, 53127 Bonn, Germany.
Aylar TafazzoliInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
Sukanya HorpaopanInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Chiang Mai 50200, Thailand.
Siegfried UhlhaasInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Dietlinde StienenInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Nicolaus FriedrichsInstitute of Pathology, University of Cologne, 50937 Cologne, Germany.
Janine AltmüllerCologne Center for Genomics, University of Cologne, 50937 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50937 Cologne, Germany.
Andreas LanerMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany.
Stefanie HolzapfelInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
Sophia PetersInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Katrin KayserInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Holger ThieleCologne Center for Genomics, University of Cologne, 50937 Cologne, Germany.
Elke Holinski-FederMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany.
Giancarlo MarraInstitute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland.
Glen KristiansenInstitute of Pathology, University of Bonn, 53127 Bonn, Germany.
Markus M NöthenInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
Reinhard BüttnerInstitute of Pathology, University of Cologne, 50937 Cologne, Germany.
Gabriela MösleinHELIOS Klinikum Wuppertal, University of Witten/Herdecke, 42283 Wuppertal, Germany.
Regina C BetzInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
Angela BriegerMedical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
Richard P LiftonDepartment of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
Stefan AretzInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany. Electronic address: stefan.aretz@uni-bonn.de.
University of Bonn · DEUniversity of Cologne · DEGoethe University Frankfurt · DEHoward Hughes Medical Institute · USLudwig-Maximilians-Universität München · DEHelios Universitätsklinikum Wuppertal · DELife & Brain (Germany) · DEUniversity of Zurich · CHYale University · US

Funding

Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9M
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007205 · NIGMS · YALE UNIVERSITY · PI KAZMIERCZAK, BARBARA I · 1985 to 2019
$42.9M
Yale Center for Mendelian GenomicsUM1HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2016 to 2020
$14.8M
Yale Center for Mendelian DisordersU54HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2012 to 2015
$11.0M
NCATS NIH HHS UL1 TR001863NHGRI NIH HHS U54 HG006504NHGRI NIH HHS UM1 HG006504NIGMS NIH HHS T32 GM007205
6 · The paper itself

Abstract

In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

Indexed as

AllelesAdenomatous Polyposis ColiAdolescentAdultChild, PreschoolColorectal NeoplasmsDNA-Binding ProteinsDNA Mutational AnalysisExomeFemaleGenes, RecessiveGerm-Line MutationHumansMaleMiddle AgedMismatch Repair Endonuclease PMS2DNA-Binding ProteinsMismatch Repair Endonuclease PMS2MSH3 protein, humanMutS Homolog 3 ProteinPMS2 protein, humanadenomatous polyposiscandidate genesexome sequencingfamilial colorectal cancerhereditary tumor syndromesmassive parallel sequencingmismatch repair

Identifiers

PMID27476653
PMCPMC4974087
OpenAlexW2482458164

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Registered trials

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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.