Evidence map›Paper›PMID 29706558›Full record

ArticleThe lancet. Gastroenterology & hepatology2018

Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.

Eleanor Fewings, Alexey Larionov, James Redman, Mae A Goldgraben, James Scarth, Susan Richardson, Carole Brewer, Rosemarie Davidson, Ian Ellis, D Gareth Evans and 18 more

Registry-linked trialOpen access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The lancet. Gastroenterology & hepatology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03950908 (Single-bite Versus Double-bite Technique for Mapping Biopsies During Endoscopic Surveillance of Hereditary Diffuse Gastric Cancer), which is not on this map. Cited by 62 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
62citing papers in PubMed, 2 pooled it
10.1field-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.

NCT03950908 nacompletednot on this map

Single-bite Versus Double-bite Technique for Mapping Biopsies During Endoscopic Surveillance of Hereditary Diffuse Gastric Cancer: a Single Center, Randomized Controlled Trial

TypeinterventionalSponsorUniversity of CambridgeRan2017 to 2018Enrolled48ConditionsHereditary Diffuse Gastric CancerArmsSingle bite biopsy technique, Double bite biopsy technique
3 · Its place in the literature

Who cites it

62 citing papers in PubMed, 2 syntheses or guidelines pooled it, 105 citations in OpenAlex.

  1. A Systematic Literature Review of Whole Exome and Genome Sequencing Population Studies of Genetic Susceptibility to Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020
    Pooled it
  2. Guideline
  3. Germline whole-exome sequencing identifies CTNND1 as a candidate gene for hereditary gastric cancer in a large Brazilian cohort.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2026
    Article
  4. Observational
  5. ATR-CHK1 Axis Inhibitors in Gastric Cancer Treatment.International journal of molecular sciences · 2025
    Review
  6. Article
  7. Hereditary diffuse gastric cancer: the evolution of a cancer syndrome.Journal of the Royal Society of New Zealand · 2025
    Review
  8. Article
  9. Article
  10. Review
  11. Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2023
    Article
  12. Review
  13. Article
  14. Review
  15. [Hereditary diffuse gastric cancer].Chirurgie (Heidelberg, Germany) · 2023
    Review
  16. Article
  17. Review
  18. Hereditary cancer syndromes.World journal of clinical oncology · 2023
    Review
  19. Review
  20. Article

2 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

28 authors at 18 institutions in 3 countries.

Eleanor FewingsAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
Alexey LarionovAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
James RedmanAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
Mae A GoldgrabenAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
James ScarthAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
Susan RichardsonFamilial Gastric Cancer Study, Department of Oncology, University of Cambridge, Cambridge, UK.
Carole BrewerPeninsula Clinical Genetics Service, Exeter, UK.
Rosemarie DavidsonWest of Scotland Genetics Services, Glasgow, UK.
Ian EllisCheshire and Merseyside Regional Genetic Service, Liverpool, UK.
D Gareth EvansManchester Centre for Genomic Medicine, Manchester, UK.
Dorothy HallidayOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Louise IzattClinical Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Peter MarksWest Midlands Regional Genetics Service, Birmingham, UK.
Vivienne McConnellNorthern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
Louis VerbistDepartment of Gastroenterology, ZNA Jan Palfijn, Antwerp, Belgium.
Rebecca MayesCentre for Cancer Genetic Epidemiology, Strangeway's Research Laboratory, University of Cambridge, Cambridge, UK.
Graeme R ClarkAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
James HadfieldCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK; Precision Medicine and Genomics, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, UK.
Suet-Feung ChinCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Manuel R TeixeiraDepartment of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal; Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
Olivier T GigerDepartment of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Richard HardwickDepartment of Oesophago-Gastric Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Massimiliano di PietroMedical Research Council (MRC) Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
Maria O'DonovanDepartment of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Paul PharoahCentre for Cancer Genetic Epidemiology, Strangeway's Research Laboratory, University of Cambridge, Cambridge, UK.
Carlos CaldasCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
Rebecca C FitzgeraldMedical Research Council (MRC) Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
Marc TischkowitzAcademic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK. Electronic address: mdt33@cam.ac.uk.
University of Cambridge · GBCambridge University Hospitals NHS Foundation Trust · GBNational Institute for Health Research · GBMRC Epidemiology Unit · GBNIHR Cambridge Biomedical Research CentreCancer Research UK · GBCancer Research UK Cambridge Center · GBGuy's and St Thomas' NHS Foundation Trust · GBHutchison/MRC Research Centre · GBInstituto Português de Oncologia Francisco Gentil · PTMerseytravel · GBMRC Cancer Unit · GBNIHR Manchester Biomedical Research Centre · GBOxford University Hospitals NHS Trust · GBPeninsula College of Medicine and Dentistry · GBUniversity of Ulster · GBWessex Regional Genetics Laboratory · GBZiekenhuisnetwerk Antwerpen Stuivenberg · BE

Funding

Cancer Research UK 10119Cancer Research UK 16561Cancer Research UK 16942Medical Research Council MC_UU_12022/2
6 · The paper itself

Abstract

backgroundGermline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.

methodsWe did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.

findingsProtein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.

interpretationThe results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families.

fundingUK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

Indexed as

Genetic Predisposition to DiseaseGerm-Line MutationAdultAgedAtaxia Telangiectasia Mutated ProteinsBRCA2 ProteinCell Cycle ProteinsClinical Decision-MakingExome SequencingFanconi Anemia Complementation Group N ProteinFemaleFrameshift MutationHumansLoss of Function MutationMaleMiddle AgedAtaxia Telangiectasia Mutated ProteinsATR protein, humanBRCA2 ProteinBRCA2 protein, humanCell Cycle ProteinsFanconi Anemia Complementation Group N ProteinMSH2 protein, humanMutS Homolog 2 ProteinNBN protein, humanNuclear ProteinsPALB2 protein, humanRecQ HelicasesRECQL5 protein, human

Identifiers

PMID29706558
PMCPMC5992580
OpenAlexW2800483172

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Registered trials

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.