Evidence map›Paper›PMID 28420421›Full record

ArticleGenome medicine2017

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Zachary R Chalmers, Caitlin F Connelly, David Fabrizio, Laurie Gay, Siraj M Ali, Riley Ennis, Alexa Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki and 14 more

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

Article in Genome medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04263688 (Multicenter Observational Study for Correlation Between Tumor Mutation Burden and Immunotherapy Efficacy of Advanced Non-small Cell Lung Cancer With Malignant Pleural Effusion), which is not on this map. Cited by 2,182 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
2,182citing papers in PubMed, 2 pooled it
105.4field-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.

NCT04263688 unknown statusnot on this mapstarted 2020, after this paper: background citation

Multicenter Observational Study for Correlation Between Tumor Mutation Burden and Immunotherapy Efficacy of Advanced Non-small Cell Lung Cancer With Malignant Pleural Effusion

TypeobservationalSponsorGuangzhou Institute of Respiratory DiseaseRan2020 to 2022Enrolled300ConditionsNon-Small Cell Lung CancerArmsNon-Intervention
3 · Its place in the literature

Who cites it

2,182 citing papers in PubMed, 2 syntheses or guidelines pooled it, 3,672 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Trial
  4. Trial
  5. LRP1b Loss Predicts Sensitivity to Immunotherapy in Patients with NSCLC: An Analysis of the Phase III CheckMate-026 Randomized Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
    Trial
  6. Trial
  7. Trial
  8. Trial
  9. Article
  10. Article
  11. Article
  12. Review
  13. Review
  14. Article
  15. Article
  16. Review
  17. Review
  18. Review
  19. Review
  20. Article

2,122 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

24 authors at 4 institutions in 2 countries.

Zachary R ChalmersFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Caitlin F ConnellyFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
David FabrizioFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Laurie GayFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Siraj M AliFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Riley EnnisFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Alexa SchrockFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Brittany CampbellThe Hospital for Sick Children, Toronto, Ontario, Canada.
Adam ShlienThe Hospital for Sick Children, Toronto, Ontario, Canada.
Juliann ChmieleckiFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Franklin HuangDana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Yuting HeFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
James SunFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Uri TaboriThe Hospital for Sick Children, Toronto, Ontario, Canada.
Mark KennedyFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Daniel S LieberFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Steven RoelsFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Jared WhiteFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Geoffrey A OttoFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Jeffrey S RossFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Levi GarrawayDana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Vincent A MillerFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Phillip J StephensFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA.
Garrett M FramptonFoundation Medicine Inc., 150 Second St., Cambridge, MA, 02141, USA. gframpton@foundationmedicine.com.
Foundation Medicine (United States)Hospital for Sick Children · CADana-Farber Cancer Institute · USHarvard University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundHigh tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.

methodsIn this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types.

resultsWe demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB.

conclusionsThese results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.

Indexed as

DNA Mutational AnalysisGenome, HumanMutationAdolescentAdultAgedAged, 80 and overAge FactorsCell Transformation, NeoplasticChildDNA, NeoplasmExomeHumansMiddle AgedMismatch Repair Endonuclease PMS2NeoplasmsDNA, NeoplasmMismatch Repair Endonuclease PMS2Cancer genomicsMismatch repairPMS2Tumor mutational burden

Identifiers

PMID28420421
PMCPMC5395719
OpenAlexW2606495925

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

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.