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

Zachary R. Chalmers, Caitlin Connelly, David Fabrizio, Laurie M. Gay, Siraj M. Ali, Riley Ennis, Alexa B. Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki, Franklin W. Huang, Yuting He, James Sun, Uri Tabori, Mark Kennedy, Daniel S. Lieber, Steven Roels, Jared White, Geoffrey A. Otto, Jeffrey S. Ross, Levi A. Garraway, Vincent A. Miller, P. J. Stephens, Garrett M. Frampton · Genome Medicine · 2017 · medicine · 10.1186/s13073-017-0424-2 · record chalmers2017-analysis-of-100-000-human-cancer-g
tag layer · index · concepts · authors · עברית
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Other fields define these differently the same word, defined another way in another discipline
false discovery rate 6 fields · biomarker 2 fields

Tags on this paper

Every tag the record carries, each linking to every other paper in the corpus that carries it. A tag appears here whether or not its words occur in the article — the spans below are only the ones a sentence in this paper licenses. Of the 12 concept tags on this paper, all 12 are grounded in a quoted sentence. All carry the tagger's gloss of what the term means in this paper, which is not something the article can license.
TMB mutation load biomarker Synonymous mutations MSI-High MSI score CGP WES neoantigens percentage deviation germline polymorphisms effect size sampling variance rising as the panel shrinks synonymous mutations as a process signal germline filtering without a matched normal high TMB R2 = 0.74 R2 = 0.98 principal components analysis false discovery rate omics-profiling
Method, as described: targeted comprehensive genomic profiling of 315 genes with germline filtering and no matched normal, validated against matched whole exome sequencing and against in-silico subsetting of TCGA exomes

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relation to other workclaim_relationshow this paper stands to another: agrees, contradicts, extends, qualifies
claim typeclaim_typethe shape of the claim: existence, mechanism, method, critique, prediction, null
concept edgeconcept_edgesan asserted relation between two concepts, with the sentence asserting it
conceptconceptsan idea the paper works with, quoted where the paper uses it
content tagcontent_tagsa finding, definition, quantity, statistic or variable named in the paper
contributioncontributionwhat the paper claims to add
controlcontrolsan experiment run to eliminate a rival explanation
limitationlimitationswhat the paper says its evidence cannot support
mechanismmechanismshow the reported effect is said to come about
methodmethodhow the paper produced its evidence
object of studyobject_of_studywhat the paper is about — the thing it investigates
phenomenonphenomenonthe effect or regularity under study
research questionresearch_questionthe question the paper sets itself
sensesensesa distinct use of a term, quoted where the paper fixes it
transfertransfersa method or concept carried in from another field

The paper

The full text is not reproduced here. This article is not cleared for redistribution, so the page carries the tag layer only. Its evidence sentences are withheld; the grounding status remains with each tag, and the article itself is at https://doi.org/10.1186/s13073-017-0424-2. The reading view exists for the papers whose licence permits it.

Every tag on this page

claim_relations 3 · claim_type 1 · concept_edges 2 · concepts 12 · content_tags 16 · contribution 1 · controls 6 · limitations 6 · mechanisms 3 · method 1 · object_of_study 1 · phenomenon 1 · research_question 1 · senses 4 · transfers 2

Relations on this page carry a quotation for the claim. Where a relation was separately evidenced — and so tested against the vocabulary for its type — the row says so; 2 of 2 relations here carry that mark. The rest are the tagger’s reading of the sentence quoted beside them.

facettagfieldconf.whose words
object_of_studytumour mutational burden as a biomarker - how it is counted, how little genome is enough to count it, and how it is distributed across cancer types
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object_of_studythe paper's words
research_questionwhether a 1.1 Mb targeted panel can stand in for whole exome sequencing when measuring mutational burden, and what the burden looks like across a hundred thousand clinical specimens
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research_questionthe paper's words
contributiona validated targeted measurement of TMB, a downsampling analysis showing where it stops working, and the distribution of TMB across more than 100 tumour types
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contributionthe paper's words
claim_typeexistence
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claim_typethe paper's words
phenomenona clinical category - high mutational burden - whose membership depends on an assay's size, a list of exclusions, and a threshold stated once in a figure caption
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phenomenonthe paper's words
methodomics-profiling
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methodthe paper's words
mechanismsTMB is a rate estimated from a sample of the genome, so the fewer megabases read the noisier the estimate; the effect is worst where the underlying rate is low, because the expected count in the sampled region approaches zero
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mechanisms[0]0.95the tagger's words
mechanismsa synonymous change cannot itself create a neoantigen, but it is produced by the same mutational process that produced the nonsynonymous ones elsewhere, so counting it raises the sample size of the rate estimate without changing what the rate is about
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
mechanisms[1]0.95the tagger's words
mechanismswith no normal tissue sequenced, inherited variants must be removed by matching against reference databases - so the filter's accuracy is the databases' coverage of the patient's ancestry
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mechanisms[2]0.95the tagger's words
limitationsthe germline filter depends on reference databases, so it will be least accurate for patients from ethnic backgrounds not well represented in them - stated by the authors
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limitations[0]0.95the tagger's words
limitationsthe MSI cut points were set by manual unsupervised clustering against a reference that was itself partly APPROXIMATED by the same pipeline's homopolymer indel counts
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limitations[1]0.95the tagger's words
limitationsthe accuracy figure rests on 29 specimens with matched whole exome sequencing; the two 0.98 correlations are the assay against itself and an in-silico subsetting
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limitations[2]0.95the tagger's words
limitationsknown mismatch-repair and replication genes account for less than 10% of high-TMB cases, so the molecular basis of most of the phenomenon is unexplained
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limitations[3]0.95the tagger's words
limitationsthe PMS2 promoter mutations are not shown to be causal, and the TOP2A association rests on eight cases
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limitations[4]0.95the tagger's words
limitationstargeted profiling measures the burden but cannot identify the neoantigens the mechanism depends on, since those may occur in any gene
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limitations[5]0.95the tagger's words
transfersprincipal components analysis, carried from multivariate statistics to collapse 228 repeat-length measurements into a single MSI score that can be cut into categories
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transfers[0]0.95the tagger's words
transfersresampling simulation, carried from survey methodology to ask how small a genomic panel may be before the rate it estimates stops being the rate
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transfers[1]0.95the tagger's words
controlsthe same biopsy specimens measured by both the targeted panel and whole exome sequencing, so the panel is checked against a different measurement rather than against itself
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eliminates: the targeted panel's own gene selection as the explanation of the burden it reports - the same biopsy measured by a method that selects no genes gives a correlated answer · outcome: partial
controls[0]0.95the tagger's words
controls60 replicate pairs run through the same assay, separating precision from accuracy
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
eliminates: assay noise as the explanation of the remaining disagreement with whole exome sequencing - the assay repeats itself at R2 0.98, so what is left is between methods and not within one · outcome: held
controls[1]0.95the tagger's words
controlssimulating the measurement at smaller panel sizes to find where sampling variance makes the estimate unusable, rather than asserting that 1.1 Mb is enough
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eliminates: sampling variance as a hidden contributor at the panel size actually used - the simulation measures it rather than assuming 1.1 Mb is enough, and names where it stops being enough · outcome: partial
controls[2]0.95the tagger's words
controlsan independent check on 8,917 TCGA exomes, comparing total mutations against those in the 315 assay genes
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eliminates: this laboratory's own cohort and pipeline as the source of the agreement - the same comparison on 8,917 independently generated exomes reproduces it · outcome: held
controls[3]0.95the tagger's words
controlscohort filtering declared in advance - duplicates removed, coverage floor, and a minimum of 50 specimens before a cancer type is analysed at all
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eliminates: duplicate specimens and under-covered samples as contributors to the reported distribution · outcome: held
controls[4]0.95the tagger's words
controlschecking whether more than the first principal component of the MSI score was needed
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
eliminates: further principal components as carriers of microsatellite signal the one-dimensional score discards - none of the others explains more than 4% of the variance · outcome: held
controls[5]0.95the tagger's words
conceptsTMB
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: TMB
concepts[0]0.95the paper's words
conceptsmutation load
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: mutation load
concepts[1]0.95the paper's words
conceptsbiomarker
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: biomarker
concepts[2]0.95the paper's words
conceptsSynonymous mutations
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
concepts[3]0.95the paper's words
conceptsMSI-High
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: MSI-High
concepts[4]0.95the paper's words
conceptsMSI score
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: MSI score
concepts[5]0.95the paper's words
conceptsCGP
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: CGP
concepts[6]0.95the paper's words
conceptsWES
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: WES
concepts[7]0.95the paper's words
conceptsneoantigens
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: neoantigens
concepts[8]0.95the paper's words
conceptspercentage deviation
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
concepts[9]0.95the paper's words
conceptsgermline polymorphisms
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
concepts[10]0.95the paper's words
conceptseffect size
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: effect size
concepts[11]0.95the paper's words
senses"high TMB" - AS USED throughout the abstract, results, discussion and conclusions: an unquantified clinical category of patients who might benefit from immunotherapy
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
senses[0]0.95the tagger's words
senses"high TMB" - AS DEFINED: more than 20 mutations per megabase. The threshold appears once in the paper, in the caption of Fig. 3, and nowhere in the prose
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
senses[1]0.95the tagger's words
sensesagreement of targeted CGP with whole exome - AS ACCURACY: R2 = 0.74, from 29 specimens where both measurements were made on the same biopsy
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
senses[2]0.95the tagger's words
sensesagreement of targeted CGP with whole exome - AS PRECISION: R2 = 0.98, the assay against itself on 60 replicate pairs. The paper labels this one precision, and it is the number that looks like agreement without being it
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
senses[3]0.95the tagger's words
claim_relationsqualifies → PD-1/PD-L1 expression by immunohistochemistry as the companion diagnostic for checkpoint inhibitors
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
claim_relations[0]0.95the tagger's words
claim_relationsextends → whole exome measurement of tumour mutational burden, by showing a 1.1 Mb targeted panel reproduces it
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
claim_relations[1]0.95the tagger's words
claim_relationsqualifies → neoantigen load as the predictor of immunotherapy response - correlated, but with no recurrent neoantigens found that predict response
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
claim_relations[2]0.95the tagger's words
concept_edgesMSI-High —part-of→ TMB
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
the relation itself is separately evidenced · strength of the relation: 0.85 · the relation stated: MSI-High samples are largely a subset of the high-TMB population, and not the reverse
also in: MSI-High · TMB
concept_edges[0]0.95the tagger's words
concept_edgesmutation load —same-as→ TMB
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
the relation itself is separately evidenced · strength of the relation: 0.9 · the relation stated: one quantity under two names, given in apposition at first use
also in: mutation load · TMB
concept_edges[1]0.95the tagger's words
content_tagsTargeted sequencing identifies high-TMB specimens well, but deviation rises at intermediate TMB, especially below 0.5 Mb sequenced.
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.findings[0]0.95the tagger's words
content_tags83% of MSI-High samples have high TMB but only 16% of high-TMB samples are MSI-High - two markers of genomic instability that do not substitute for each other
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.findings[1]0.95the tagger's words
content_tagsthe overlap between MSI-High and high TMB depends on the cancer type - near-total in gastrointestinal cancers, rare in melanoma
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.findings[2]0.95the tagger's words
content_tagsknown mismatch-repair and replication mutations account for under 10% of high-TMB cases
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.findings[3]0.95the tagger's words
content_tagsthe number of somatic, coding, base substitution and indel mutations per megabase of genome examined, with synonymous alterations counted and seven classes of alteration excluded
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: TMB
content_tags.definitions[0]0.95the tagger's words
content_tagsmore than 20 mutations per megabase - stated once, in the caption of Fig. 3, for a category used throughout the article
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: high TMB
content_tags.definitions[1]0.95the tagger's words
content_tagsthe first principal component of the means and variances of repeat lengths at 114 intronic homopolymer loci, projected onto one dimension
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: MSI score
content_tags.definitions[2]0.95the tagger's words
content_tagsthe panel size below which measurement variance increases significantly
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.quantities[0]0.95the tagger's words
content_tagsMSI-High samples that also had high TMB
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.quantities[1]0.95the tagger's words
content_tagshigh-TMB samples classified as MSI-High - the converse, and much smaller
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content_tags.quantities[2]0.95the tagger's words
content_tagsthe initial clinical cohort, filtered to 92,439
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.quantities[3]0.95the tagger's words
content_tagsR2 = 0.74
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: R2 = 0.74
content_tags.statistics[0]0.95the tagger's words
content_tagsR2 = 0.98
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
also in: R2 = 0.98
content_tags.statistics[1]0.95the tagger's words
content_tagsprincipal components analysis
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content_tags.statistics[2]0.95the tagger's words
content_tagsfalse discovery rate
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content_tags.statistics[3]0.85the tagger's words
content_tagspercentage deviation
Quotation withheld — this record is not cleared for redistribution. The sentence is in the paper at the link above.
content_tags.variables[0]0.95the tagger's words

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