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Pan-Cancer Analysis of Whole Genomes

2020 · paper · Biomedicine

Presents an integrative analysis of 2,658 whole cancer genomes across 38 tumour types. Cancer genomes carried on average 4–5 driver mutations, about 5% had none identified, and chromothripsis is frequently an early event in tumour evolution.

Checked: PDF from nature.com, fetched 4 Oct 2026. Page numbers are those of that PDF.

6 findings

Substance Text and Fig. 2a say "91% of tumours had at least one identified driver mutation" (Fig. 2a 'All' = 91, n = 2,583), but p. 5 says "we found none in 181 tumours", which is 7.0% of 2,583 (93% with a driver).
  • p. 3 Main text, Panorama of driver mutations
    We found that 91% of tumours had at least one identified driver mutation
  • p. 5 PCAWG tumours with no apparent drivers
    we found none in 181 tumours
  • p. 4 Fig. 2a bar plot, 'All'
    91
  • p. 1 Abstract
    in around 5% of cases no drivers were identified

Only the authors can say what is right here.

Judge's note: Checked p.3 (91% text), Fig. 2a on p.4 ('All' bar = 91, legend n = 2,583), p.5 (181 tumours) and ED Fig. 4a. 181/2,583 = 7.0%, so 93.0% would have a driver; 91% would mean about 232 tumours without one. Using 2,658 as the denominator does not reconcile the figures either, and I found no statement that the two counts use different driver definitions. The abstract's 'around 5%' is accounted for by the p.6 sentence giving 5.3% 'after accounting for technical issues and novel drivers', so that part is explained. The 91% vs 181 mismatch remains for the authors to resolve.

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Substance "This affected 35 myeloproliferative neoplasms in PCAWG, in which the JAK2V617F driver mutation should have been called", but ED Table 1 lists only 26 Myeloid-MPN cases (about 23 in ED Fig. 4a).
  • p. 5 PCAWG tumours with no apparent drivers, right column
    This affected 35 myeloprolif
  • p. 8 Fig. 5a, sample sizes across top (Myeloid−MPN)
    23
  • p. 45 Extended Data Table 1, Myeloid-MPN row
    Myeloproliferative neoplasm 26
  • p. 5 PCAWG tumours with no apparent drivers, right column
    This affected 35 myeloproliferative neoplasms in PCAWG

Only the authors can say what is right here.

Judge's note: p.5 text says 35. ED Table 1 (p.45) gives Myeloid-MPN = 26 cases of 2,658. The ED Fig. 4a Myeloid-MPN bar (p.27) is about 23, with a few in red (no driver). The number affected cannot exceed the number of MPNs in the cohort, and I found no other population that explains 35.

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Reference or label The main text describes the rare-variant analysis as "in individuals with European ancestry (Extended Data Fig. 11a–c)" (Fig. 6c: "European ancestry (n = 1,201)"), but the ED Fig. 11 legend says "two-sided rare-variant association testing across n = 2,583 patients" for panels a–d, f.
  • p. 10 Main text, rare-variant association paragraph
    in individuals with European ancestry (Extended Data Fig. 11a–c)
  • p. 9 Fig. 6c legend
    European ancestry (n = 1,201)
  • p. 40 Extended Data Fig. 11 legend
    two-sided rare-variant association testing across n = 2,583 patients

Only the authors can say what is right here.

Judge's note: Page 10 main text and the page 9 Fig. 6c legend both say European ancestry, n = 1,201. The ED Fig. 11 legend (p40) gives n = 2,583 for panels a–d and f, which is the full white-listed cohort (p1/Methods). The population is therefore labelled two ways for the same QQ-plot panels. I did not use the reviewer's ED Fig. 11g counts; the main mismatch is enough.

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Reference or label Ref. 4 is printed as "Rheinbay, E. et al. Analyses of non-coding somatic drivers in 2,693 cancer whole genomes. Nature ..."; the companion paper's published title gives 2,658.
  • p. 11 Reference list, ref. 4
    Analyses of non-coding somatic drivers in 2,693 cancer whole genomes

Only the authors can say what is right here.

Judge's note: Rests on outside knowledge: that the published Rheinbay et al. (2020) title reads '2,658 cancer whole genomes'. The page 11 crop shows 2,693. Inside the files, the cohort is 2,658 (ED Table 1 total; refs 7 and 18 use '2,658'), and 2,693 appears nowhere else in the paper.

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Reference or label Extended Data Fig. 12 legend letters g–j do not match the figure: legend g (ancestry/MEI-type correlation heat map) is panel I, h (PCAWG vs 1KGP AF) is J, "i, Evaluation of TraFiC-mem false-discovery rate" is G, and j (Illumina vs Nanopore length) is H.
  • p. 42 Extended Data Fig. 12 legend, panels g–j
    i, Evaluation of TraFiC-mem false-discovery rate
  • p. 41 Extended Data Fig. 12 panels G, H, I, J
    FDR = 10%

Judge's note: Page image p.41 shows G = ONT-read FDR bar chart (DO50807, NCI-BL2087, FDR = 10%), H = Length (ONT) vs Length (Illumina), I = Spearman heat map of ancestry by Alu/SVA/L1, J = AF 1KGP vs PCAWG. The legend crop (p.42) assigns g = heat map, h = AF correlation, i = FDR, j = length. All four letters point to the wrong panels.

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Wording The consortium author list prints "Ruben M. Drews170, Serge Serge2", alphabetically between Drews and Dudderidge, so the surname appears to have been replaced by a repeat of the given name.
  • p. 13 Consortium author list
    Ruben M. Drews170, Serge Serge2

Only the authors can say what is right here.

Judge's note: The page 13 crop confirms 'Serge Serge' (affiliation 2) placed among Dr–Du surnames in a list that is otherwise alphabetical by surname. Only the authors can supply the correct surname.

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26 minor (typos and the like; most checked by the judge only)
Substance Extended Data Table 1 gives Myeloid-AML 10 and Myeloid-MPN 26 cases, while the Fig. 5a sample-size row gives Myeloid-AML 13 and Myeloid-MPN 23.
  • p. 45 Extended Data Table 1, Myeloid-AML and Myeloid-MPN rows
    Acute myeloid leukaemia 10 3 7
  • p. 8 Fig. 5a, number of samples for Myeloid−AML / Myeloid−MPN
    13
  • p. 45 Extended Data Table 1, Myeloid rows
    Acute myeloid leukaemia 10

Only the authors can say what is right here.

Judge's note: ED Table 1 (p.45): AML 10, MDS 2, MPN 26, total 2,658. Fig. 5a (p.8, image plus layout text lines 944-988): AML 13, MDS 2, MPN 23. The Fig. 5a counts sum to 2,658. Every other type matches: Fig. 5a splits Kidney-RCC (111+33 = 144) and Skin-Melanoma (20+86+1 = 107) and merges Bone-Benign (7+9 = 16), all consistent with the table. Only the AML/MPN split differs, and no statement in the paper explains a reclassification. Only the authors can say which split is right.

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Reference or label The Fig. 1 legend says "assessed in the validation exercise across n = 63 PCAWG samples", whereas the text says validation sequencing covered "50 of these cases" and ED Fig. 2 gives "n = 50 samples in the validation dataset".
  • p. 3 Fig. 1 legend, panel a
    assessed in the validation exercise across n = 63 PCAWG samples
  • p. 2 Benchmarking of genetic variant calls
    For 50 of these cases, we per- formed validation
  • p. 25 Extended Data Fig. 2 legend
    across the n = 50 samples in the validation dataset

Only the authors can say what is right here.

Judge's note: p.2 says pipelines ran on 63 pilot pairs and validation was performed on 50 of them; the ED Fig. 2 legend (p.25) gives n = 50. The Fig. 1 legend gives n = 63 for the validation exercise. 63 may refer to the pilot set the callers were run on, but the label describes it as the validation set. Population label ambiguity.

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Reference or label Fig. 1b colours Sanger, DKFZ and MuTect2 blue (core) and SMuFin black, but Fig. 1d ('indel calls ... for the core algorithms') and ED Fig. 2b use DKFZ, Sanger and SMuFin as the core indel callers.
  • p. 3 Fig. 1b and legend
    Core algorithms included in the final PCAWG call set are shown in blue.
  • p. 3 Extended Data Fig. 2b x-axis
    SMuFin
  • p. 3 Fig. 1b, algorithms shown in blue
    MuTect2

Only the authors can say what is right here.

Judge's note: In the p.3 image, Fig. 1b plainly shows blue labels for Sanger, DKFZ and MuTect2 and a black SMuFin. The Fig. 1d legend lists DKFZ, SMuFin and Sanger, as does the ED Fig. 2b x-axis (p.25). The legend says 'core algorithms ... shown in blue', so the panels disagree about which indel caller is core. Only the authors can say which is right.

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Reference or label Fig. 3c panel titles read "Chromosome 5: 1,259,228" and "Chromosome 5: 1,259,250" for the two TERT promoter hotspots.
  • p. 5 Fig. 3c panel titles
    Chromosome 5: 1,259,228
  • p. 5 Fig. 3c panel titles
    Chromosome 5: 1,259,250

Only the authors can say what is right here.

Judge's note: Rests on outside knowledge: the TERT promoter hotspots (C228T/C250T) are at chr5:1,295,228 and 1,295,250 in GRCh37. The page image shows 1,259,228 and 1,259,250, which looks like a 95→59 transposition. The paper itself gives no coordinates to check against.

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Reference or label Fig. 3a/b uses the label "Bone–Cart", but the legend says "Abbreviations of the tumour types are defined in Extended Data Table 1", and ED Table 1 has no Bone-Cart entry.
  • p. 5 Fig. 3a/b x-axis
    Bone–Cart
  • p. 5 Fig. 3 legend
    Abbreviations of the tumour types are defined in Extended Data Table 1

Judge's note: ED Table 1 (p.45) lists Bone-Benign, Bone-Epith, Bone-Osteosarc, SoftTissue-Leiomyo and SoftTissue-Liposarc, but no Bone-Cart. ED Fig. 4b also uses Bone-Cart, Bone-Leiomyo and Lymph-NOS, which are absent from the table, though that legend does not point to ED Table 1.

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Reference or label "evenly distributed across truncating SNVs, SVs and shallow deletions (Extended Data Fig. 13c)": panel c shows clonality by cluster with no shallow-deletion category. Shallow deletions appear only in panel b.
  • p. 11 Replicative immortality section, left column
    evenly distributed across truncating SNVs, SVs and shallow dele-
  • p. 44 Extended Data Fig. 13 legend
    c, Distribution of clonality of driver mutations in genes
  • p. 11 Replicative immortality, paragraph on RB1 in C1
    truncating SNVs, SVs and shallow dele-tions (Extended Data Fig. 13c)
  • p. 44 Extended Data Fig. 13 legend, panel c
    c, Distribution of clonality of driver mutations in genes relevant to telomere maintenance across clusters.

Only the authors can say what is right here.

Judge's note: The ED Fig. 13 image (p43) shows panel B with an Alterations legend that includes Truncating, Shallow deletion and Structural Variant. Panel C shows clonal [early/late/NA], subclonal and NA rows, with markers for Nonsense, Missense, Indel, Splice_Site, SV and Promoter only. The legend (p44) describes c as clonality. Panel c partly supports the sentence (SNVs, SVs) but not the shallow deletions, so the pointer probably should be 13b, or b and c.

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Reference or label Extended Data Table 3 row 'Mutation distribution across genome' cites "11,12,15", but ref. 11 is "Zapatka, M. et al. The landscape of viral associations in human cancers".
  • p. 47 Extended Data Table 3, 'Mutation distribution across genome' row
    11,12,15
  • p. 11 Reference 11
    The landscape of viral associations in human cancers

Only the authors can say what is right here.

Judge's note: Checked ED Table 3 (p.47) and the reference list (p.11 crop). The row's findings (epigenetic state, cell of origin, TADs; tumour-type identification) match refs 15 (Akdemir, chromatin folding domains) and 12 (Jiao, deep-learning classification). Ref. 11 is about viral associations, and the table has no virus row even though its footnote says the key findings come from associated papers 4–18. The citation looks misplaced, but only the authors can say what was intended.

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Wording Text says "a few had power in the 70–90% range (Fig. 3b ...)", but Fig. 3b shows a Bone–Osteosarc no-driver tumour with average detection sensitivity of about 0.2.
  • p. 5 PCAWG tumours with no apparent drivers, left column
    power in the 70–90% range (Fig. 3b and Extended Data Fig. 4b)
  • p. 5 Fig. 3b, Bone–Osteosarc
    Average detection sensitivity

Only the authors can say what is right here.

Judge's note: In the Fig. 3b image (p.5), the Bone–Osteosarc violin extends to 0 and has a dot at about 0.2. The other low points (Liver-HCC, Stomach, Biliary) are about 0.7–0.85. The sentence does not mention the outlier far below 70%, so the summary understates the range shown.

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Wording "89 separate chromothripsis events that affected 66 melanomas (61%)": with 107 melanomas (ED Table 1; 86 cutaneous + 21 acral/mucosal in the next sentence), 66/107 = 61.7%, which rounds to 62%.
  • p. 7 Timing clustered mutations in evolution
    affected 66 melanomas (61%)
  • p. 7 Timing clustered mutations, right column
    thripsis events that affected 66 melanomas (61%)
  • p. 45 Extended Data Table 1, Skin-Melanoma
    107

Only the authors can say what is right here.

Judge's note: The page 7 crop shows 66 (61%). ED Table 1 (p45 image) lists Skin-Melanoma as 107, and the same paragraph gives 10/86 cutaneous and 11/21 acral or mucosal, which also totals 107. No other melanoma denominator is stated nearby. The 61% looks truncated rather than rounded, or the authors used a different analysis set. This is a one-point discrepancy, so it is minor; the authors should confirm which denominator they used.

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Wording In Europeans the rs12628403 minor allele is "protective against APOBEC3B-like mutagenesis (β = −0.43...)", but the East Asian validation is printed as "βrs12628403 = 0.57" with a positive sign. Query to the authors: which allele does each β refer to?
  • p. 9 Germline effects on somatic mutations
    βrs12628403 = 0.57, Prs12628403 = 4.2 × 10−12
  • p. 9 same paragraph
    protective against APOBEC3B-like mutagenesis (β = −0.43, P = 5.6 × 10−9

Only the authors can say what is right here.

Judge's note: Both crops confirm the signs as printed: −0.43 in Europeans and 0.57 in East Asians, with no minus sign visible in the image. For rs2142833 the sign agrees across populations (0.23 and 0.58), so the rs12628403 reversal stands out in a sentence describing an independent validation. The ED Fig. 10 legend (p38) gives no allele coding. A different effect-allele coding in the East Asian GWAS could explain the reversal, but nothing in the files states this. Only the authors can say whether the sign or the coding is intended.

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Wording Text: "38% (1,075 out of 2,814) of PCAWG donors" in the paragraph citing ED Fig. 12d, whose bars are labelled "All (2813)" and "Hot (2813)".
  • p. 10 Main text, L1 paragraph
    38% (1,075 out of 2,814) of PCAWG donors
  • p. 41 Extended Data Fig. 12d axis labels
    All (2813)

Judge's note: The page 10 crop shows 2,814 and the ED Fig. 12d image (p41) shows 2813. The difference is one donor, and the percentage is 38% with either denominator. ED Fig. 12f counts MEIs by continental ancestry, a different analysis, so I did not use its total.

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Wording The text says "all Plinian elements were infrequent (MAF ≤ 2%) in PCAWG donors (Extended Data Fig. 12c", but ED Fig. 12c shows one of the eight Plinian loci at an allele frequency of roughly 18%.
  • p. 10 Main text, L1 paragraph
    all Plinian elements were infrequent (MAF ≤ 2%)
  • p. 41 Extended Data Fig. 12c, Plinian column
    Plinian (8)

Only the authors can say what is right here.

Judge's note: In the ED Fig. 12c image (p41), the Plinian (8) column has most points near 0–2% and one red point clearly higher, at about 18% on the 0–100 allele frequency axis. The value is read from the plot, so the claim of 'all ≤ 2%' does not match the figure as drawn. The authors should clarify.

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Wording Extended Data Fig. 2 legend defines "union, calls made by all variant-calling algorithms", but a union is the set of calls made by any algorithm.
  • p. 25 Extended Data Fig. 2 legend
    union, calls made by all variant- calling algorithms

Judge's note: Checked p.25. In both panels the union boxes have the highest sensitivity and among the lowest precision, which is how a union behaves. intersect3 ('any three') shows the opposite pattern and, with three core callers, is effectively 'all'. So 'all' misdescribes the union; 'any' was presumably meant. This is a wording slip in the legend, and the data are unaffected.

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Typo "more-targeted driver events such as point mutations or fusion genes of focal CNAs" should read "fusion genes or focal CNAs".
  • p. 6 Main text, right column, end of paragraph on aneuploidy
    mutations or fusion genes of focal CNAs
  • p. 6 Missing-driver cases paragraph
    point mutations or fusion genes of focal CNAs
  • p. 6
    such as point mutations or fusion genes of focal CNAs

Judge's note: The p.6 text reads 'of'. The sentence is a list of alternative driver event types, so 'or' is meant.

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Typo Fig. 6b axis label reads "Chr. 5: 14,8202,017–148,202,805"; the start coordinate should be 148,202,017.
  • p. 9 Fig. 6b, x-axis label of long-read panel
    Chr. 5: 14,8202,017–148,202,805

Judge's note: The crop of the Fig. 6b long-read panel shows the misplaced comma. The end coordinate 148,202,805 shows the intended format. This is a cosmetic digit-grouping typo.

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Typo Fig. 6b legend: "inserted inbetween the tandem duplication" should read "in between".
  • p. 9 Fig. 6b legend
    inserted inbetween the tandem duplication

Judge's note: Visible in the Fig. 6 legend crop on page 9. Cosmetic spelling error.

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Typo The author list prints "Fei-Fei Fei Liu141,469", a duplicated name element.
  • p. 14
    Fei-Fei Fei Liu141,469

Judge's note: The page 14 crop shows 'Fei-Fei Fei Liu' in the image itself, so it is not an extraction artefact. The intended form is likely 'Fei-Fei Liu'.

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Typo Affiliation 519 is printed as "519 32Program in Computational Biology and Bioinformatics, Yale University", with a stray '32' before the text.
  • p. 18
    51932Program in Computational Biology and

Judge's note: The page 18 crop shows superscript 519 followed by '32Program' in normal-size type, so the stray digits are in the PDF itself.

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Typo Methods: "We tested different merging strategies using validation data, and choses the optimal method" should read "chose".
  • p. 20 Methods, Uniform processing and somatic variant calling
    and choses the optimal method for each variant type

Judge's note: Visible in the page 20 crop. Grammatical typo.

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Typo Extended Data Fig. 1 legend: "Europen Molecular Biology Laboratory (EMBL)" should read "European".
  • p. 24 Extended Data Fig. 1 legend
    Europen Molecular Biology

Judge's note: Seen in crop C033-a (p.24) as printed.

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Typo Extended Data Fig. 4b legend: "(the width proportional is to density)" should read "the width is proportional to density".
  • p. 27 Extended Data Fig. 4 legend, panel b
    the width proportional is to density
  • p. 27 Extended Data Fig. 4 legend, panel b
    (the width proportional is to density)

Judge's note: Seen in crop C035-a (p.27) as printed.

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Typo Extended Data Fig. 6 legend: "two-sided Mann–Whittney U-test" should read "Mann–Whitney".
  • p. 30 Extended Data Fig. 6 legend
    Mann– Whittney U-test
  • p. 30 Extended Data Fig. 6 legend
    two-sided Mann–Whittney U-test

Judge's note: Seen in crop C036-a (p.30). The Extended Data Fig. 12 legend (p.42) spells it 'Mann–Whitney'.

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Typo Extended Data Fig. 11a,c panel titles read "SV tandem dupliation" (five panels) instead of "duplication".
  • p. 39 Extended Data Fig. 11a,c panel titles
    SV tandem dupliation

Judge's note: Page image p.39: the misspelling appears in the panel A title and in all four panel C titles.

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Typo Extended Data Figs 11k and 13b use the label "Bone-Leiomyo", whereas Extended Data Table 1 and Fig. 5a define leiomyosarcoma as "SoftTissue-Leiomyo".
  • p. 43 Extended Data Fig. 13b tumour-type legend
    Bone-Leiomyo
  • p. 43 Extended Data Table 1
    SoftTissue-Leiomyo

Judge's note: Seen on p.43 (ED Fig. 13b tumour-type legend: 'Bone-Leiomyo'; ED Fig. 13a legend uses 'SoftTissue-Leiomyo') and on p.39 (ED Fig. 11k axis: 'Bone-Leiomyo'). ED Table 1 (p.45) lists only 'SoftTissue-Leiomyo'. This is a label inconsistency, and the intended type can be inferred.

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Typo Extended Data Table 1, second Bone-Benign row: "Chrondromyxoid fibroma" should read "Chondromyxoid fibroma".
  • p. 45 Extended Data Table 1, second Bone-Benign row
    Chrondromyxoid fibroma

Judge's note: Seen in page image p.45 as printed.

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Typo Reporting Summary lists "BWA-MEM v0.78.8-r455"; the version string appears malformed, probably for v0.7.8-r455.
  • p. 48 Reporting Summary, Software and code – Data analysis
    BWA-MEM v0.78.8-r455

Only the authors can say what is right here.

Judge's note: Rests on outside knowledge: BWA releases are numbered 0.7.x, and r455 corresponds to 0.7.8. Crop C043-a (p.48) confirms the printed string 'v0.78.8-r455'. The main text (Methods) names BWA-MEM without a version, so there is nothing to cross-check against.

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