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Cited by 307BRCA gene mutations in cancerCancer Genomics and DiagnosticsBreast Cancer Treatment Studies

Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study

Open access
Staaf, Johan, Glodzik, Dominik, Bosch, Ana, Vallon-Christersson, Johan, Reuterswärd, Christel, Häkkinen, Jari, Degasperi, Andrea, Amarante, Tauanne Dias +13 more·2019·Nature Medicine
DOI 10.1038/s41591-019-0582-4PMC PMC6859071
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Abstract

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.

Integrity signals

Registry

Crossref · 10.1038/s41591-019-0582-4

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 24 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    237 (93%) had WGS data of sufficient quality for comprehensive genomic profiling.

    “237 (93%) had WGS data of sufficient quality for comprehensive genomic profiling.”
    Quote in the paperSubstantial claim
  • Findingown data

    Mobile element analysis found a germline SVA retrotransposon 1.8 kb downstream of the first coding exon of BRCA1 in patient PD35958a.

    “identified a germline SINE-VNTR-Alu (SVA) retrotransposon 1.8kb downstream of the first coding exon of BRCA1 in one patient, PD35958a.”
    Quote in the paperSubstantial claim
  • Findingown data

    HRDetect-intermediate tumors had the poorest outcomes.

    “HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had poorest outcomes.”
    Quote in the paperSubstantial claim
  • Findingown data

    About 4.7% of HRDetect-low cancers were mismatch-repair-deficient.

    “~4.7% were mismatch-repair-deficient”
    Quote in the paperSubstantial claim
  • Findingown data

    In the Skåne region, 4,665 patients were registered with invasive breast cancer during September 1, 2010 to March 31, 2015.

    “4665 patients were registered with invasive breast cancer in that period.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 40
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Nine percent (n=408) of those invasive breast cancers were TNBC, consistent with national TNBC incidence of about 9% in 2015.

    “Nine percent (n=408) were TNBCs, consistent with national TNBC incidence (~9% in 2015).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SCAN-B had inclusion rates of about 85% and had recruited more than 13,500 patients since 2010.

    “High inclusion rates of ~85% have resulted in >13,500 patients recruited since 2010.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Genomic features in the SCAN-B TNBC cohort were comparable to a previously reported WGS cohort.

    “These genomic features in the SCAN-B TNBC cohort were comparable to a previously reported WGS cohort8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    HRDetect classified 58.6% of the TNBCs as HRDetect-high, 35.9% as HRDetect-low, and 5.5% as intermediate.

    “More than half of TNBCs (58.6%) were classified as HRDetect-high (exceeding predefined score of 0.7, predictive of BRCA1/BRCA2-deficiency9). 35.9% were classified as HRDetect-low (score <0.2), 5.5% fell within an HRD-intermediate category (score 0.2-0.7)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    HRDetect-high scores were also observed in tumors with 1-10% ER staining, in middle-aged and older patients, and in non-basal-like expression profiles.

    “However, HRDetect-high scores were also observed in tumors with ER-staining (62.1% of cases with 1-10% ER-staining intensity), in middle-aged patients (58% of HRDetect-high were 50-70 years) and older patients (>70 years, 36.4% HRDetect-high cases), as well as tumors with non-basal-like gene expression profiles”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Among the 254 patients, 2.4% had metastatic disease at diagnosis and 6.7% received neoadjuvant treatment.

    “Among 254 patients, 2.4% had metastatic disease at diagnosis, and 6.7% received neoadjuvant treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HRDetect-high classification was enriched in young patients, high-grade tumors, and basal-like expression subtypes.

    “HRDetect-high classification was enriched in expected subgroups such as young patients (88.5% of women <50 years), high-grade tumors and a basal-like expression subtype”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    340 TNBC patients enrolled in SCAN-B, and 254 had material for matched tumor-normal WGS/RNAseq analysis.

    “340 had enrolled into SCAN-B. Clinical re-review and availability of material for genomic/transcriptomic sequencing left 254 cases for matched tumor-normal WGS/RNAseq analysis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For overall survival, the adjusted hazard ratio was 0.46 (95% CI 0.19-1.13) and non-significant, implying a potential effect with longer follow-up.

    “Although not significant for OS (HR=0.46, CI=0.19-1.13), it implies a potential effect with longer follow-up time”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    49 of 254 recruited patients had prior routine oncogenetic screening for pathogenic germline BRCA1/BRCA2 variants, with 12 positive findings (nine BRCA1 and three BRCA2 carriers).

    “As part of routine oncogenetic clinical screening, 49 of 254 recruited patients were previously screened for pathogenic germline variants in BRCA1 and BRCA2, with 12 positive findings (nine BRCA1- and three BRCA2-carriers).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingreasoning

    Smaller tumors are slightly less common in the RNA-sequenced cohort.

    “To note, the RNA sequencing cohort has a slightly lower inclusion of smaller tumors, due to that the SCAN-B tissue sampling is performed by a pathologist after enough tissue has been secured for routine diagnostics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Five tumors had pathogenic germline PALB2 variants, and four showed wild-type allele inactivation by somatic mutation or loss of heterozygosity.

    “Five tumors had pathogenic germline PALB2 variants, three cases with c.509_510delGA variant (two biallelic, one monoallelic), one c.3239_3240delAA variant, one c.1039G>T variant. Four had wild-type allele inactivation through somatic pathogenic mutation in three cases and loss-of-heterozygosity in one instance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    340 of the 408 patients enrolled in SCAN-B, and 254 with concurrent RNAseq were selected for extensive clinical review and WGS.

    “340 of these patients were enrolled in the SCAN-B study5,33,34 (ClinicalTrials.gov ID NCT02306096), which is a prospective, observational, population-based cohort study, from which 254 with concurrent RNAseq were selected for extensive clinical review and WGS.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Saal, L. H. et al. The Sweden Cancerome Analysis Network-Breast (SCAN-B) initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine. Genome Med. 7, 20 (2015). source

      Not checked in the free run.

    • cites [33] Brueffer, C. et al. Clinical value of RNA sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: a report from the population-based multicenter Sweden Cancerome Analysis Network–Breast initiative. JCO Prec. Oncol. 2, 1–18 (2018). source

      Not checked in the free run.

    • cites [34] Chen, X. et al. TNBCtype: a subtyping tool for triple-negative breast cancer. Cancer Inf. 11, 147–156 (2012).

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the adjuvant chemotherapy group, overall survival was improved in HRDetect-high versus HRDetect-low patients but was non-significant (log-rank p=0.06).

    “An improved OS was also observed (log-rank p=0.06, Figure 4C), albeit non-significant because of limited follow-up interval.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the SVA case, wild-type allele loss of heterozygosity was noted and BRCA1 expression was markedly reduced.

    “Moreover, wild-type allele LOH was noted and BRCA1 expression was markedly reduced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With a two-cluster consensus solution, over 70% of HRDetect-high tumors fall in cluster 1, and 40-70% of HRDetect-low samples also fall there.

    “E.g., for HRDetect-high cases (left heatmap) using a k=2 solution, >70% of these tumors are located in cluster 1, together with 40-70% of HRDetect-low samples (as seen in right heatmap).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PTEN driver mutations and activating PIK3CA and AKT1 mutations were differently enriched between HRDetect-high and HRDetect-low groups: PTEN 29% vs 14%, PIK3CA 2.2% vs 25%, and AKT1 0.7% vs 7.1%.

    “(29% versus 14% for PTEN, 2.2% versus 25% for PIK3CA, and 0.7% versus 7.1% for AKT1 for HRDetect-high versus HRDetect-low, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In multivariable Cox regression adjusting for tumor size, age, grade, and lymph node status, HRDetect classification among chemotherapy-treated patients was independently prognostic for invasive disease-free survival (HR=0.42, 95% CI 0.20-0.87) and distant relapse-free interval (HR=0.31, 95% CI 0.13-0.76).

    “We found that HRDetect classification amongst chemotherapy-treated patients provided independent prognostic information favouring a better outcome in HRDetect-high cases compared to HRDetect-low cases, for IDFS (Hazard ratio, HR=0.42, 95% confidence interval, CI=0.20-0.87) and DRFI (HR=0.31, CI=0.13-0.76).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In TNBC patients who did not receive adjuvant treatment, there were no differences in overall survival, invasive disease-free survival, or distant relapse-free interval between HRDetect-high and HRDetect-low categories (log-rank p>0.05).

    “For these patients, there were no differences observed in overall survival (OS), invasive disease-free survival (IDFS), or distant relapse-free interval (DRFI) between HRDetect-high and HRDetect-low categories (log-rank p>0.05).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The HRDetect-intermediate cohort with scores 0.2-0.7 comprised 13 cases (5.5%).

    “we explored the HRDetect-intermediate cohort (scores 0.2-0.7, n=13, 5.5%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In the SCAN-B catchment area between 1 September 2010 and 31 March 2015, there were 8587 primary resectable breast cancers; 5417 of these enrolled in SCAN-B, and 3520 had RNA sequencing data that passed basic quality criteria.

    “Based on data from the national breast cancer quality registry in Sweden (NKBC), a background population of primary resectable breast cancers from the entire SCAN-B catchment region during September 1 2010 to March 31 2015 was identified (same time period from which the TNBC cases in the current study were selected), comprising of 8587 patients.”
    • Also stated in: § Extended Data · plain
      “Of these 8587 patients, 5417 were enrolled in SCAN-B, with 3520 patients having RNA sequencing data passing basic quality criteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The four biallelic PALB2 and five RAD51C cases (6.5% of HRDetect-high) showed a BRCA2-null phenotype with elevated Signature 3, elevated Rearrangement Signatures 2 and 5, and no Rearrangement Signature 3.

    “the four biallelic PALB2 and five RAD51C cases (6.5% of HRDetect-high cases) consistently showed a BRCA2-null phenotype16 including elevated Substitution Signature 3, elevated Rearrangement Signatures 2 and 5, and no Rearrangement Signature 3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Polak, P. et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 49, 1476–1486 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The broadened intermediate category was enriched for hypermutators of rearrangement signature RS1, with RS1 predominant and exceeding 100 RS1 rearrangements.

    “The intermediate category is also enriched for hypermutators of a rearrangement signature of long tandem-duplications (RS1) (where RS1 is predominant, exceeding 100 RS1 rearrangements)26.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Glodzik, D. et al. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nat. Genet. 49, 341–348 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    148 of 153 patients (97%) were eligible for relapse analysis, and 20% developed a relapse of some type.

    “148 of 153 patients (97%) were eligible for relapse analysis, of which 20% developed a relapse of some type”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The broadened HRDetect-intermediate group (scores 0.1-0.9, n=32) had a high prevalence of driver amplifications (75%, 24/32) and harbored 47% of all CCNE1 amplifications.

    “The broadened HRDetect-intermediate group had high prevalence of driver amplifications (75%, 24/32 cases) and harbored 47% of all CCNE1 amplifications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    When compared with HRDetect as reference, the CNA-based HRD assay had a 13% false negative rate and 16% false positive rate.

    “When compared with HRDetect as reference, the “HRD assay” has a false negative rate of 13%, and 16% of CNA-based HRD-high cases were false positives.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Paquet, E. R. & Hallett, M. T. Absolute assignment of breast cancer intrinsic molecular subtype. J. Natl Cancer Inst. 107, 357 (2014).

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Neither unsupervised consensus clustering nor machine-learning supervised classification found distinct transcriptional patterns distinguishing HRDetect-high and HRDetect-low groups.

    “Neither was able to find distinct transcriptional patterns distinguishing HRDetect-high and HRDetect-low groups (Extended Data 4A-E). Likewise, exhaustive machine-learning-based exploration could also not achieve high prediction accuracy for HRDetect-high and HRDetect-low subgroups”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Adding BRCA1/BRCA2 abrogated status as a covariate, HRDetect classification persisted as an independent positive prognostic indicator for invasive disease-free survival (HR=0.38, 95% CI 0.17-0.85, p=0.02).

    “HRDetect classification persisted as a meaningful independent positive prognostic indicator for IDFS (HR=0.38, CI=0.17-0.85, p=0.02).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    83.5% of HRDetect-high tumors had scores exceeding 0.99, and nearly all were BRCA1/BRCA2-null.

    “We noted that 83.5% of HRDetect-high tumors had scores exceeding 0.99, and nearly all were BRCA1/BRCA2-null tumors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Eight substitution/indel driver genes were enriched but non-discriminatory between HRDetect groups: TP53, PTEN, ARID1B, and MLLT4 for HRDetect-high; PIK3CA and AKT1 for HRDetect-low; and RB1 and FBXW7 for HRDetect-high and HRDetect-intermediate.

    “Eight substitution/indel driver genes were enriched, albeit non-discriminatory between groups (TP53, PTEN, ARID1B, MLLT4 for HRDetect-high, PIK3CA and AKT1 for HRDetect-low, and RB1 and FBXW7 for HRDetect-high and HRDetect-intermediate) (Chi-square test p<0.05”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Among the 153 eligible patients, 41% had at least 5 years of follow-up, 25% had 4-5 years, 31% had 2-4 years, and 4% had less than 2 years.

    “41% had ≥5 years of follow-up, 25% 4-5 years, 31% 2-4 years, and 4% <2 years of follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Six of the unexplained HRDetect-high cases were monoallelic for BRCA1/BRCA2 and had low tumor cellularity.

    “Six were monoallelic for BRCA1/BRCA2 and had low tumor cellularity.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All patients with suspected breast cancer were offered recruitment into SCAN-B without exception.

    “All patients with suspected breast cancer are offered recruitment without exception.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SCAN-B is an ongoing population-based observational study involving nine hospitals in southern Sweden, serving nearly two million inhabitants, about 20% of the Swedish population.

    “The Sweden Cancerome Analysis Network – Breast (SCAN-B; ClinicalTrials.gov identifier NCT02306096)5 is an on-going population-based observational study currently involving nine hospitals in the South of Sweden serving nearly two million inhabitants or ~20% of the Swedish population.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Saal, L. H. et al. The Sweden Cancerome Analysis Network-Breast (SCAN-B) initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine. Genome Med. 7, 20 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cancer whole-genome sequencing is feasible, and thousands of matched tumor-normal pairs have been sequenced, revealing novel biological insights.

    “Cancer whole genome sequencing (WGS) is now feasible, with thousands of matched tumor-normal pairs successfully sequenced to date, revealing novel biological insights2–4.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012). source

      Not checked in the free run.

    • cites [3] Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012). source

      Not checked in the free run.

    • cites [4] Ryden, L. et al. Minimizing inequality in access to precision medicine in breast cancer by real-time population-based molecular analysis in the SCAN-B initiative. Br. J. Surg. 105, e158–e168 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The HRD phenotype identified by HRDetect is enriched for but not restricted to typical basal-like tumors of young TNBC patients.

    “Consequently, the HRD phenotype identified by HRDetect is enriched for but not restricted to typical basal-like tumors characteristic of young patients in TNBC.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    HRDetect is a mutational-signature-based algorithm designed to detect BRCAness or homologous-recombination-repair deficiency, using default breast-cancer-specific parameters.

    “we applied a mutational-signature-based algorithm, HRDetect9 designed to detect “BRCA”ness or Homologous-recombination-repair deficiency (HRD)10, using default breast-cancer-specific parameters.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017). source

      Not checked in the free run.

    • cites [10] Paquet, E. R. & Hallett, M. T. Absolute assignment of breast cancer intrinsic molecular subtype. J. Natl Cancer Inst. 107, 357 (2014).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Expression-based profiling and Integrative Clusters cannot adequately discriminate HRDetect groups, suggesting HRDetect provides a novel independent angle to TNBC stratification.

    “expression-based profiling (e.g., PAM50) and Integrative Clusters13,15 are not adequately able to discriminate HRDetect groups, suggesting that HRDetect provides a novel, independent angle to TNBC stratification.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Lehmann, B. D. et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750–2767 (2011). source

      Not checked in the free run.

    • cites [15] Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 22, 3764–3773 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The SCAN-B study was approved by the Regional Ethical Review Board in Lund, Sweden, and all patients provided written informed consent before enrolment.

    “The SCAN-B study was approved by the Regional Ethical Review Board in Lund, Sweden (applicable registration numbers 2009/658, 2015/277, 2016/742, 2018/267, and 2019/01252 for this study). All patients provided written informed consent prior to enrolment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    PIK3CA/AKT1/PTEN mutations identified through targeted sequencing are differentially enriched in HRDetect categories, with different survival likelihoods.

    “we show that PIK3CA/AKT1/PTEN mutations identified through targeted sequencing are differentially enriched in HRDetect categories, with different survival likelihoods.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    This study argues for WGS to improve TNBC patient stratification.

    “In short, this study argues for WGS to improve TNBC patient stratification.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The HRDetect-intermediate group is difficult to distinguish using customary genomic scar approaches or individual substitution signatures but is important to recognize because its biology predicts poor outcome and may be differently targetable.

    “the HRDetect-intermediate group is a subset of tumors that are difficult to distinguish using customary genomic scar approaches or individual substitution signatures but are important to recognize because their idiosyncratic tumor biology is a harbinger of poor outcome and may be differently targetable in terms of therapeutics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HRDetect-low cases derive limited benefit from current standard-of-care, warranting re-appraisal of systemic therapies for this subgroup.

    “this suggests that HRDetect-low cases are deriving limited benefit from current standard-of-care, warranting a re-appraisal of systemic therapies for this now-identifiable subgroup with poor outcome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Chemotherapy-treated and untreated HRDetect-low patients are comparable enough for their invasive disease-free survival to be compared.

  • May combine two claims.

    Study design and conductreasoning

    PAM50 molecular subtypes and given treatments show year-by-year representativeness for the RNA-sequenced patients.

    “Demonstration of the year to year representativity of molecular subtypes in breast cancer (PAM50, top panel) and administered treatments based on data from the NKBC (lower panel) for patients identified in D.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The AIMS PAM50 method classifies each sample independently and does not require cohort-wide mean centering of expression data, so it should not be affected by potential year-to-year inclusion bias.

    “PAM50 subtyping was performed using the AIMS method (Paquet et al.) (as for the TNBC cases in the current study) as this classifier is a single sample classifier that does not rely on a mean centering of gene expression data across a cohort (thus is not sensitive to e.g. potential bias in year to year inclusion).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Paquet et al.

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The final RNA-sequenced cohort reflects the broader group of enrolled SCAN-B patients and the entire catchment-area patient population.

    “The lower panels demonstrate the clinicopathological characteristics of the different subgroups in the consort diagram, demonstrating the representativity of the end RNA sequencing cohort compared to all enrolled SCAN-B patients and the total patient population in the catchment region.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HRDetect is more specific than current substitution signature and CNA approaches and extends HRD identification to a wider set of samples.

    “HRDetect is therefore more specific than current substitution signature and CNA approaches, while extending identification of HRD to a wider set of samples”
    Quote in the paperSubstantial claim
47 of 47

  • The paper relies on this without support.

    The 1000 Genomes dataset is a sufficient reference for judging whether the SVA insertion is novel.

    “This specific mobile element has not been reported in the 1000 genomes dataset.”

  • The paper relies on this without support.

    Chemotherapy-treated and untreated HRDetect-low patients are comparable enough for their invasive disease-free survival to be compared.

    “chemotherapy-treated HRDetect-low patients had a similar IDFS to patients that did not receive adjuvant chemotherapy, in spite of superior fitness and lower age of diagnosis (75% <70 years)”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • We cannot formally exclude that these observations originate from differences in cohort inclusion criteria that could skew numbers.

    “However, we cannot formally exclude that these observations originate from differences in cohort inclusion criteria that could skew numbers (e.g. due to more recruitment of patients with triple negative breast cancer which has higher HRD rates12).”

    From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [12]

    The Introduction (page not provided) reports that the HRD phenotype is enriched in basal-like tumors within the triple-negative breast cancer cohort. It does not compare HRD rates in triple-negative versus other breast cancers, so it does not establish the cited parenthetical's claim of higher rates. The possibility that cohort inclusion criteria skewed the citing study's numbers is the citing authors' own caveat, not a finding attributed to this source. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • RAD51C and PALB2 inactivation result in BRCA2-type HRD.

    “with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD.”

    From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [12]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Sequencing-depth failure rates imply too few failures

    Major

    Of 254 sequenced cases, 237 passed quality control, implying 17 failures. Applying the stated failure rates to 170 cases at 30-fold depth and 84 at 15-fold depth gives approximately 5 and 9 failures, respectively-14 in total, even allowing for rounding.

  • Overlapping causes leave more than 46 high-scoring cases unexplained

    Minor

    The reported causes cover 29 BRCA1/BRCA2 cases, 55 BRCA1-hypermethylated cases, four biallelic PALB2 cases, and five RAD51C cases. Because one case belongs to both of the first two groups, these counts cover at most 92 distinct patients, leaving at least 47 of the 139-not 46-without a stated cause.

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Authors
Staaf, J., Glodzik, D., Bosch, A., Vallon-Christersson, J., Reuterswärd, C., Häkkinen, J., Degasperi, A., Amarante, T. D., Saal, L. H., Hegardt, C., Stobart, H., Ehinger, A., Larsson, C., Rydén, L., Loman, N., Malmberg, M., Kvist, A., Ehrencrona, H., Davies, H. R., Borg, Å., & Nik-Zainal, S.
Affiliations
  • Lund University (SE)
  • University of Cambridge (GB)
Corresponding author
Staaf, Johan
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-09-30
Volume
25
Issue
10
Pages
1526-1533
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-019-0582-4
PMC
PMC6859071
OpenAlex
W2976898289
Cited by
307
References
38
Citations by year
2026: 27 · 2025: 33 · 2024: 50 · 2023: 41 · 2022: 56 · 2021: 58 · 2020: 41 · 2019: 1
FWCI
23.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (WT100183MA)
  • Cancer Research UK (C60100/A25274, C60100/A23916)
  • Cancerfonden (SIA190013)
  • Sveriges Regering ((ALF) 2018/40612)
  • Fru Berta Kamprads Stiftelse (FBKS-2018-4-146)
  • Crafoordska Stiftelsen (20180543)
  • Stiftelsen Konung Gustaf V:s Jubileumsfond (174271)
  • Vetenskapsrådet
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
triple-negative breast cancer, whole genome sequencing, homologous recombination deficiency, mismatch repair deficiency, BRCA1, BRCA2, BRCA1 promoter hypermethylation, PALB2, adjuvant chemotherapy, disease-free survival, distant recurrence-free survival, prognostic factors, trial stratification
MeSH terms
Whole Genome Sequencing, Adult, Aged, Aged, 80 and over, Female, Genetics, Population, Humans, Middle Aged, Neoplasm Recurrence, Local, Prognosis, Promoter Regions, Genetic, Germ-Line Mutation, Disease-Free Survival, DNA Methylation, Triple Negative Breast Neoplasms

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

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