CoChat
Sign Up
Cited by 93BRCA gene mutations in cancerCancer Genomics and DiagnosticsGenetic factors in colorectal cancer

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers

Open access
Nones, K., Johnson, J., Newell, F., Patch, A.M., Thorne, H., Kazakoff, S.H., de Luca, X.M., Parsons, M.T. +24 more·2019·Annals of Oncology
DOI 10.1093/annonc/mdz132PMC PMC6637375
Open this paper in CoChat — free account

Abstract

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Integrity signals

Registry

Crossref · 10.1093/annonc/mdz132

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Some non-BRCA1/2 tumours had quiet genomes with few somatic mutations.

    “quiet genomes with few somatic mutations”
    Quote in the paperNot a substantial claim
  • Findingown data

    Some non-BRCA1/2 tumours had a high burden of rearrangement signature 4, consisting of clustered rearrangements.

    “a high burden of rearrangement signature 4 (clustered rearrangements)”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Some non-BRCA1/2 tumours had a high single nucleotide variant burden linked to the APOBEC substitution signature.

    “a high SNV burden associated with APOBEC substitution signature [8]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Alexandrov LB Nik-Zainal S Wedge DC Signatures of mutational processes in human cancer Nature 2013 500 7463 415 421 23945592 PMC3776390 source

      Not checked in the free run.

  • Findingown data

    In the cohort, 79 of the 93 previously reported breast cancer driver genes carried mutations.

    “Seventy-nine out of the 93 previously identified BC driver genes [9] were mutated”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Nik-Zainal S Davies H Staaf J Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature 2016 534 7605 47 54 27135926 PMC4910866 source

      Not checked in the free run.

  • Findingcitation

    Five substitution signatures and five rearrangement signatures were detected.

    “Five substitution and five rearrangement signatures [8, 9] were identified”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Alexandrov LB Nik-Zainal S Wedge DC Signatures of mutational processes in human cancer Nature 2013 500 7463 415 421 23945592 PMC3776390 source

      Not checked in the free run.

    • cites [9] Nik-Zainal S Davies H Staaf J Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature 2016 534 7605 47 54 27135926 PMC4910866 source

      Not checked in the free run.

  • May combine two claims. 38
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Findingown data

    Most BRCA1-like tumours were grade 3 and triple-negative, but the group also included two grade 2, four ER/PR-positive, and three HER2-positive tumours.

    “Most tumours were grade-3 and triple-negative, but included two histological grade-2, four ER/PR-positive and three HER2-positive tumours”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All non-BRCA1/2-like tumours were BRCA-proficient (HRDetect <0.7), whereas all BRCA1-like and BRCA2-like tumours were BRCA-deficient.

    “All tumours stratified as ‘non-BRCA1/2-like’ were BRCA-proficient (HRDetect scores <0.7), while all ‘BRCA1-like’ and ‘BRCA2-like’ tumours were BRCA-deficient”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Combining multiple mutational signatures or using HRDetect classified tumour HR status better than individual mutational signatures alone.

    “We show that the combination of multiple mutational signatures or HRDetect [7] enabled better classification of the HR status in tumours than when using individual mutational signatures alone”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Davies H Glodzik D Morganella S HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures Nat Med 2017 23 4 517 525 28288110 PMC5833945 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Twenty-nine tumours had BRCA1-like signatures; all showed biallelic BRCA1 inactivation and were BRCA-deficient by HRDetect.

    “Twenty-nine tumours showed ’BRCA1-like’ mutational signatures; all had biallelic inactivation of BRCA1 and were BRCA-deficient according to HRDetect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ten tumours (13%) clustered away from their original BRCA status: two BRCA1, two BRCA2, and six non-BRCA1/2 tumours.

    “Ten tumours (13%) clustered away from their ‘original BRCA status’, including two BRCA1-, two BRCA2- and six non-BRCA1/2-tumours.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The BRCA2-like group included 20 of 22 BRCA2 tumours, each with biallelic BRCA2 inactivation; 19 ER/PR-positive tumours, 9 grade 2 tumours, and 2 invasive lobular carcinomas.

    “This group included 20 of the 22 BRCA2-tumours, each with biallelic inactivation of BRCA2; 19 ER/PR-positive tumours, 9 grade-2 tumours, and 2 invasive lobular carcinomas”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Each of those four tumours had somatic BRCA1 loss of heterozygosity, and three had somatic BRCA1 promoter methylation.

    “Each tumour had somatic LOH of BRCA1 and three exhibited somatic BRCA1 promoter methylation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four cases in the complex rearrangement subgroup had germline pathogenic variants in ATM, CHEK2, or TP53, all with somatic LOH.

    “Four cases within this group harboured germline pathogenic variants in ATM [23], CHEK2 [24] or TP53 [25], all with somatic LOH.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Sandoval N Platzer M Rosenthal A Characterization of ATM gene mutations in 66 ataxia telangiectasia families Hum Mol Genet 1999 8 1 69 79 9887333 source

      Not checked in the free run.

    • cites [24] Schmidt MK Hogervorst F van Hien R Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers J Clin Oncol 2016 34 23 2750 2760 27269948 PMC5019754 source

      Not checked in the free run.

    • cites [25] Bougeard G Renaux-Petel M Flaman JM Revisiting Li-Fraumeni syndrome from TP53 mutation carriers J Clin Oncol 2015 33 21 2345 2352 26014290 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    A MUTYH germline pathogenic variant and somatic loss of the wild-type allele were later found in case FBC070205.

    “We subsequently identified a MUTYH germline pathogenic variant (c.1556G>A; p.Arg519Gln) and somatic loss of the wild-type allele”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WGS of non-BRCA1/2 case FBC020031 confirmed a previously identified PALB2 nonsense variant and found somatic loss of the wild-type allele.

    “WGS of non-BRCA1/2 case FBC020031 confirmed the previously identified PALB2 nonsense variant (rs180177132; c.3113G>A p.Trp1038*) and detected somatic loss of the wild-type allele.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Twenty-four tumours had BRCA2-like signatures, and all were BRCA1/2-deficient by HRDetect.

    “Twenty-four tumours contained ‘BRCA2-like’ signatures and all were BRCA1/2-deficient according to HRDetect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The other thirteen non-BRCA1/2-like tumours were younger at diagnosis (median 44 versus 62 years) and had a high contribution of rearrangement signature 4, with complex rearrangements clustered to one or a few chromosomes.

    “The remaining thirteen tumours were younger at diagnosis (median age 44 versus 62 years) and displayed a high contribution of rearrangement signature 4, involving complex rearrangements clustered to one or a few chromosomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Case FBC070169 had a strong APOBEC substitution signature accounting for 94% of somatic mutations, but no APOBEC3A or APOBEC3B germline variants previously linked to this signature were found.

    “Case FBC070169 had a strong APOBEC substitution signature accounting for 94% of the somatic mutations, yet there was no evidence of the APOBEC3A or APOBEC3B germline variants previously associated with this signature [15, 16].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Nik-Zainal S Wedge DC Alexandrov LB Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer Nat Genet 2014 46 5 487 491 24728294 PMC4137149 source

      Not checked in the free run.

    • cites [16] Middlebrooks CD Banday AR Matsuda K Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors Nat Genet 2016 48 11 1330 1338 27643540 PMC6583788 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The BRCA2 variant was absent from gnomAD and the 560 breast cancer genomes cohort, and ClinVar classified it as Class 3 uncertain significance.

    “The variant was not reported in gnomAD or in the 560 BC genomes cohort [9] and is described by ClinVar (Variation ID: 135816) as ‘Class 3 Uncertain significance’”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Nik-Zainal S Davies H Staaf J Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature 2016 534 7605 47 54 27135926 PMC4910866 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Twenty-five tumours were non-BRCA1/2-like, including 24 from non-BRCA1/2 cases and one BRCA2 tumour that lacked somatic inactivation of the BRCA2 wild-type allele.

    “Twenty-five tumours were classified as ‘non-BRCA1/2-like’ and included 24 tumours from non-BRCA1/2 cases and a BRCA2-tumour (FBC016006, NM_000059.3, c.1310_1313delAAGA) that lacked somatic inactivation of the BRCA2 wild-type allele”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The FBC020031 tumour was BRCA2-like with a high burden of substitution signature 3 and rearrangement signature 5.

    “The tumour was ‘BRCA2-like’ with a high burden of substitution signature 3 and rearrangement signature 5”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Case FBC070205 had a BRCA1 germline pathogenic variant and somatic loss of the wild-type allele, and the tumour had a high contribution of somatic rearrangement signature 3.

    “Case FBC070205 carried a BRCA1 germline pathogenic variant (c.5244_5245delAA; p.Lys1748fs) and somatic loss of the wild-type allele, and the tumour showed a high contribution of the somatic rearrangement signature 3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Case FBC090235 had a BRCA2 germline pathogenic variant found by germline testing; WGS showed mono-allelic BRCA2 loss and a BRCA1 germline structural rearrangement with somatic loss of the wild-type allele.

    “Case FBC090235 carried a BRCA2 germline pathogenic variant (c.574_575delAT; p.Met192ValfsX13) identified by germline testing. WGS revealed not only mono-allelic loss of BRCA2 but also a BRCA1 germline structural rearrangement (chr17: g.41230286_41236428dup) coupled with somatic loss of the wild-type allele”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The FBC060681 tumour had somatic loss of the wild-type allele and BRCA2-like mutational signatures.

    “The tumour presented somatic loss of the wild-type allele, as well as ‘BRCA2-like’ mutational signatures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 8 of 13 tumours, rearrangement patterns suggested Breakage-Fusion-Bridge cycles; two more tumours had events resembling chromothripsis and BFB.

    “in 8/13 tumours, the patterns of rearrangements suggested evidence for Breakage–Fusion–Bridge (BFB) cycles; two additional tumours had events resembling chromothripsis and BFB”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The BRCA2 variant lies in a highly conserved amino acid and is predicted to create a de novo donor splice-site in exon 17, but no experimental evidence supported this.

    “The variant is in a highly conserved amino acid and is predicted to create a de novo donor splice-site in exon 17, although no experimental evidence supported this [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Whiley PJ Parsons MT Leary J Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1: c.122A>G(p.His41Arg) is a pathogenic mutation PLoS One 2014 9 1 e86836 24489791 PMC3904950 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Among non-BRCA1/2-like tumours, 22 were ER/PR-positive, six were HER2-positive, and all were considered BRCA-proficient.

    “Twenty-two tumours were ER/PR-positive; six were HER2-positive; and all were considered BRCA-proficient”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    With WGS and HRDetect, all BRCA1 tumours, 91% of BRCA2 tumours, and the PALB2 tumour had biallelic inactivation of the respective gene and strong evidence of HR deficiency.

    “Using this approach, all BRCA1-tumours, 91% of BRCA2-tumours and the PALB2 tumour had bialleic inactivation of said gene and strong evidence of HR-deficiency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only two of 22 (9% versus 46%) BRCA2-carrier tumours lacked biallelic inactivation; one was BRCA-deficient due to biallelic BRCA1 inactivation, and the other was BRCA-proficient and unlikely to benefit from such therapies.

    “In contrast to a recent report, only two tumours (2/22, 9% versus 46% [5]) from BRCA2 carriers did not exhibit biallelic inactivation of the gene; one tumour was BRCA-deficient due to the biallelic inactivation of BRCA1, whereas the other was BRCA-proficient, and hence this latter patient would be unlikely to benefit from such therapies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Maxwell KN Wubbenhorst B Wenz BM BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers Nat Commun 2017 8 1 319 28831036 PMC5567274 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BRCA1 promoter methylation was absent in blood from the four cases and relatives, suggesting these tumours were likely driven by somatic biallelic BRCA1 inactivation.

    “BRCA1 promoter methylation was tested in the blood of all four cases and other family members, but all were found to be unmethylated, suggesting that these tumours are likely driven by somatic biallelic inactivation of BRCA1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Loss of BRCA1, BRCA2, or PALB2 function produces a high mutation burden and specific signatures indicating defective homologous recombination.

    “Loss of function of BRCA1, BRCA2 and PALB2 yield a high mutation burden and specific signatures inferring defective HR [7, 9, 10, 13].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Davies H Glodzik D Morganella S HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures Nat Med 2017 23 4 517 525 28288110 PMC5833945 source

      Not checked in the free run.

    • cites [9] Nik-Zainal S Davies H Staaf J Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature 2016 534 7605 47 54 27135926 PMC4910866 source

      Not checked in the free run.

    • cites [10] Waddell N Pajic M Patch AM Whole genomes redefine the mutational landscape of pancreatic cancer Nature 2015 518 7540 495 501 25719666 PMC4523082 source

      Not checked in the free run.

    • cites [13] Polak P Kim J Braunstein LZ A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer Nat Genet 2017 49 10 1476 1486 28825726 PMC7376751 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    This study is the largest cohort of familial breast cancer cases examined by WGS and the first report from high-risk non-BRCA1/2 families.

    “This study represents the largest cohort of familial BC cases examined by WGS, and the first report from high-risk, non-BRCA1/2 families.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    WGS provided evidence about tumorigenesis drivers in many cases, including germline BRCA2 VUS, PALB2, CHEK2, ATM, and TP53 variants; BRCA1 promoter methylation; APOBEC mutagenesis; and oncogene amplification.

    “WGS provided evidence regarding the drivers of tumorigenesis in many cases, including germline carriers of variants in BRCA2 (VUS), PALB2, CHEK2, ATM and TP53; BRCA1 promoter methylation, APOBEC mutagenesis and oncogene amplification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Tumours with TP53, ATM, or CHEK2 germline variants lack BRCA-deficient signatures but have highly complex clustered chromosomal rearrangements.

    “Despite the role of TP53, ATM and CHEK2 in DNA-damage signalling and double-strand breaks detection, these tumours do not show evidence of BRCA-deficient signatures, as previously described [9, 13, 19], but instead they harbour highly complex clustered chromosomal rearrangements.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Nik-Zainal S Davies H Staaf J Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature 2016 534 7605 47 54 27135926 PMC4910866 source

      Not checked in the free run.

    • cites [13] Polak P Kim J Braunstein LZ A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer Nat Genet 2017 49 10 1476 1486 28825726 PMC7376751 source

      Not checked in the free run.

    • cites [19] Weigelt B Bi R Kumar R The landscape of somatic genetic alterations in breast cancers from ATM germline mutation carriers J Natl Cancer Inst 2018 110 9 1030 1034 29506079 PMC6136925 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Combined germline and somatic WGS can act as a companion diagnostic to clarify cancer risk and guide treatment decisions.

    “The findings demonstrate the impact that combined germline and somatic WGS can offer as a companion diagnostic in clarifying cancer risk in individuals and in aiding decisions regarding treatment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Whole-genome sequencing detects a broad repertoire of somatic and/or germline alterations in an unbiased manner.

  • May combine two claims.

    Premisecitation

    Co-occurring BRCA1 and BRCA2 germline pathogenic variants are rare (0.3%, 93/32,295 cases), and carriers are more likely to be diagnosed with breast cancer than carriers of only BRCA1 or BRCA2.

    “Co-occurring germline pathogenic variants in BRCA1 and BRCA2 are rare (0.3%, 93/32, 295 cases) and carriers are more likely to be diagnosed with BC than BRCA1 or BRCA2 only carriers [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Rebbeck TR Friebel TM Mitra N Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32, 295 women Breast Cancer Res 2016 18 112 PMC5106833 27836010 source

      Not checked in the free run.

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

    Interpretationcitation

    Telomeric erosion causing dicentric chromosome formation could lead to BFB and/or chromothripsis.

    “raising the possibility that dicentric chromosome formation due to telomeric erosion could lead to BFB and/or chromothripsis [17, 18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Crasta K Ganem NJ Dagher R DNA breaks and chromosome pulverization from errors in mitosis Nature 2012 482 7383 53 58 22258507 PMC3271137 source

      Not checked in the free run.

    • cites [18] Glodzik D Purdie C Rye IH Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers Ann Oncol 2018 PMC6290883 30252041 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These rearrangement patterns have been reported in breast cancer but not associated with germline predisposition.

    “Whilst these patterns of rearrangements have been reported in BC [28, 29], they have not been associated with a germline predisposition.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Stephens PJ Greenman CD Fu B Massive genomic rearrangement acquired in a single catastrophic event during cancer development Cell 2011 144 1 27 40 21215367 PMC3065307 source

      Not checked in the free run.

    • cites [29] Ferrari A Vincent-Salomon A Pivot X A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers Nat Commun 2016 7 12222 PMC4947184 27406316 source

      Not checked in the free run.

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

    Premisecitation

    Chromothripsis and BFB occur in many tumour types, and germline ATM and TP53 variants have been linked to such complex rearrangements in acute lymphoblastic leukaemia and medulloblastoma.

    “Chromothripsis and BFB have been reported in numerous tumour types, and intriguingly, germline variants in ATM and TP53 were associated with such complex structural rearrangements in acute lymphoblastic leukaemia [26] and medulloblastoma [27].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Ratnaparkhe M Hlevnjak M Kolb T Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis Leukemia 2017 31 10 2048 2056 28196983 source

      Not checked in the free run.

    • cites [27] Rausch T Jones DT Zapatka M Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations Cell 2012 148 1–2 59 71 22265402 PMC3332216 source

      Not checked in the free run.

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

    Premisecitation

    More than 60% of breast cancers in germline TP53 carriers are ERBB2/HER2 amplified, and complex structural rearrangements are suggested to drive amplification in such cancers.

    “Interestingly, >60% of BC in germline TP53 carriers are ERBB2/HER2 amplified [30] and complex structural rearrangements are suggested to drive amplification in such cancers [29].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Wilson JR Bateman AC Hanson H A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations J Med Genet 2010 47 11 771 774 20805372 source

      Not checked in the free run.

    • cites [29] Ferrari A Vincent-Salomon A Pivot X A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers Nat Commun 2016 7 12222 PMC4947184 27406316 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The complex rearrangements were associated with oncogene amplification and showed evidence of BFB and chromothripsis as a potential tumorigenesis mechanism.

    “The complex rearrangements were associated with amplification of various oncogenes and showed evidence of BFB and chromothripsis as a potential mechanism driving tumorigenesis [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Glodzik D Purdie C Rye IH Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers Ann Oncol 2018 PMC6290883 30252041 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Matched germline/tumour WGS can improve identification of the underlying genetic cause over BRCA1 and BRCA2 germline screening alone and likely improves clinical management of individuals and potentially families.

    “In summary, matched germline/tumour WGS can improve the identification of the underlying genetic cause of disease over BRCA1 and BRCA2 germline screening alone and that this will likely improve the clinical management of individuals and potentially their families.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Whole-genome sequencing detects a broad repertoire of somatic and/or germline alterations in an unbiased manner.

  • May combine two claims.

    Interpretationown data

    WGS gives the most robust assessment of BRCA deficiency and can identify oncogenic drivers in BRCA-proficient tumours, which may improve selection of targeted therapies.

    “Furthermore, WGS yields the most robust assessment of BRCA-deficiency and can also identify oncogenic drivers in BRCA-proficient tumours, which collectively may enhance the selection of targeted therapies for patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Whole-genome sequencing detects a broad repertoire of somatic and/or germline alterations in an unbiased manner.

  • May combine two claims.

    Interpretationown data

    These cases were predicted to be good candidates for platinum-based chemotherapy or PARP inhibitors, including 12 tumours that would not otherwise meet this recommendation (grade 2, ER/PR-positive, or invasive lobular carcinoma).

    “These cases would be predicted to be good candidates for platinum-based chemotherapy or PARPi, and included 12 tumours that would not otherwise fall into this recommendation of treatment (i.e. histological grade-2, ER/PR-positive [31], or invasive lobular carcinoma).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Lips EH Debipersad RD Scheerman CE BRCA1-mutated estrogen receptor-positive breast cancer shows BRCAness, suggesting sensitivity to drugs targeting homologous recombination deficiency Clin Cancer Res 2017 23 5 1236 1241 27620280 source

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    For most families with familial breast cancer, the underlying genetic contribution to cancer risk is unknown.

    “Pathogenic variants in BRCA1, BRCA2 or other moderate to highly penetrant susceptibility genes (e.g. TP53, ATM, CHEK2, PALB2 and PTEN) account for <50% of familial BC and thus for the majority of families the underlying genetic contribution to their cancer risk remains unknown.”

  • The paper relies on this without support.

    Whole-genome sequencing detects a broad repertoire of somatic and/or germline alterations in an unbiased manner.

    “WGS detects a broad repertoire of somatic and/or germline alterations in an unbiased manner.”

  • The paper relies on this without support.

    Most familial breast cancers are non-BRCA1/2, involving germline variants in other moderate- to highly penetrant genes or an unknown genetic cause.

    “Most familial BC fall under the umbrella term of non-BRCA1/2, involving germline variants in other moderate- to highly penetrant genes, or where the underlying genetic cause is unknown.”
3 of 3

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?

  • 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 [11]

    The Results section on ‘BRCA2-like’ mutational signatures reports a PALB2-inactivated tumour with a BRCA2-like signature, and the Discussion describes strong evidence of homologous-recombination deficiency in that tumour. Our copy does not report RAD51C inactivation producing BRCA2-type HRD, so the RAD51C part is unsupported. Page numbers are not available in the indexed passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

1 of the 32 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Nones, K., Johnson, J., Newell, F., Patch, A. M., Thorne, H., Kazakoff, S. H., de Luca, X. M., Parsons, M. T., Ferguson, K., Reid, L. E., McCart Reed, A. E., Srihari, S., Lakis, V., Davidson, A. L., Mukhopadhyay, P., Holmes, O., Xu, Q., Wood, S., Leonard, C., Beesley, J., Harris, J. M., Barnes, D., Degasperi, A., Ragan, M. A., Spurdle, A. B., Khanna, K. K., Lakhani, S. R., Pearson, J. V., Nik-Zainal, S., Chenevix-Trench, G., Waddell, N., & Simpson, P. T.
Affiliations
  • QIMR Berghofer Medical Research Institute (AU)
  • The University of Queensland (AU)
  • The University of Melbourne (AU)
  • Queensland University of Technology (AU)
  • University of Cambridge (GB)
Corresponding author
  • Waddell, N.
  • Simpson, P.T.
ORCID
Venue
Annals of Oncology
Publisher
Elsevier BV
Published
2019-07
Volume
30
Issue
7
Pages
1071-1079
ISSN
0923-7534 (ISSN-L)
DOI
10.1093/annonc/mdz132
PMC
PMC6637375
OpenAlex
W2946104064
Cited by
93
References
32
Citations by year
2026: 9 · 2025: 6 · 2024: 12 · 2023: 14 · 2022: 15 · 2021: 15 · 2020: 17 · 2019: 5
FWCI
7.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Oncology (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by-nc)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • NHMRC Australia project (APP1080985, APP1028742)
  • NHMRC (10.13039/501100000925, APP1017028, APP1113867, APP1139071, APP1061779)
  • Australian Government Research Training Program (RTP) Scholarship
  • Keith Boden fellowship
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
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
hereditary breast cancer, BRCA1, BRCA2, germline pathogenic variants, somatic mutational signatures, homologous recombination deficiency, biallelic inactivation, BRCA1 promoter methylation, PALB2, oncogene amplification, TP53, ATM, CHEK2, PARP inhibitor therapy, platinum-based chemotherapy, early-onset breast cancer, tumour aetiology
MeSH terms
Whole Genome Sequencing, Fanconi Anemia Complementation Group N Protein, Adult, Breast Neoplasms, DNA, Neoplasm, Female, Humans, Middle Aged, Prognosis, Germ-Line Mutation, BRCA1 Protein, Genetic Predisposition to Disease, BRCA2 Protein

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review