Journal Article
. 2019 Oct;25(10).
doi: 10.1038/s41591-019-0582-4.

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

Johan Staaf 1 Dominik Glodzik 2 Ana Bosch 2 Johan Vallon-Christersson 2 Christel Reuterswärd 2 Jari Häkkinen 2 Andrea Degasperi 3 Tauanne Dias Amarante 3 Lao H Saal 2 Cecilia Hegardt 2 Hilary Stobart 4 Anna Ehinger 2 Christer Larsson 5 Lisa Rydén 6 Niklas Loman 2 Martin Malmberg 2 Anders Kvist 2 Hans Ehrencrona 7 Helen R Davies 3 Åke Borg 2 Serena Nik-Zainal 8 
  • PMID: 31570822
  •     19 citations


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 ( 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.

Identifying Biomarkers to Pair with Targeting Treatments within Triple Negative Breast Cancer for Improved Patient Stratification.
Holly Tovey, Maggie Chon U Cheang.
Cancers (Basel), 2019 Nov 27; 11(12). PMID: 31769425    Free PMC article.
Holistic cancer genome profiling for every patient.
Serena Nik-Zainal, Yasin Memari, Helen R Davies.
Swiss Med Wkly, 2020 Jan 28; 150. PMID: 31986218    Free PMC article.
A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies.
Andrea Degasperi, Tauanne Dias Amarante, +14 authors, Serena Nik-Zainal.
Nat Cancer, 2020 Mar 03; 1(2). PMID: 32118208    Free PMC article.
Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.
Ugo Testa, Germana Castelli, Elvira Pelosi.
Med Sci (Basel), 2020 Mar 27; 8(1). PMID: 32210163    Free PMC article.
RNA-sequencing and microarray data mining revealing: the aberrantly expressed mRNAs were related with a poor outcome in the triple negative breast cancer patients.
Hongjun Fei, Songchang Chen, Chenming Xu.
Ann Transl Med, 2020 May 02; 8(6). PMID: 32355807    Free PMC article.
Molecular subtypes and precision treatment of triple-negative breast cancer.
Shen Zhao, Wen-Jia Zuo, Zhi-Ming Shao, Yi-Zhou Jiang.
Ann Transl Med, 2020 May 13; 8(7). PMID: 32395543    Free PMC article.
Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer.
Jamie R Kutasovic, Amy E McCart Reed, +2 authors, Peter T Simpson.
Cancers (Basel), 2020 Apr 05; 12(4). PMID: 32244556    Free PMC article.
Analysis of BRCA1 and RAD51C Promoter Methylation in Italian Families at High-Risk of Breast and Ovarian Cancer.
Silvia Tabano, Jacopo Azzollini, +6 authors, Siranoush Manoukian.
Cancers (Basel), 2020 Apr 12; 12(4). PMID: 32276467    Free PMC article.
Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
Neha Chopra, Holly Tovey, +19 authors, Nicholas C Turner.
Nat Commun, 2020 May 31; 11(1). PMID: 32471999    Free PMC article.
Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup.
Joline Roze, Glen Monroe, +13 authors, Ronald Zweemer.
Cancers (Basel), 2020 May 28; 12(5). PMID: 32455687    Free PMC article.
The mutREAD method detects mutational signatures from low quantities of cancer DNA.
Juliane Perner, Sujath Abbas, +4 authors, Rebecca C Fitzgerald.
Nat Commun, 2020 Jun 25; 11(1). PMID: 32576827    Free PMC article.
ShallowHRD: detection of homologous recombination deficiency from shallow whole genome sequencing.
Alexandre Eeckhoutte, Alexandre Houy, +9 authors, Tatiana Popova.
Bioinformatics, 2020 Apr 22; 36(12). PMID: 32315385    Free PMC article.
Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers.
Dominik Glodzik, Ana Bosch, +20 authors, Johan Staaf.
Nat Commun, 2020 Jul 29; 11(1). PMID: 32719340    Free PMC article.
The RECAP Test Rapidly and Reliably Identifies Homologous Recombination-Deficient Ovarian Carcinomas.
Lise M van Wijk, Sylvia Vermeulen, +11 authors, Maaike P G Vreeswijk.
Cancers (Basel), 2020 Oct 03; 12(10). PMID: 33003546    Free PMC article.
Pan-cancer landscape of homologous recombination deficiency.
Luan Nguyen, John W M Martens, Arne Van Hoeck, Edwin Cuppen.
Nat Commun, 2020 Nov 06; 11(1). PMID: 33149131    Free PMC article.
Isobaric Tags for Relative and Absolute Quantitation in Proteomic Analysis of Potential Biomarkers in Invasive Cancer, Ductal Carcinoma In Situ, and Mammary Fibroadenoma.
Hao Wu, Xian-Yu Zhang, +7 authors, Da Pang.
Front Oncol, 2020 Nov 17; 10. PMID: 33194682    Free PMC article.
Genomic Profiling Comparison of Germline BRCA and Non-BRCA Carriers Reveals CCNE1 Amplification as a Risk Factor for Non-BRCA Carriers in Patients With Triple-Negative Breast Cancer.
Xin Huang, Di Shao, +9 authors, Qiang Sun.
Front Oncol, 2020 Nov 17; 10. PMID: 33194720    Free PMC article.
RAD51-Mediated DNA Homologous Recombination Is Independent of PTEN Mutational Status.
Asha Sinha, Ali Saleh, +9 authors, Sachin Katyal.
Cancers (Basel), 2020 Nov 04; 12(11). PMID: 33138032    Free PMC article.
Comprehensive Genomic Profile of Heterogeneous Long Follow-Up Triple-Negative Breast Cancer and Its Clinical Characteristics Shows DNA Repair Deficiency Has Better Prognostic.
Ernesto Rojas-Jiménez, Javier César Mejía-Gómez, +18 authors, Felipe Vaca-Paniagua.
Genes (Basel), 2020 Nov 25; 11(11). PMID: 33227964    Free PMC article.