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Nat Med. 2019 Oct;25(10):1526-1533. doi: 10.1038/s41591-019-0582-4. Epub 2019 Sep 30.

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

Author information

1
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden. johan.staaf@med.lu.se.
2
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
3
Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
5
Department of Oncology, Skåne University Hospital, Lund, Sweden.
6
Academic Department of Medical Genetics, The Clinical School University of Cambridge, Cambridge Biomedical Research Campus, Cambridge, UK.
7
Independent Cancer Patients' Voice, London, UK.
8
Department of Clinical Genetics and Pathology, Department of Laboratory Medicine, Office for Medical Services, Lund, Sweden.
9
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
10
Division of Surgery, Department of Clinical Sciences, Lund University, Lund, Sweden.
11
Department of Surgery, Skåne University Hospital, Lund, Sweden.
12
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
13
MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge Biomedical Research Campus, Cambridge, UK.
14
Academic Department of Medical Genetics, The Clinical School University of Cambridge, Cambridge Biomedical Research Campus, Cambridge, UK. snz@mrc-cu.cam.ac.uk.
15
MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge Biomedical Research Campus, Cambridge, UK. snz@mrc-cu.cam.ac.uk.

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.

PMID:
31570822
PMCID:
PMC6859071
DOI:
10.1038/s41591-019-0582-4
[Indexed for MEDLINE]
Free PMC Article

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