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

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Bosch, Ana 
Vallon-Christersson, Johan  ORCID logo  https://orcid.org/0000-0002-2195-0385
Reuterswärd, Christel 

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.

Adult, Aged, Aged, 80 and over, DNA Methylation, Disease-Free Survival, Female, Genetics, Population, Germ-Line Mutation, Humans, Middle Aged, Neoplasm Recurrence, Local, Prognosis, Promoter Regions, Genetic, Triple Negative Breast Neoplasms, Whole Genome Sequencing
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Nat Med
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Springer Science and Business Media LLC
Cancer Research UK (23916)
Cancer Research UK (25274)
Cancer Research UK (23433)
Financial support for this study was provided by the Swedish Cancer Society (CAN 2016/659, CAN 2018/685, and Senior Investigator Award SIA190013), the Mrs Berta Kamprad Foundation (FBKS-2018-3-166 and FBKS-2018-4-146), the Crafoord Foundation (20180543), the Swedish Research Council, the Lund-Lausanne L2-Bridge/Biltema Foundation (F 2016/1330), the Mats Paulsson Foundation (IACD 2017), the Gustav V:s Jubilee Foundation (174271), Governmental Funding of Clinical Research within the National Health Service (ALF) (2018/40612). Whole genome sequencing and analysis was funded by a Wellcome Trust Intermediate Clinical Fellowship (WT100183MA) and a CRUK Advanced Clinician Scientist Award (C60100/A23916) and a CRUK Grand Challenge Award (C60100/A25274).