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Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study
- Source :
- Nature medicine
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Oncology
Adult
medicine.medical_specialty
PALB2
Population
Triple Negative Breast Neoplasms
General Biochemistry, Genetics and Molecular Biology
Germline
Article
Disease-Free Survival
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Humans
education
Promoter Regions, Genetic
Germ-Line Mutation
Aged
Whole genome sequencing
Aged, 80 and over
education.field_of_study
Whole Genome Sequencing
business.industry
Hazard ratio
General Medicine
DNA Methylation
Middle Aged
Prognosis
Confidence interval
3. Good health
030104 developmental biology
Genetics, Population
030220 oncology & carcinogenesis
DNA methylation
RAD51C
Female
Neoplasm Recurrence, Local
business
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....4dc74df99ad06ae02125a2ab827f8ff3