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

Source: https://onco.cc/key-papers/paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019/  
OnCo record `paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reading the whole genome of 254 Swedish triple-negative cancers showed that 59% carry the signature of broken BRCA-type DNA repair, two-thirds of them explained by BRCA1 or BRCA2 mutation, BRCA1 or RAD51C promoter methylation or PALB2 loss, and that these patients did best on standard chemotherapy.

## Summary

254 TNBCs from the population-based SCAN-B project (NCT02306096; TNBC was 9% of the cohort) were whole-genome sequenced; 237 (93%) gave sufficient data, with 3% failure at 30-fold depth and 11% at 15-fold. HRDetect classified 58.6% as HRDetect-high, 5.5% intermediate and 35.9% low; 88.5% of women under 50 were HRDetect-high. Of 139 high cases, 29 (21%) had biallelic BRCA1/2 loss (20 germline, 9 somatic), 55 (40%) BRCA1 promoter hypermethylation with loss of the other allele, five pathogenic germline PALB2 variants and five RAD51C hypermethylations; 33% were unexplained. A germline SINE-VNTR-Alu retrotransposition abrogating BRCA1 was discovered. HRDetect-high patients had better invasive disease-free survival (HR 0.42) and distant relapse-free interval (HR 0.31) on adjuvant chemotherapy; intermediate had the poorest outcome; about 4.7% of HRDetect-low tumours were mismatch-repair deficient and the low group was enriched for PIK3CA/AKT1 pathway abnormalities. The copy-number-based HRD assay had a 13% false-negative rate against HRDetect.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature Medicine
- Year: 2019
- DOI: 10.1038/s41591-019-0582-4
- Authors: Staaf J, Glodzik D, Bosch A, et al.
- Findings: HRDetect-high 58.6%, intermediate 5.5%, low 35.9% of 237 TNBC genomes.; Causes of high scores: BRCA1/2 biallelic loss 21%, BRCA1 promoter hypermethylation 40%, PALB2 and RAD51C 6.5%, unexplained 33%.; HRDetect-high: invasive disease-free survival HR 0.42 and distant relapse-free HR 0.31 on adjuvant chemotherapy; 4.7% of HRDetect-low tumours mismatch-repair deficient.
- What it means: It is the best population-based estimate of how much TNBC is homologous recombination deficient, shows that most of it is not germline BRCA, and argues that whole-genome sequencing at diagnosis could stratify trials and pick out the low group that needs something other than DNA-damaging chemotherapy.
- Caveats: Prognostic, not predictive: the outcome benefit was on chemotherapy, with no untreated comparison.; Swedish population; ancestry-specific founder effects are absent.

## Sources

- Staaf et al., Nat Med 2019: whole-genome sequencing of 254 population-based TNBCs (SCAN-B): https://doi.org/10.1038/s41591-019-0582-4
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31570822/

## Connected records

- cancers: [Early triple-negative breast cancer](https://onco.cc/cancers/tnbc-early/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [HRD & BRCA testing](https://onco.cc/technologies/hrd-testing/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [PALB2](https://onco.cc/targets/palb2/), [RAD51C](https://onco.cc/targets/rad51c/)
- institutions: [Skåne University Hospital / Lund University Cancer Centre](https://onco.cc/institutions/lund-skane/)
- pathways: [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/)
- terms: [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [Mutational signature](https://onco.cc/terms/mutational-signature/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)
- biomarkers: [HRD-positive (genomic instability score)](https://onco.cc/biomarkers/hrd-positive/), [Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations](https://onco.cc/biomarkers/brca-somatic/)

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