{"entity":{"id":"paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","kind":"paper","name":"Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study","aka":[],"tldr":"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.","asOf":"2026-09-24","links":[{"label":"Staaf et al., Nat Med 2019: whole-genome sequencing of 254 population-based TNBCs (SCAN-B)","url":"https://doi.org/10.1038/s41591-019-0582-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31570822/"}],"tags":[],"related":[],"cancers":["tnbc","tnbc-early"],"sections":[],"technologies":["wes-wgs","hrd-testing"],"targets":["brca","palb2","rad51c","mmr"],"drugs":[],"companies":[],"institutions":["lund-skane"],"pathways":["homologous-recombination-repair","mutagenesis-signatures"],"terms":["hrd","mutational-signature"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-medicine"],"dependsOn":[],"notes":[],"journal":"Nature Medicine","year":2019,"doi":"10.1038/s41591-019-0582-4","pmid":"31570822","authors":"Staaf J, Glodzik D, Bosch A, et al.","paperType":"translational","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."],"whatItMeans":"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."],"changedPractice":false,"participants":254},"route":"/key-papers/paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019/","neighbours":{"cancer":[{"id":"tnbc-early","kind":"cancer","name":"Early triple-negative breast cancer","route":"/cancers/tnbc-early/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"hrd-testing","kind":"technology","name":"HRD & BRCA testing","route":"/technologies/hrd-testing/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"palb2","kind":"target","name":"PALB2","route":"/targets/palb2/"},{"id":"rad51c","kind":"target","name":"RAD51C","route":"/targets/rad51c/"}],"institution":[{"id":"lund-skane","kind":"institution","name":"Skåne University Hospital / Lund University Cancer Centre","route":"/institutions/lund-skane/"}],"pathway":[{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"}],"term":[{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"}],"journal":[{"id":"nature-medicine","kind":"journal","name":"Nature Medicine","route":"/journals/nature-medicine/"}],"biomarker":[{"id":"hrd-positive","kind":"biomarker","name":"HRD-positive (genomic instability score)","route":"/biomarkers/hrd-positive/"},{"id":"brca-somatic","kind":"biomarker","name":"Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations","route":"/biomarkers/brca-somatic/"}]}}