Fig. 3: The genetic causes of HRD in patients from the HMF and PCAWG datasets.

a The bar plot shows the probability of HRD for each patient (total bar height) with each bar being divided into segments indicating the probability of BRCA1-type HRD (orange) and BRCA2-type HRD (purple). 310 patients were predicted HRD while 4812 were predicted HRP by CHORD. b A one-tailed Fisher’s exact test identified enrichment of BRCA1 (q = 9.4e-51), BRCA2 (q = 4.8e-101), RAD51C (q = 5.6e-5) and PALB2 (q = 0.02) biallelic inactivation in CHORD-HRD vs. CHORD-HRP patients (from a list of 781 cancer and HR related genes). Each point represents a gene with its size/color corresponding to the statistical significance as determined by the Fisher’s exact test, with axes indicating the percentage of patients (within either the CHORD-HRD or CHORD-HRP group) in which biallelic inactivation was detected. Multiple testing correction was performed using the Hochberg procedure. c Biallelic inactivation of BRCA2, RAD51C and PALB2 was associated with BRCA2-type HRD, whereas only BRCA1 inactivation was associated with BRCA1-type HRD. Top: BRCA1- and BRCA2-type HRD probabilities from CHORD. Middle: SV contexts (duplications 1–10 kb and 10–100 kb) used by CHORD to distinguish BRCA1- from BRCA2-type HRD. Bottom: The biallelic status of each gene. Samples were clustered according to HRD subtype, and by the impact of a biallelic/monoallelic event (based on ‘P-scores’ as detailed in the methods). Clusters 1, 2, 3, and 5 correspond to patients with identified inactivation of BRCA2, RAD51C, PALB2 and BRCA1, while clusters 4 and 6 correspond to patients without clear biallelic inactivation of these 4 genes. Tiles marked as “Known pathogenic” refer to variants having a “pathogenic” or “likely pathogenic” annotation in ClinVar. “Other” variants include various low impact variants such as splice region variants or intron variants (these are fully specified in Supplementary Data 4). LOH: loss-of-heterozygosity. Only data from samples that passed CHORD’s QC criteria are shown in this figure (MSI absent, ≥50 indels, and ≥30 SVs if a sample was predicted HRD).