Bi-allelic pathogenic alterations affecting HR-related genes affect multiple cancer types and are associated with genomics features of HR deficiency. a Incidence of bi-allelic pathogenic alterations in HR-related genes in TCGA samples stratified according germ-line or somatic origin. It is important to note that germ-line bi-allelic alterations most commonly consisted of a germ-line pathogenic mutation and a somatic loss of heterozygosity. b Incidence of bi-allelic alterations of HR-related genes according to cancer type. c Association of LST and signature 3 in HBOC cancers. Bi-allelic pathogenic alterations and bi-allelic VUSs in HR-related genes are associated with elevated LST and signature 3 (pathogenic: p < 2.2*10−16 and p < 2.2*10−16, respectively; VUS: p = 0.02 and p = 0.017, respectively). Mono-allelic pathogenic alterations were not associated with either LST or signature 3 (p = 0.26 and p = 0.14, respectively). d LST for each genotype; cases with dominant signature 3 colored red (see methods). The box plot center line represents the median, the box limits represent the 1st and 3rd quartiles, respectively, and the whiskers extend from box limits to the largest value up to 1.5 times the interquartile range. e Pan-cancer analysis shows bi-allelic pathogenic alterations associated with an elevated LST and signature 3 (p < 2.2*10−16 and p < 2.2*10−16, respectively). Mono-allelic pathogenic alterations were not associated with elevated LST or signature 3 (p = 0.98 and p = 0.76, respectively). All p-values from the Wilcoxon-rank sum test. Error bars represent s.e.m.