Extended Data Fig. 4: Evidence of biallelic TP53 targeting in the cases with multiple TP53 hits.
a, Scatter plot of the two maximum TP53 variant allele frequency (VAF) values from cases with multiple TP53 mutations and no copy-neutral LOH or deletion at TP53 locus (n=90). Points are annotated according to the level of information of the mutation pairs. In 67% (n=60) of pairs the sum of the two VAFs exceeded 50% so that the mutations were considered to be in the same cells as per the pigeonhole principle (triangle and diamond points). In 18 cases, the genomic distance between two mutations was within sequencing read length and it was therefore possible to phase the mutations. In all those cases the mutations were observed to be unphased, that is, in trans (square and diamond points). Within those 18 pairs of unphased mutations, 10 pairs had a sum of VAFs above 50%, that is, mutations were necessarily on different alleles and in the same cells, implying biallelic targeting (diamond points). b, c, Scatter plots of the VAF of TP53 mutations and minor allele frequency of 17p heterozygous SNPs from cases with one TP53 mutation and 17p deletion (b., n=69) or 17p copy-neutral LOH (c., n=61). The high correlations in (a.), (b.) and (c.) (R2 of 0.77, 0. 94 and 0.97, respectively) are indicative of biallelic targeting of TP53. d, Table of pairs of TP53 mutations from the same patients that could be phased. All pairs were in trans, that is, mutations were supported by different alleles. e, Representative IGV example of unphased mutations (patient p12 from table (d.)).
