Fig. 3: Biallelic inactivation of Polδ leads to hypermutability. | European Journal of Human Genetics

Fig. 3: Biallelic inactivation of Polδ leads to hypermutability.

From: Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells

Fig. 3

A Top two rows: Mutability (mut/Mb) of normal and cancer colon samples from individuals with constitutional mutations in the exonuclease domain of POLE or POLD1 (sequencing data obtained from Robinson et al. [6] and produced in this study). Dots mark hyper- and ultra-mutated samples from heterozygous carriers of constitutional pathogenic mutations in POLD1 exonuclease (violet dots - two cancer samples sequenced in this study; orange dot – adenoma sample from Robinson et al. [6]). Bottom four rows: Mutation rates in endometrial cancer samples from The Cancer Genome Atlas (TCGA_UCEC) with somatic mismatch repair deficiency (dMMR) and/or polymerase proofreading deficiency (POLEexo- or POLD1exo-) (different combinations). B 96-nucleotide context mutational spectrum of the ultra- of hyper-mutated cancer samples from the POLD1 L474P heterozygote (IV.1; Fig. 1A) and from a POLD1 D316H heterozygote. C Fraction of mutations attributed to SBS10c and SBS10d mutational signatures in normal crypts, polyps6 and cancer samples from heterozygous carriers of POLD1 variants. D Variant allele frequency (top) and total coverage (bottom) along chromosome 19 of the cancer samples of the POLD1 L474P heterozygote (IV.1; Fig. 1A), showing cnLOH of the genomic region. The red line indicates the position of POLD1 L474P. E Probabilities of cnLOH at one nucleotide site for each tumor and joint probabilities to observe cnLOH in two or three tumors simultaneously. F Fold change in mutation rate in bins of different replication timings compared to the bin of the earliest replication timing. The p-value corresponds to the significance of the interaction term between the replication timing bin and homozygosity status in a binomial regression model. G Mutation rate in TCGA_UCEC cancer samples with heterozygous somatic POLD1 exonuclease mutations and varying statuses of MMR deficiency/proficiency. Y-axis represents the median of the distribution of tumor mutational burden in the corresponding subset of samples.

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