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. 2016 Feb;26(2):174-82.
doi: 10.1101/gr.197046.115. Epub 2016 Jan 11.

APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication

Vladimir B Seplyarskiy  1 , Ruslan A Soldatov  2 , Konstantin Y Popadin  3 , Stylianos E Antonarakis  3 , Georgii A Bazykin  1 , Sergey I Nikolaev  4
Affiliations

APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication

Vladimir B Seplyarskiy et al. Genome Res. 2016 Feb.

Abstract

APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mutations occur as clusters ("kataegis") in single-stranded DNA produced during repair of double-stranded breaks (DSBs). However, the properties of the remaining 87% of nonclustered APOBEC-induced mutations, the source and the genomic distribution of the ssDNA where they occur, are largely unknown. By analyzing genomic and exomic cancer databases, we show that >33% of dispersed APOBEC-induced mutations occur on the lagging strand during DNA replication, thus unraveling the major source of ssDNA targeted by APOBEC in cancer. Although methylated cytosine is generally more mutation-prone than nonmethylated cytosine, we report that methylation reduces the rate of APOBEC-induced mutations by a factor of roughly two. Finally, we show that in cancers with extensive APOBEC-induced mutagenesis, there is almost no increase in mutation rates in late replicating regions (contrary to other cancers). Because late-replicating regions are depleted in exons, this results in a 1.3-fold higher fraction of mutations residing within exons in such cancers. This study provides novel insight into the APOBEC-induced mutagenesis and describes the peculiarity of the mutational processes in cancers with the signature of APOBEC-induced mutations.

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Figures

Figure 1.
Figure 1.
Properties of cancers associated with the APOBEC mutational signature (rapo). (A,B) Correlation between rapo and the number of kataegistic mutations +0.5 per tumor in WGS (A) and WES (B) data sets. (C) Correlation of rapo and the level of expression of APOBEC3B per tumor in the WES data set. (D) Box plots representing rapo per tumor type; WES data set: (ACC) adrenocortical carcinoma; (BLCA) bladder cancer; (BRCA) breast cancer; (CESC) cervical squamous cell carcinoma; (ESCA) esophageal carcinoma; (HNSC) head and neck squamous cell carcinoma; (LUAD) lung adenocarcinoma; (LUSC) lung squamous cell carcinoma; (READ) rectum adenocarcinoma; (SKCM) cutaneous melanoma. (E) Distributions of rapo in WGS and WES data sets. Tumors with rapo < 1 were categorized as APOpoor, and tumors with rapo > 5, as APOrich. (F) Enrichment of dispersed and clustered APOBEC signature mutations in the proximity of rearrangement breakpoints (used as a proxy for DSBs) in the WGS data set. The observed mutation rates in the proximity (up to 100 kb) of rearrangement breakpoints were compared with the average mutation rates per tumor in APOrich tumors.
Figure 2.
Figure 2.
APOBEC mutational signature as a function of fork polarity in cancer genomes. (A) Diagram explaining the correspondence between the reference strand being replicated as leading or lagging and the direction of the replication fork. (B) Characteristics of the 50 genomic regions of lengths of 100 kb each with the highest (left) and lowest (right) FP on WGS data set for APOrich tumors. Horizontal axis: coordinates within the considered genomic regions. (Upper) average of the replication times (RT) across these 50 regions; (middle) fork polarity values reconstructed as derivatives of RT represented in the upper panel; FP > 0 corresponds to the leading strand, and FP < 0 corresponds to the lagging strand; (bottom) color-coded APOBEC signature mutations on reference strand within these regions. Each vertical line corresponds to a mutation. (C,D,E) The ratio of the mutation rates of the considered mutation type to its reverse compliment on the reference strand as a function of the propensity of the replication fork to replicate the reference strand as lagging or leading. Horizontal axis: genome split by FP values into nine bins from low FP (bin 1) to high FP (bin 9). Vertical bars represent 95% confidence intervals. (C) Pol ε_exo* produces mutations on the leading strand; APOBEC causes mutations on the lagging strand in WGS (D) and WES (E) data sets.
Figure 3.
Figure 3.
Mutations in early versus late replicating regions. Horizontal axis: genome split into 10 bins of equal size from early to late RT. (A) Mutation rates as a function of replication time (RT), relative to the mutation rate in the early RT bin. (B) Percentage of mutations in exons that fall into this bin (among all mutations in the genome) as a function of RT. Three percent of mutations in APOrich tumors and only 2.3% of mutations in APOpoor tumors occur in exons. Vertical bars represent 95% confidence interval.
Figure 4.
Figure 4.
Noncanonical mutation signatures of APOBEC3. Properties of TpCpS → TpKpS (noncanonical mutation type 1, nc1) (A,B) and TpCpN → TpApN (noncanonical mutation type 2, nc2) (C,D) induced by APOBEC3. (A,C) Correlations of enrichments of noncanonical (rapo_nc1 and rapo_nc2) and canonical rapo APOBEC3-induced mutations across tumors. (B,D) The ratio of the mutation rates of the considered mutation type to its reverse compliment on the reference strand as a function of the propensity of the replication fork to replicate the reference strand as lagging or leading. Horizontal axis in C and D: genome split by FP values into nine bins from low (bin 1) to high (bin 9). Vertical bars represent 95% confidence interval. Analysis performed using WGS data set.
Figure 5.
Figure 5.
Mutation rates of 5-methylcytosines versus nonmethylated cytosines at CpG sites. (A) APOrich tumors. (B) Tumors with rapo < 2. Methylation (Meissner et al. 2008) and mutation (WGS) data sets are tissue matched. Vertical bars represent 95% confidence intervals.
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