Spatial genomic diversity associated with APOBEC mutagenesis in squamous cell carcinoma arising from ovarian teratoma

Abstract

Although the gross and microscopic features of squamous cell carcinoma arising from ovarian mature cystic teratoma (MCT‐SCC) vary from case to case, the spatial spreading of genomic alterations within the tumor remains unclear. To clarify the spatial genomic diversity in MCT‐SCCs, we performed whole‐exome sequencing by collecting 16 samples from histologically different parts of two MCT‐SCCs. Both cases showed histological diversity within the tumors (case 1: nonkeratinizing and keratinizing SCC and case 2: nonkeratinizing SCC and anaplastic carcinoma) and had different somatic mutation profiles by histological findings. Mutation signature analysis revealed a significantly enriched apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) signature at all sites. Intriguingly, the spread of genomic alterations within the tumor and the clonal evolution patterns from nonmalignant epithelium to cancer sites differed between cases. TP53 mutation and copy number alterations were widespread at all sites, including the nonmalignant epithelium, in case 1. Keratinizing and nonkeratinizing SCCs were differentiated by the occurrence of unique somatic mutations from a common ancestral clone. In contrast, the nonmalignant epithelium showed almost no somatic mutations in case 2. TP53 mutation and the copy number alteration similarities were observed only in nonkeratinizing SCC samples. Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT‐SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC‐mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT‐SCC.

Clonal origin and genomic diversity in Lynch syndrome‐associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H

“…Whole‐exome sequencing was performed as previously described 20–22 . Briefly, DNA samples were fragmented using a Covaris.…”

“…The mutation signature was detected as previously described 21,22 . We used the identified somatic SNVs of clonal populations detected by PyClone described above for mutational signature analysis.…”

“…Whole-exome sequencing was performed as previously described. [20][21][22] Briefly, DNA samples were fragmented using a Covaris. Target gene enrichment was conducted with SureSelectXT Human All Exon Kit V6 (Agilent Technologies, CA, USA).…”

“…Somatic copy number alterations (SCNAs) were detected as previously described. 21,22 SCNAs were sought using FACETS using the information on the total sequence read count and allelic imbalance in tumor or non-tumor epithelium samples and the matched blood samples. 31 Germline polymorphic sites were retrieved from the VCF file generated by the 1000 Genomes Project.…”

“…Variant detection and mutation annotation were performed as previously described. 21,22 Somatic single nucleotide variants (SNVs) and short insertions/deletions (Indels) in coding exons and splice sites were called using Strelka2 (version 2.9.10). 35 We used the information about candidate Indel sites provided by Manta (version 1.6.0) for somatic Indel calling.…”