Shujiro Okuda

Genomic profiling of meiotic errors and early malignant transformation events in ovarian mature teratoma

Abstract Ovarian mature teratoma (OMT) exhibits copy-neutral loss of heterozygosity (CN-LOH) derived from meiotic errors. Studies have classified OMT into five types using these CN-LOH patterns. However, tumor purity issues have hindered accurate classification and molecular characterization. Moreover, the relationship between OMT genomic abnormalities and malignant transformation remains unclear. Here, we used laser microdissection to selectively collect 29 epithelial regions from 22 OMT cases and 1 carcinoma in situ (CIS) region from a squamous cell carcinoma case arising from OMT. We then conducted whole-exome sequencing. Copy number analysis enabled classification according to the established system. In cases with multi-regional sampling, the CN-LOH patterns were identical within the same tumor, while bilateral tumors showed distinct patterns, indicating that each tumor originated independently. Among the type II OMTs, which are believed to result from meiosis II error, 2 cases exhibited a chromosomal gain. Assessment of heterozygosity suggested that these cases had meiosis I error before meiosis II error. Somatic mutation analysis revealed an extremely low mutation burden, with 1 case harboring a PIK3CA mutation. In the CIS region, additional copy number alterations were present alongside the underlying CN-LOH pattern. TP53 mutations and loss of the wild-type allele were detected. The tumor mutation burden of CIS was 6.2 mutations per megabase. Mutational signature analysis showed enrichment of apolipoprotein B mRNA editing enzyme catalytic subunit-associated signatures. This study suggests novel perspectives on the mechanisms of OMT tumor development and malignant transformation.

XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary

AbstractMolecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.