Multiregion exome sequencing of ovarian immature teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components

Abstract

Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multi-region whole exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from 10 females with ovarian immature teratomas, with bilateral tumors present in 5 cases and peritoneal dissemination in 7 cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the 4 analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord–Stromal Tumors: A Contemporary Review

“…The authors show that copy neutral loss of heterozygosity results from meiotic errors at different stages that can be identified based on the copy number variation profile of individual tumors ( Figure 3C) [56]. This study also suggested that while bilateral disease arises from different clonal events, spread to the peritoneum is driven by a single clone, even in bilateral disease [56]. Seventeen patients with immature teratoma are included in the GENIE/AACR database.…”

“…Available data suggest that MOGCTs have a low mutational burden with marked aneuploidy [42]. This pattern is hypothesized to arise from abnormal segregation of chromosomes during meiosis and/or mitosis [42,56]. A whole exome sequencing study of 24 MOGCTs found a median of 2.5 (range 0-8) non-synonymous mutations per tumor; an average of 35% of the genome was affected by copy number alterations in 87 patients.…”

“…Variants without known functional significance were detected in TP53, NF1, CTNBB1 , and NOTCH2 (once each). The authors show that copy neutral loss of heterozygosity results from meiotic errors at different stages that can be identified based on the copy number variation profile of individual tumors ( Figure 3 C) [ 56 ]. This study also suggested that while bilateral disease arises from different clonal events, spread to the peritoneum is driven by a single clone, even in bilateral disease [ 56 ].…”

Primary mucinous ovarian neoplasms rarely show germ cell histogenesis

“…Rarely, MOTs may arise in the context of ovarian teratoma. In such cases, genomic studies have shown the mucinous neoplasms to have identical genetic patterns to those of the adjacent teratoma, indicating a shared cell of origin 3,4 . Ovarian teratomas are believed to develop from a retained oocyte within the ovary.…”

“…Ovarian teratomas are believed to develop from a retained oocyte within the ovary. Extensive loss of heterozygosity (LOH) and an extremely low mutational burden are the genetic hallmarks of teratoma, implying meiotic abnormalities during different stages of germ cell evolution in tumour development 4–6 . Although a germ cell origin for the subset of MOTs associated with teratomas has been confirmed by multiple studies, such tumours with both mucinous and teratomatous components are rare, and the incidence of MOTs showing the genetic hallmarks of teratoma, among MOTs in which no teratoma is identified, remains unknown.…”