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 multiregion whole-exome sequencing to interrogate the genetic zygosity, clonal relationship,
DNA copy number, and mutational status of 52 pathologically distinct
tumor components from ten females with ovarian
immature teratomas, with bilateral
tumors present in five cases and peritoneal dissemination in seven 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 four analyzed bilateral
teratomas showed distinct patterns of zygosity changes in the right versus left sided
tumors, indicating independent clonal origins. All disseminated
teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian
tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian
immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from nondisjunction errors during meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian
immature teratomas from germ cells.