| Summary: | Adult granulosa cell tumors (AGCTs) harbor a somatic <i>FOXL2</i> c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic <i>TP53</i> mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29–80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. <i>FOXL2</i>-wildtype AGCTs harbored <i>DICER1</i>, <i>TERT</i>(C228T) and <i>TP53</i> mutations and similar CNV profiles as <i>FOXL2</i>-mutant tumors. Our study confirms that absence of the <i>FOXL2</i> c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients.
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