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Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup

Roze, J., Monroe, G., Kutzera, J., Groeneweg, J., Stelloo, E., Paijens, S., Nijman, H., Meurs, H. V., Lonkhuijzen, L. V., Piek, J., Lok, C., Jonges, G., Witteveen, P., Verheijen, R., Haaften, G. V. & Zweemer, R., 21-May-2020, In : Cancers. 12, 5, 22 p., 1308.

Research output: Contribution to journalArticleAcademicpeer-review

  • Joline Roze
  • Glen Monroe
  • Joachim Kutzera
  • Jolijn Groeneweg
  • Ellen Stelloo
  • Sterre Paijens
  • Hans Nijman
  • Hannah van Meurs
  • Luc van Lonkhuijzen
  • Jurgen Piek
  • Christianne Lok
  • Geertruida Jonges
  • Petronella Witteveen
  • René Verheijen
  • Gijs van Haaften
  • Ronald Zweemer

Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 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 TP53 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. FOXL2-wildtype AGCTs harbored DICER1, TERT(C228T) and TP53 mutations and similar CNV profiles as FOXL2-mutant tumors. Our study confirms that absence of the FOXL2 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.

Original languageEnglish
Article number1308
Number of pages22
JournalCancers
Volume12
Issue number5
Publication statusPublished - 21-May-2020

    Keywords

  • whole genome sequencing, granulosa cell tumors, ovarian cancer, FOXL2, tumor heterogeneity, MONOSOMY 22, CANCER, FRAMEWORK

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