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The genetic landscape of 87 ovarian germ cell tumors

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  • Els Van Nieuwenhuysen
  • Pieter Busschaert
  • Patrick Neven
  • Sileny N Han
  • Philippe Moerman
  • Michalis Liontos
  • Maria Papaspirou
  • Jolanta Kupryjanczyk
  • Claus Hogdall
  • Estrid Hogdall
  • Ana Oaknin
  • Angel Garcia
  • Sven Mahner
  • Fabian Trillsch
  • David Cibula
  • Florian Heitz
  • Nicole Concin
  • Paul Speiser
  • Helga Salvesen
  • Jalid Sehouli
  • Diether Lambrechts
  • Ignace Vergote
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BACKGROUND: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized.

METHODS: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape.

RESULTS: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas.

CONCLUSION: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.

Original languageEnglish
JournalGynecologic Oncology
Issue number1
Pages (from-to)61-68
Number of pages8
Publication statusPublished - Oct 2018

    Research areas

  • Adolescent, Adult, Chromosomes, Human/genetics, DNA Copy Number Variations/genetics, DNA Mutational Analysis/methods, Female, Germ-Line Mutation/genetics, Humans, Neoplasms, Germ Cell and Embryonal/genetics, Ovarian Neoplasms/genetics, PTEN Phosphohydrolase/genetics, Phosphatidylinositol 3-Kinases/genetics, Proto-Oncogene Proteins c-akt/genetics, Proto-Oncogene Proteins c-kit/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Signal Transduction/genetics, Whole Exome Sequencing/methods, Young Adult

ID: 55847993