Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Mutational landscape  of adult granulosa cell tumours of the ovary from whole exome sequencing (#157)

Peter J Fuller 1 , Maria Alexiadis 1 , Simon Chu 1 , Dilys TH Leung 1 , Simone M Rowley 2 , Jason Li 2 , Kaushalya C Amarasinghe 2 , Ian G Campbell 2
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Granulosa cell tumors of the ovary (GCT) are a unique subset of malignant ovarian tumours.  Adult GCT are defined by the presence  of the C134W somatic mutation in the FOXL2 gene. Although GCT are generally regarded as having a good prognosis, late recurrences occur which usually lead to the patient’s demise. Neither reliable methods of predicting relapse, nor the molecular mechanisms of relapse or aggressive behaviour are known.  We sought to identify the additional somatic mutations responsible for recurrence and/or aggressive behaviour.

Tumoral DNA from 21 fresh frozen, FOXL2 C134W mutation positive, GCT (14 x stage 1 and 8 x stage 3) were subjected to whole exome sequencing. In addition, known mutations in the promoter of the telomerase gene (TERT) were sought using targeted PCR.

In all cases the FOXL2 mutation was confirmed, a de facto positive control. The initial analysis identified on average 78 coding and essential splice-site variants (SNV and/or indels) in each aGCT. A subset of these variants has been independently validated by Sanger sequencing. Recurrent mutations were not identified, while pathway analysis did not associate mutations to specific pathway(s). Copy number analysis confirmed previous cytogenetic observations that trisomy at chromosomes 12 and 14 occurs in ~30% of GCT and monosomy at 22 in ~40%; other large scale changes are more random and less frequent. A relatively high frequency of a TERT promoter mutation was found.

This first comprehensive exome-wide analysis of the mutational landscape of aGCT suggests that recurrence and/or aggressive behaviour is not defined by activation or loss of specific genes or pathways however further studies are needed to exclude a role for splice-variants or genomic rearrangements. Conversely, the TERT mutation represents a potential prognostic factor in GCT.