Poster Presentation 39th Annual Lorne Genome Conference 2018

Repetitive RNA and genomic instability in high-grade serous ovarian cancer progression and development  (#261)

James R Torpy 1 , Nenad Bartonicek 1 , Marcel E Dinger 1 2 3 , David DL Bowtell 1 4
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Kinghorn Centre for Clinical Genomics, Sydney, NSW, Australia
  3. GenomeOne, Darlinghurst, NSW, Australia
  4. Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Ovarian cancer is a highly complex disease with a range of different histological subtypes. This highly lethal disease is estimated to be t­he fifth most common cause of death from cancer in females, with a five-year relative survival rate of 46.2%. High-grade serous ovarian cancer (HGSOC), characterized by widespread genomic instability, accounts for 70-80% of ovarian cancer deaths, and survival rates have not improved significantly for the last few decades. Furthermore, the underlying cause of around 1/3 of HGSOC cases cannot be explained.

Evidence suggests that RNA derived from repetitive regions of the genome plays a role in genomic instability and development of cancers such as high-grade serous ovarian cancer, and may play a role in the unexplained HGSOC cases. Aberrant expression of centromere-derived RNA causes dysfunctional chromosomal segregation during mitosis and aneuploidy. Telomere-derived RNA maintains telomeres, preventing chromosomal fusion, breakage and subsequent rearrangement of the chromosomes. Retrotransposable elements such as LINE1s and Alus insert into different genomic locations, disrupting sequences and causing rearrangements such as duplications, inversions and translocations.

We have analysed over 120 HGSOC case and control RNA-sequencing data sets of primary samples from the Australian Ovarian Cancer Study, comparing differences in expression of repetitive RNA transcripts across multiple HGSOC subtypes and controls. We found a range of differentially expressed repetitive RNA species including LINE1, Alu and centromere-derived RNA which may be contributing to genomic instability in these tumours. In order to investigate the potential causes of the differences in repeat RNA levels, their expression was correlated with expression of a range of methyltransferases such as DNMT1 and DNMT3A-C that are known to regulate methylation at repetitive heterochromatin, controlling RNA expression from these regions. Expression of RNAi-associated factors such as Dicer was also assessed as these factors can contribute to repetitive RNA regulation.