TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer

Jeremy Chien, Hugues Sicotte, Jian Bing Fan, Sean Humphray, Julie M. Cunningham, Kimberly R. Kalli, Ann L. Oberg, Steven N. Hart, Ying Li, Jaime I. Davila, Saurabh Baheti, Chen Wang, Sabine Dietmann, Elizabeth J. Atkinson, Yan W. Asmann, Debra A. Bell, Takayo Ota, Yaman Tarabishy, Rui Kuang, Marina BibikovaR. Keira Cheetham, Russell J. Grocock, Elizabeth M. Swisher, John Peden, David Bentley, Jean Pierre A. Kocher, Scott H. Kaufmann, Lynn C. Hartmann, Viji Shridhar, Ellen L. Goode

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

Original languageEnglish (US)
Pages (from-to)6945-6958
Number of pages14
JournalNucleic acids research
Volume43
Issue number14
DOIs
StatePublished - Feb 2 2015

ASJC Scopus subject areas

  • Genetics

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    Chien, J., Sicotte, H., Fan, J. B., Humphray, S., Cunningham, J. M., Kalli, K. R., Oberg, A. L., Hart, S. N., Li, Y., Davila, J. I., Baheti, S., Wang, C., Dietmann, S., Atkinson, E. J., Asmann, Y. W., Bell, D. A., Ota, T., Tarabishy, Y., Kuang, R., ... Goode, E. L. (2015). TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer. Nucleic acids research, 43(14), 6945-6958. https://doi.org/10.1093/nar/gkv111