TY - JOUR
T1 - TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer
AU - Chien, Jeremy
AU - Sicotte, Hugues
AU - Fan, Jian Bing
AU - Humphray, Sean
AU - Cunningham, Julie M.
AU - Kalli, Kimberly R.
AU - Oberg, Ann L.
AU - Hart, Steven N.
AU - Li, Ying
AU - Davila, Jaime I.
AU - Baheti, Saurabh
AU - Wang, Chen
AU - Dietmann, Sabine
AU - Atkinson, Elizabeth J.
AU - Asmann, Yan W.
AU - Bell, Debra A.
AU - Ota, Takayo
AU - Tarabishy, Yaman
AU - Kuang, Rui
AU - Bibikova, Marina
AU - Cheetham, R. Keira
AU - Grocock, Russell J.
AU - Swisher, Elizabeth M.
AU - Peden, John
AU - Bentley, David
AU - Kocher, Jean Pierre A.
AU - Kaufmann, Scott H.
AU - Hartmann, Lynn C.
AU - Shridhar, Viji
AU - Goode, Ellen L.
N1 - Publisher Copyright:
© 2015 The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2015/2/2
Y1 - 2015/2/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84940202151&partnerID=8YFLogxK
U2 - 10.1093/nar/gkv111
DO - 10.1093/nar/gkv111
M3 - Article
C2 - 25916844
AN - SCOPUS:84940202151
SN - 0305-1048
VL - 43
SP - 6945
EP - 6958
JO - Nucleic acids research
JF - Nucleic acids research
IS - 14
ER -