TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.
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.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Jeremy
J
Chien
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Sicotte.Hugues@mayo.edu.
Hugues
H
Sicotte
Illumina, Inc., San Diego, CA 92122, USA.
Jian-Bing
JB
Fan
Illumina Cambridge Ltd, Little Chesterford, Essex CB10 1, UK.
Sean
S
Humphray
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Julie M
JM
Cunningham
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Kimberly R
KR
Kalli
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Ann L
AL
Oberg
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Steven N
SN
Hart
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Ying
Y
Li
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Jaime I
JI
Davila
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Saurabh
S
Baheti
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Chen
C
Wang
Wellcome Trust, Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, UK.
Sabine
S
Dietmann
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Elizabeth J
EJ
Atkinson
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA.
Yan W
YW
Asmann
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Debra A
DA
Bell
Department of Internal Medicine, Rinku General Medical Center, Izumi-sano, 598-8577, Japan.
Takayo
T
Ota
Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
Yaman
Y
Tarabishy
Department of Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, MN 55414, USA.
Rui
R
Kuang
Illumina, Inc., San Diego, CA 92122, USA.
Marina
M
Bibikova
Illumina Cambridge Ltd, Little Chesterford, Essex CB10 1, UK.
R Keira
RK
Cheetham
Illumina Cambridge Ltd, Little Chesterford, Essex CB10 1, UK.
Russell J
RJ
Grocock
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98109, USA.
Elizabeth M
EM
Swisher
Illumina Cambridge Ltd, Little Chesterford, Essex CB10 1, UK.
John
J
Peden
Illumina Cambridge Ltd, Little Chesterford, Essex CB10 1, UK.
David
D
Bentley
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Jean-Pierre A
JP
Kocher
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Scott H
SH
Kaufmann
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA hartmann.lynn@mayo.edu.
Lynn C
LC
Hartmann
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA shridhar.vijayalakshmi@mayo.edu.
Viji
V
Shridhar
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Ellen L
EL
Goode
D002277:Carcinoma / Q000235:genetics; D019915:DNA Primase / Q000235:genetics; D005260:Female; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D059645:Mutation Rate; D010051:Ovarian Neoplasms / Q000235:genetics*; D059767:Recombinational DNA Repair; D057891:Tetraploidy
D019915:DNA Primase; C525356:PRIM2 protein, human