Genomic and transcriptomic plasticity in treatment-naive ovarian cancer.
Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the ovaries. Several cancer genes such as NF1, CDKN2A, and FANCD2 were affected by lesion-specific breakpoints. Furthermore, the intra-tumor variability involved different mutational hallmarks including lesion-specific kataegis (local mutation shower coinciding with genomic breakpoints), rearrangement classes, and coding mutations. In one extreme case, we identified two independent TP53 mutations in ovary tumors and omentum/peritoneum metastases, respectively. Examination of gene expression dynamics revealed up-regulation of key cancer pathways including WNT, integrin, chemokine, and Hedgehog signaling in only subsets of tumor samples from the same patient. Finally, we took advantage of the multilevel tumor analysis to understand the effects of genomic breakpoints on qualitative and quantitative gene expression changes. We show that intra-tumor gene expression differences are caused by site-specific genomic alterations, including formation of in-frame fusion genes. These data highlight the plasticity of ovarian cancer genomes, which may contribute to their strong capacity to adapt to changing environmental conditions and give rise to the high rate of recurrent disease following standard treatment regimes.
Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
Marlous
M
Hoogstraat
Mirjam S
MS
de Pagter
Geert A
GA
Cirkel
Markus J
MJ
van Roosmalen
Timothy T
TT
Harkins
Karen
K
Duran
Jennifer
J
Kreeftmeijer
Ivo
I
Renkens
Petronella O
PO
Witteveen
Clarence C
CC
Lee
Isaac J
IJ
Nijman
Tanisha
T
Guy
Ruben
R
van 't Slot
Trudy N
TN
Jonges
Martijn P
MP
Lolkema
Marco J
MJ
Koudijs
Ronald P
RP
Zweemer
Emile E
EE
Voest
Edwin
E
Cuppen
Wigard P
WP
Kloosterman
D000368:Aged; D002869:Chromosome Aberrations; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009456:Neurofibromatosis 1 / Q000235:genetics; D009852:Omentum / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D015514:Oncogene Proteins, Fusion; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53