One of the most comprehensive studies of genetic mutations in ovarian cancer was published today, demonstrating an unprecedented level of genetic variation that exists in both primary tumors and metastatic lesions of ovarian cancer. The study highlights potential new pathways for therapeutic intervention and suggests that sampling and sequencing of multiple disease sites may be required for effective targeted treatments.
The paper, titled “Genomic and transcriptomic plasticity in treatment-naïve ovarian cancer,” is available online at the journal Genome Research and is authored by scientists at the University Medical Center Utrecht in The Netherlands and Life Technologies Corporation in Carlsbad, Calif. With an annual global incidence of 220,000 and mortality of 140,0001, ovarian cancer is a leading cause of cancer deaths in women, making it a disease in urgent need of improved treatment.
The researchers examined a total of 27 archived tumor biopsy samples, both from primary tumors as well as distant metastatic sites, gathered from three women with late stage (IIIC/IV) ovarian cancer. Tumor samples and matched normal tissue samples were analyzed using a variety of methods, including transcriptome and mate-pair sequencing and several targeted gene sequencing panels.
Sequencing was conducted on the Applied Biosystems® SOLiD 5500xL and Ion Personal Genome Machine (PGM™), both from Life Technologies, using Life’s Ion AmpliSeq™ Comprehensive Cancer Panel, a panel of more than 400 genes that have been implicated in cancer. This study represents the first peer-reviewed, scientific publication employing this panel of 409 oncogenes.
The sequencing data revealed a striking degree of genetic heterogeneity within each individual’s cancer. This was evident from profiles of coding mutations, genomic structural variation and gene expression changes. Of note, one of the individuals displayed independent TP53 driver mutations, each of which was present in only subsets of the ovarian tumor samples.
This level of heterogeneity was also manifested in different evolutionary pathways that each instance of cancer took, with some cancers following a linear progression while the TP53 instance displayed early branching, in which each branch has its own genetic set of mutations.
“Ovarian cancers are typically diagnosed when the disease is at an advanced stage and the tumor mass is often large with numerous metastases throughout the abdominal cavity,” said Wigard P. Kloosterman, a principal investigator at the University Medical Center Utrecht and lead author of the study. “Following primary debulking surgery, we obtained a large number of samples from each of these women, which enabled the study of intra-tumor heterogeneity before chemotherapeutic or other drug treatments were applied. The current study, representing the most comprehensive data set to date, reveals extensive heterogeneity, which is probably one of the reasons this disease is so difficult to treat.”
The study did reveal marked gene expression differences between tumor biopsies from the same patient. These include altered expression of WNT, integrin and Hedgehog pathway members in subsets of tumor biopsies. Currently, targeted therapies for ovarian cancer patients are being developed and proper patient stratification is essential for successful treatment. For example, application of Hedgehog pathway inhibitors is an emerging strategy that could only prove useful in those patients displaying changes in Hedgehog signaling. The results from this study suggest that fine-tuning of patient stratification for targeted therapy would require analysis of multiple biopsies per patient.
"This study is a key first step in the community’s effort towards personalized medicine, one in which we characterize the mutational landscape within an individual’s cancer," said Timothy Harkins, a Director of R&D with Life Technologies and co-author on the study. “This study was both comprehensive and rapid, as the experimental design encompassed not only the genetic characterization of all tumors within an individual, but it also used multiple sequencing technologies, allowing mutations to be validated at the same pace that they were detected."
“The divergence of mutation profiles within tumors from individual women suggests that sequencing of multiple samples from a single patient may be necessary before a drug treatment protocol can be devised,” said Paul Billings, Chief Medical Officer for Life Technologies. “Very different evolutionary pathways for each woman were observed in the study, which would have been missed if only one section of the primary tumor or just one of the metastatic lesions had been sequenced. The data suggest that if only one metastasis were to be biopsied and sequenced, a number of relevant driver mutations and druggable targets would likely be missed, which would be expected to lead to poor treatment outcomes."The Applied Biosystems SOLiD 5500 and Ion Personal Genome Machine (PGM™) are for Research Use Only. Not intended for diagnostic purposes.
Life Technologies ContactSuzanne Clancy
Suzanne Clancy | EurekAlert!
Multi-year study finds 'hotspots' of ammonia over world's major agricultural areas
17.03.2017 | University of Maryland
Diabetes Drug May Improve Bone Fat-induced Defects of Fracture Healing
17.03.2017 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy