Navigation Links
Clinical ovarian cancers display extensive genetic heterogeneity, study suggests multiple treatment

CARLSBAD, Calif. and UTRECHT, The Netherlands Nov. 12, 2013 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-nave 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."


Contact: Suzanne Clancy
Life Technologies

Related biology news :

1. Elseviers Biochimica et Biophysica Acta (BBA) journal series adds open access journal: BBA Clinical
2. Baxter Completes Enrollment In Phase III Clinical Trial Of BAX 855, Extended Half-life Recombinant FVIII For Hemophilia A
3. Development and clinical approval of biodegradeble magnesium alloy
4. Use of Biomarkers in Clinical Trials for Drugs Outside of Oncology is Increasing
5. KaloBios to Present KB004 Interim Phase 1 Clinical Data in Hematologic Malignancies at ASH
6. Breastfeeding as a possible deterrent to autism -- a clinical perspective
7. Projecis Cloud-based Collaboration Platform Selected by Spaulding Clinical to Manage Phase I Clinical Trial Projects and Timelines
8. Arcturus Therapeutics Raises $5 Million in Series A Funding to Maintain its Momentum in Nominating Lead Clinical Candidate in 2014
9. Picofemto Deploys Cloud-Based Cliniscan EEG Analytics and Clinical Decision Support
10. UNLV, Sen. Reid Announce $20 Million NIH grant to support clinical health research
11. Wistar receives $1.5 million Department of Defense grant to ready prostate drug for clinical use
Post Your Comments:
(Date:11/12/2015)... 2015  A golden retriever that stayed healthy despite ... has provided a new lead for treating this muscle-wasting ... Institute of MIT and Harvard and the University of ... Cell, pinpoints a protective gene that ... effects. The Boston Children,s lab of Lou Kunkel ...
(Date:11/11/2015)... MedNet Solutions , an innovative SaaS-based eClinical technology company that ... announce that it will be a Sponsor of the ... held November 17-19 in Hamburg , Germany.  ... iMedNet , MedNet,s easy-to-use, proven and affordable eClinical ... able to deliver time and cost savings of up to ...
(Date:11/9/2015)... 09, 2015 ... the "Global Law Enforcement Biometrics Market ... --> ) has announced the ... Biometrics Market 2015-2019" report to their ... ( ) has announced the addition ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... FAR HILLS, N.J. (PRWEB) , ... November 24, 2015 , ... ... University, as the recipient of the 2016 USGA Green Section Award. Presented annually since ... of golf through his or her work with turfgrass. , Clarke, of ...
(Date:11/24/2015)... ... 2015 , ... International Society for Pharmaceutical Engineering (ISPE) closed ... events for pharmaceutical manufacturing: 2015 Annual Meeting. The conference took place in Philadelphia, ... number of attendees in more than a decade. , “The 2015 Annual ...
(Date:11/24/2015)... ... November 24, 2015 , ... The Academy of Model ... Group (SIG), MultiGP, also known as Multirotor Grand Prix, to represent the First–Person View ... years. Many AMA members have embraced this type of racing and several new model ...
(Date:11/24/2015)... FRANCISCO , Nov. 24, 2015  Twist ... announced that Emily Leproust, Ph.D., Twist Bioscience chief ... Jaffray Healthcare Conference on December 1, 2015 at ... Hotel in New York City. --> ... . Twist Bioscience is on Twitter. ...
Breaking Biology Technology: