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Clinical Ovarian Cancers Display Extensive Genetic Heterogeneity, Study Suggests Multiple Treatment Protocols May Be Necessary

15.11.2013
Sequencing Study Underscores Difficulty of Treating Ovarian Cancer, Points to Diverse Patterns of Ovarian Cancer Evolution

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.

1World Cancer Research Fund International http://www.wcrf.org/cancer_statistics/data_specific_cancers/ovarian_cancer_statistics.php
About Life Technologies
Life Technologies Corporation (NASDAQ: LIFE) is a global biotechnology company that is committed to providing the most innovative products and services to leading customers in the fields of scientific research, genetic analysis and applied sciences. With a presence in more than 180 countries, the company's portfolio of 50,000 end-to-end solutions is secured by more than 5,000 patents and licenses that span the entire biological spectrum -- scientific exploration, molecular diagnostics, 21st century forensics, regenerative medicine and agricultural research. Life Technologies has approximately 10,000 employees and had sales of $3.8 billion in 2012.
Life Technologies’ Safe Harbor Statement
This press release includes forward-looking statements about our anticipated results that involve risks and uncertainties. Some of the information contained in this press release, including, but not limited to, statements as to industry trends and Life Technologies’ plans, objectives, expectations and strategy for its business, contains forward-looking statements that are subject to risks and uncertainties that could cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Any statements that are not statements of historical fact are forward-looking statements. When used, the words “believe,” “plan,” “intend,” “anticipate,” “target,” “estimate,” “expect” and the like, and/or future tense or conditional constructions (“will,” “may,” “could,” “should,” etc.), or similar expressions, identify certain of these forward-looking statements. Important factors which could cause actual results to differ materially from those in the forward-looking statements are detailed in filings made by Life Technologies with the Securities and Exchange Commission. Life Technologies undertakes no obligation to update or revise any such forward-looking statements to reflect subsequent events or circumstances.

Life Technologies Contact

Suzanne Clancy
760-602-4545
858-205-4235 (mobile)
Suzanne.Clancy@lifetech.com

Suzanne Clancy | EurekAlert!
Further information:
http://www.lifetech.com

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