33IN - Challenges of dealing with next generation sequencing for hereditary cancer in clinical practice

Date 29 September 2012
Event ESMO Congress 2012
Session How can medical oncologists deal with the new wave of genetic information about their patients?
Topics Hereditary syndromes
Personalised/Precision medicine
Basic Principles in the Management and Treatment (of cancer)
Presenter Kathleen Claes
Authors K. Claes
  • Department Of Nephrology And Transplantation,, Ghent University Hospital, 9000 - Gent/BE


Next generation sequencing is one of the most significant technological advances in the biological sciences of the last 20-30 years. These recent advances have brought a paradigm shift in how medical researchers investigate both rare and common disorders. The ability to generate enormous amount of sequence data in a short time at an affordable cost makes this approach ideal for a wide range of applications from 1) sequencing a panel of genes associated with a particular disease, 2) all coding regions (« exome sequencing ») to 3) the entire human genome. However, while the technology promises to reduce the cost of sequencing an entire human genome to less than US$1000, one must question the diagnostic utility of complete genome sequencing for routine clinical testing, given the many interpretive challenges posed by this approach. Knowing that in 5-6% of the breast cancer patients analysed for the coding regions of BRCA1/2 variants of unknown clinical significance (VUS) are identified, several thousands of VUS are being found by whole exome sequencing whereby the coding region of more than 20,000 genes are investigated. These, individually rare, VUS potentially have a negative impact on the individual concerned as they create greater uncertainty. Currently, large scale implementation of functional assays is not a realistic option in diagnostic settings. Therefore, at present, to our opinion, for familial cancer syndromes, it appears that next-generation DNA sequencing may provide the greatest benefit to routine clinical testing by enabling comprehensive multigene panel sequencing. This should provide an advantage over traditional Sanger-based sequencing strategies while limiting the total test output to sets of genes with known diagnostic value. The finding of a deleterious mutation in such genes guarantees the patient the possibility of adequate clinical management and follow up according to (international) established guidelines.

During the presentation we will discuss the current and near future state of clinical testing approaches for the best known and most frequent familial cancer syndromes and explore what (bioinformatic, quality control metrics and other) challenges must be addressed in order to extract diagnostic value from whole-exome and whole-genome sequencing for hereditary cancers.


The author has declared no conflicts of interest.