There has been an explosion of interest in genomic medicine driven along by the release of next-generation sequencing instruments like MiSeq and PGM, as well as the development of methods to assay small numbers of loci at very low cost and fast turnaround. Many academic centre's are working on NGS tests using amplicons or capture of gene panels or even exomes.
We have been working with the Fluidigm AccessArray system for a number of years and using this with a MiSeq it is possible to sequence, in duplicate, 48 patients for 48 loci of 150-250bp at over 1000x coverage for just £20 each. This is a very low cost compared to other medical tests and the potential of somatic screening is so great that I think it has to be made available to as many patients as possible.
Of course sequencing more can often be better and with technologies like Nextera capture, Ampliseq, Haloplex, etc an awful lot can be sequenced nowadays pretty easily.One company that sems to be putting all the right pieces together is Foundation Medicine...
Foundation Medicine: is a relatively new company making big strides in cancer genomic testing. They are trying to take recent advances in our understanding of cancer genomics to inform patient treatment, and aim to " improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer". Find out more on their website www.foundationmedicine.com.
About six months ago they released the Foundation One caner genome profiling test. This targets all known cancer drivers as well as genes somatically altered in Human cancer that have known therapeutic impact. The test uses and NGS capture-based assay and reports on genomic alterations including substitutions, insertions, deletions, copy number changes and some rearrangements. It can be run on any solid tumor with an input requirement of just 50ng FFPE DNA, and is run in their own CLIA labs.
The Foundation One test: Foundation Medicine are using in-solution capture of NGS libraries. They prepare sequencing libraries from very low amounts of starting material, and it is not clear to me which technology they are using (TruSeq, Rubicon, Nextera, or something else). Libraries are captured using Agilent SureSelect and sequenced on HiSeq.
The poster: there is a very nice poster from 2012 ASCOmeeting available on their website. This presents the results from the first 304 commercial cases run on the assay, which sequences the all exons of 182 cancer genes (over 3000 exons) plus introns from 14 commonly rearranged cancer genes to >500x coverage.
The poster has a nice graph showing how penetrant each gene is in cancer. It reads like the usual Top 10 list with, TP53, KRAS and PIK3CA in the top 3.
|Commonly altered gens in Cancer identified by FoundationOne
A recent paper in European Urology presented the Foundation One test results from 45 Prostate cancer patients using 50ng of FFPE DNA used in hybrid capture and sequencing of targeted loci to over 900x coverage. They found mutations and alterations in AR, TMPRSS2:ERG fusions; and loss of or mutation in PTEN, TP53, RB, MYC, and PIK3CA. They also found alterations in the key DNA repair genes BRCA2 and ATM which they suggested could be targets for PARP inhibitors, and discovered an actionable rearrangement involving BRAF. In an earlier paper in Nature Medicine, they found ALK and RET mutations when testing 64 colorectal or non–small cell lung cancers (this is also available as a poster on their website).
Interestingly the earlier paper described a test analysing just over 2500 exons in 145 cancer-relevant genes with the same number (37) of introns from 14 commonly rearranged cancer genes. This suggests to me that Foundation Medicine understand fully the need to keep the test current and are watching the literature for new candidates to add.
It does make me wonder though if smaller panels might be the best way to go for general screening of all patients first?
The reports: There is not a copy of a Foundation One report available on their website but you can get a good idea of what is covered by watching the video on their website. The test is supported by a bioinformatic pipeline that sits on top of a curated database of research and clinical publications, as well as previous cases. The mutational profile is reported along with suggestions for targeted therapy and clinical trial opportunities.
|A FoundationOne report
One of the challenges discussed in rolling cancer genome analysis out to the clinic has been teaching people how to interpret the data. Foundation Medicine is not the first to offer genomic data backed up by published research (my 23andMe profile was pretty clearly explained), but they have obviously seen that to make the test easy to adopt they need to make it easy to understand.