Dear All,
I have likely a difficult and too general question. We have a possibility to perform gene sequencing on the Illumina HiSeq 1500 platform. Could you please advise and share information which mutations may/should be tested to provide options for the GBM treatment besides the standard path (radioteraphy+TMZ and TMZ after that).
Many thanks.
I don't really have a lot of technical knowledge about sequencing platforms, but it seems like this system is more geared to high throughput screening such as whole genome and whole exome sequencing. Were you told this platform would be appropriate for targeted, high coverage sequencing of individual genes?
ReplyDeleteFor targeted sequencing, the genes most likely to be mutated in GBM (IDH wild type) are
TERT promoter
PTEN
TP53
EGFR
PIK3R1
PIK3CA
NF1
RB1
Unfortunately there's not a lot of good targeted therapy options for GBM, partly due to the fact that most of the approved drugs are approved for non-central nervous system cancers, and central nervous system pharmacokinetics (ability to reach target tissue) is often poor.
EGFR is the most likely target for targeted therapy in GBM.
PTEN, PIK3CA, PIK3R1 pertain to the PI3K/mTOR pathway, but the only approved drugs for this pathway (outside clinical trials) are mTOR inhibitors rapamycin, everolimus and temsirolimus. Adding everolimus to standard treatments actually led to worse survival than standard treatments alone in a recent GBM trial, perhaps due to increased toxicity and/or immunosuppressive effects.
With mutations in NF1, MEK inhibition could be considered (trametinib), but my comment above applies here (targeted drugs not designed for central nervous system cancers).
Gene amplifications (EGFR, CDK4/6) and deletions (CDKN2A/B) are also frequent geneetic events in GBM. I would ask if this platform could also detect amplifications and deletions.
Additional genes:
ReplyDeleteIDH1 and IDH2. This is usually tested by immunohistochemistry (IDH1 R132H mutation). Was this tested already in your case?
H3F3A G34 mutation typically found in older teens and younger adults. This is far less likely to be found in older adults. I know of one case where it was found in an adult in their late 30s. H3F3A sequencing would also cover the K27M mutation, but that one is generally only found in tumors located in the brainstem, spine, and cerebellum rather than the cerebral lobes.
Even if IDH mutation is not detected by immunohistochemistry testing (which to my knowledge is confined to the IDH 132H mutation) you should have absence (or not) of IDH mutation confirmed by genetic testing, since there are other unusual IDH132 mutations (e.g. 132S) which are equally important to correct diagnosis of the IDH type of Glioma.
DeleteThis is very true. IHC will detect the R132H mutation which accounts for about 90% of IDH1 mutations in glioma, but a negative result might lead to gene sequencing to check for one of the alternate IDH1 mutations, most especially in cases where IDH1 mutation is suspected (for example if ATRX expression is lost).
DeleteI am very grateful for your comments ad time. I spoke on the Ilumina screening with an oncologist, who suggested that in this case (a rare young adult gliosarcoma), there could be some hope to find a drug targeting a particular mutation.
DeleteI feel completely lost, as I have been also informed (prior to reading your posts) that selecting or detecting such a gene cloud be very difficult if not impossible, but the progress is fast and a hope-giving treatment may be found.
Unfortunately, after resection no gene profiling has been done, so the IDH1 and IDH2 mutations were not tested.
The ILS tests would cover tissue samples as well as screening a blood sample, and all that takes approx. ~2 months.