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GliomaSTRAT™ – A new tool for brain tumor stratification

The World Health Organization released new guidelines in June 2016 for the classification of gliomas.
After histology, determining the IDH status (CIMP) is now recommended for both low and high grade tumors. GliomaSTRAT is a rapid, multi-biomarker test panel used for the stratification of gliomas by both tumor aggressiveness and potential for drug activity. GliomaSTRAT determines the tumor’s Glioma CpG Island Methylator Phenotype (G-CIMP) using a three gene DNA methylation profile and determines whether G-CIMP is caused by the presence of the primary causative mutation in Isocitrate Dehydrogenase 1 (IDH) by assaying for both the wildtype (WT) and mutant IDH1 R132H alleles. These prognostic biomarkers identify two distinct tumor subtypes that show significant differences in overall survival, independent of initial tumor grade classification. GliomaSTRAT also detects MGMT promoter methylation, which correlates with the inactivation of the gene for the DNA repair enzyme O-6-Methylguanine-DNA Methyltransferase (MGMT), longer overall survival in patients with glioblastoma and a positive response to treatment with temozolomide (TMZ, Temodar).

Analysis of biomarkers of different types typically involves the use of different technologies and may require the sample to be split and sent to different testing laboratories. GliomaSTRAT is based on a novel technology that allows both DNA methylation and mutations to be interrogated in the same test, using just nanograms of DNA, including FFPE samples.

The components of the GliomaSTRAT test include:

  1. MGMT Methylation
    • Predicts probable sensitivity to treatment with temozolomide (Temodar®
  2. G-CIMP (Glioma CpG Island Methylator Phenotype)
    • G-CIMP identifies a group of gliomas with a distinct DNA hypermethylation profile that has been associated with improved survival, independent of WHO tumor classification.
    • G-CIMP is determined by measuring the DNA methylation of 3 genes (HFE, MAL and SOWAHA) and is considered G-CIMP+ if 2 out of 3 genes are methylated.
  3. IDH1 R132H and IDH1 WT detection
    • IDH1 R132H is the primary mutation associated with causing G-CIMP+, although it can also be caused by other mutations in IDH1 or IDH2.
    • The phenotype is determined with the DNA methylation profile, without the need for DNA sequencing. This assay will also identify the subset of G-CIMP+ tumors caused by the IDH1 R132H mutation.

GliomaSTRAT is now being offered in Ribomed’s Clinical Services Laboratory (ribomedcsl.com, CLIA ID Number: 05D2101383) as the full GliomaSTRAT panel or as individual tests for MGMT methylation, G-CIMP or IDH1 WT/R132H testing.

To order, contact info@RiboMed.com

References

  1. McCarthy et al. MethylMeter®: bisulfite-free quantitative and sensitive DNA methylation profiling and mutation detection in FFPE samples. Epigenomics 8(6), 747-765 (2016). http://www.futuremedicine.com/doi/pdf/10.2217/epi-2016-0004
  2. Van den Bent. 2010. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective. Acta Neuropathol, 120: 297–304.
  3. Bruner, et al. 1997. Diagnostic Discrepancies and Their Clinical Impact in a Neuropathology Referral Practice. Cancer, 79(4): 796-803.
  4. Coons, et al. 1997. Improving Diagnostic Accuracy and Interobserver Concordance in the Classification and Grading of Primary Gliomas. Cancer, 79(7): 1381-1393.
  5. Noushmehr, H., et al., Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell, 2010. 17(5): p. 510-22.
  6. McCarthy, D., P. Cotter, and M. Hanna, MethylMeter: A quantitative, sensitive, and bisulfite-free method for analysis of DNA methylation, in DNA Methylation, T. Tatarinova and O. Kerton, Editors. 2012, InTech: Rijeka.  https://www.researchgate.net/publication/221929219_MethylMeterr_A_Quantitative_Sensitive_and_Bisulfite-Free_Method_for_Analysis_of_DNA_Methylation