K27M- Important in DIPG?

It has been less than a year and a half since the St Jude and Canadian researchers came out simultaneously with publications on histone H3 mutations in pediatric glioblastoma and DIPG.  These were the first ever reports on a "recurrent mutation in a regulatory histone in humans to case cancer and it seemed that those mutations may be drivers to alter the chromatinc architecture underlying the formation of pediatric GBMs and DIPGs.  The H3 mutation specifically related to DIPGs seems to be  K27M.

This seemed to generate a huge amount of interest in pediatric high grade glioma/DIPG research as this SNO/PBTF Pediatric Neuro-Oncology Basic and Translational Research Conference held in Fort Lauderdale this week had several abstracts on this exact subject.   In fact 4 of the 11 abstracts in the brainstem glioma section included K27M in their title.

Functional Analysis of the H3.3-K27M Mutaton in DIPG
University of Toronto, Duke University, The Hospital for Sick Children

H3.3 K27M accelerates PDGR-induced brainstem gliomagenesis in vivo
Duke Univeristy and Laboratory of Chromatin Biology and Epigenetic (NY)

Targeting the histone H3.3-K27M mutation for the treatment of diffuse intrinsic pontine gliomas
UCSF and Georgetown

The type of histone H3-variant K27M mutation drives the agressiveness of Diffuse Intrinsic Pontine Gliomas
France and UK

In addition, another abstract lists that all the 20 previsously untreated DIPG specimens in their study had the K27M mutition.  This abstract entitled "The genomic landscape of treatment naive DIPG biopsy samples" was a combined effort from Paris, France; Barcelona, Spain; London, UK and Vancouver, Canada.

It would seem that this K27M mutation is going to dominant upcoming discussions regarding DIPG.   The Allis-Becher research alliance has already produced an elegant paper coming out electronically ahead of print the end of March in Science.  This article found that the K27M point mutation is specific to the for the mistake of methionine for lysine at that location.   No other amino acid mistake in production causes the same problems.  These authors propose that this mutation inhibits a specific complex which promotes tumor formation.   It is more complex than that but that is the general idea.

The potential of importance is varied when looking at these abstacts.   This K27M mutation could be:
-"one of the first prognositic markers when judging results of prospective trials"
-"a target for novel intervention"
-and a mechanism for DIPG formation.

For those interested in DIPG research, I predict the K27M and other histone mutation research is going to be in the forefront in the near future.

Reference:
Brainstem Tumors, Radiaiton Therapy and Medulloblastoma (Platform Presentation Abstracts)
https://soc-neuro-onc.conference-services.net/programme.asp?conferenceID=3467&action=prog_list&session=26434

Inhibition of PRC2 Activity by a Gain of Function H3 Mutation Found in Pediatric Glioblastoma
http://www.ncbi.nlm.nih.gov/pubmed/23539183

Exceptional new Allis lab Science paper on exploding area of histone H3.3 in pedaitric brain cancer
http://www.ipscell.com/tag/h3-3-k27m/

Genomic Landscape of treatment-naive DIPG Biopsy Sample

Yesterday I posted about the first International DIPG conference held in 2009 in Barcelona, Spain.  During that conference,  Dr. Jaume Mora moderated a two hour session discussing proposals for common international/interdisciplinary DIPG research agenda items.    Many things seems to be evolving collaboratively in the European DIPG arena.  The action points of the 2012 Barcelona meeting are impressive (click here to see).

In looking at the SNO/PBTF Pediatric Neuro-Oncology Basic Science and Translational  Research Conference abstracts, I noticed a somewhat unusual abstract.   This abstract (to me) highlighted the internationally collaborative nature of DIPG research today.   The authors were from 4 countries- France, England, Spain and Canada (Vancouver)!

This abstract examined the whole genome sequencing of 20 pre-treatment DIPG samples (all high grade gliomas) obtained by stereotactic biopsy in France.

Although the abstract word limits don't allow for in-depth understand of the work, there were some interesting things.  First,  the K27M mutations was seen in all cases.

It would seem that there were some cases where the initial untreated specimen was compared with a post-mortem sample.   Not really unexpected, the autopsy sample has increased number of mutations.  The authors write conclude that DIPG biopsy provides an opportunity to study the genome and identify possible intervention targets.

Something more fascinating to me - and not part of the abstract - is the question of how did these researcher get together to do this research for this abstract.   I believe the children from Spain might be offered the option of going to France for biopsy.   I believe that the children in the UK were offered that in that past as well.   In addition, Chris Jones was tasked as the responsible member for the biopsy biological studies (for SIOP-E DIPG Network).   In his Barcelona 2012 presentation, Chris Jones talked about "What to Do With Tissue".  In this, he did mention transatlantic collaboration.  

The thing that I wonder about though- is British Columbia.   Sick Kids has been a powerhouse of DIPG research out of Canada.   It would seem that Vancouver might be a place to watch as well.

Reference:
The Genomic Landscape of treatment-naive DIPG Biopsy Sample
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=738496

Genetic and histopathological spectrum of paediatric diffuse intrinsic pontine gliomas

Sick Kids instituted an brainstem glioma project back in 2003 in hopes of trying to understand diffuse intrinsic pontine glioma.   To do this the researchers reached out to families with an autopsy-based protocol asking for consideration of post-mortem tissue donation.    This decade commitment and collaborative effort against DIPG has lead to another DIPG abstract for the upcoming SNO/CBTF supported 2013 Pediatric Neuro-Oncology Basic and Translational Research Conference.  This one comes from Sick Kids in conjunction with Oren Becher from Duke.

The researchers examined 71diffuse intrinsic pontine tumors:

• 65 were high grade gliomas, 8 were low grade and 3 were PNETs.
• survival was not related to grade.
• leptomeningeal spread was present in one third of cases.
• 68% had K27M-H3.
• these tumors were histologically heterogenous, however increased homogeneity  was found of the histone mutation.
• the histone mutations were also present in low grade tumors that had worse outcomes.

The authors conclude with a call for "incorporation of histological and molecular data"- specifically stating  "histone mutational status at biopsy"- in designing new therapies for DIPG.

There has been a rash of publication regarding K27M mutations recently.   Several of the other abstracts for this meeting feature this histone mutation in DIPG.   I am sure more will be coming in the future.

Reference:
Genetic and histopathological spectrum of paediatric diffuse intrinsic pontine gliomas
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=73797

Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma

http://www.sciencemag.org/content/early/2013/03/27/science.1232245