Glioma Longitudinal AnalySiS in the Netherlands (GLASS-NL): Molecular and imaging markers for malignant evolution of IDH-mutant astrocytoma.

Each year, over 1000 new patients in the Netherlands are diagnosed with a
glioma. The vast majority of these are so-called diffuse gliomas. Primary brain
tumors account for approximately 3% of human cancers. The tumors are
characterized by diffuse infiltrative growth in the brain parenchyma. Diffuse
gliomas are amongst the most frequent and devastating brain tumors. Up till
now, curation of these tumors is impossible, and standard treatment (surgery,
irradiation and/or chemotherapy with generally a single cytotoxic agent) has
generally limited efficacy. Without exception these neoplasms thus represent a
fatal disease with high disease burden. Overall survival (OS) of patients with
the most malignant form of glioma, i.e. glioblastoma, is generally less than
1-1.5 years after diagnosis. Patients with a lower grade diffuse glioma have a
variably longer survival, but due to the fact that these tumors are generally
diagnosed in younger patients the average number of years of life lost in these
patients is even higher than for patients with glioblastoma. Especially for the
initially often less aggressive, IDH-mutant astrocytoma the disease course is
notoriously unpredictable. In other words, it is unclear which of these tumors
will rapidly progress to high grade malignancy and which patients thus need
more intense treatment right away. Gliomas that recur after a first round of
treatment are increasingly therapy resistant.
To improve the prognosis of patients with diffuse glioma we need a better
onderstanding of tumor evalutiona and appropriate timing of treatment. In
addition, we need new molecular markers of glioma that may lead to developement
of better treatments for this patient group. In only a limited group of
patients, a second surgical treatment can be considered. Thusfar it is clear
that the progressive tumors do not always mirror the primary tumor molecularly.
In addition, changes in molecular make-up of the tumor may result in different
tumor responses to the treatment.
As patients that have underwent two operations to treat their tumors are
scarce, large-scale collaborations are needed to help us understand the impact
of treatment on evolutionary dynamics and thereby develop novel treatments to
prevent and overcome resistance to treatment. GLASS-NL is part of the
international GLASS consortium, that aims to perform comprehensive molecular
profiling of matched primary and recurrent glioma specimens from 1,500
patients, 500 in each of the three major glioma molecular subtypes.
GLASS-NL, the first nationwide glioma consortium in the Netherlands, is driven
by the extremely urgent clinical need to improve the outcome for patients
suffering from a diffuse glioma. While cure of these tumors is currently
impossible, there is a lot to gain by improved timing of standard treatment and
by finding leads for new therapeutic strategies. Hopefully, these efforts will
ultimately contribute to transform diffuse gliomas into a 'chronic disease'
with not only improved survival but also increased quality of life.

Primary Objective:

The present study aims to generate detailed molecular characterization of
paired tumor samples (i.e. obtained at first operation and at the time of tumor
recurrence) of patients with glioma, with specific interest for at least 100
well-annotated patients with IDH-mutant (1p/19q non-codeleted) astrocytomas.

Molecular data will be correlated to clinical and imaging data of these
patients to identify molecular and/or imaging markers indicative for early
malignant progression.

Secondary Objective(s):
To identify molecular alterations in the recurrent tumors that occur under
pressure of different therapeutic modalities.
To identify new targets for further therapeutic interference.

GLASS-NL (Glioma Longitudinal AnalySiS in the Netherlands) is an unprecedented
collaboration of all major centers in the Netherlands treating patients with
glioma. This consortium will be using the national translation research
infrastructure as available and being extended by Health-RI, to collect, manage
and share a critically important reference data set of patients that underwent
surgery for a glioma at least twice (interval between operations is at least 6
months). At least 100 patients with IDH-mutant lower grade astrocytoma at first
diagnosis will be collected as specific group of interest of the GLASS-NL
consortium (see KWF proposal). Also patients with glioma that have not the
IDH-mutant non-1p19q co-deleted genotype and that fulfill the general inclusion
criteria of the GLASS International consortium will be collected. MR imaging
results obtained in the course of the disease process will be critically
reviewed in search for parameters that can be used as early indicators of
malignant progression. Furthermore, the paired samples of these patients will
be analyzed using whole exome sequencing, RNA sequencing and methylation
profiling. Integrated data analysis will be performed in order to approach the
full scope of molecular alterations in the course of time, and in relation to
clinical, imaging and pathological characteristics.

Patients won*t benefit personally of being enrolled in this study. There are no
significant risks for patients included in this study. The burden for patients
consists of withdrawing 20 ml of blood that is preferably taken during routine
laboratory investigation during routine follow-up. There are no direct risks
for participating subjects because of the observational nature of the study.