Molecular diagnostics of CNS embryonal tumors

Abstract

Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear β-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered “ependymoblastic” rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.

Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells

“…12 In contrast, what is called a primitive neuroectodermal tumor (PNET) is a pediatric supra-tentorial neural crest tumor. With the use of high dose multi-modal chemotherapy and radio-therapy response rates of 60-80% have been observed in children for both tumor types, although this also results in significant long-term negative sequelae for the affected child.…”

“…The chemically different HDAC inhibitors chosen for the present studies, sodium valproate and vorinostat, can both penetrate the blood brain barrier. 12,13 Sorafenib can also cross the blood brain barrier. 14 Glioblastoma is a malignancy with a highly invasive phenotype, however, established commercially available GBM cell lines do not generally exhibit the diffuse invasive nature of the disease in a patient.…”

The Role of HGF/c-Met Pathway Signaling in Human Medulloblastoma

“…The genetic heterogeneity of medulloblastoma appears to be the basis for differential response to treatment, which leads to the conclusion that current tumor classification systems based solely on histological or clinical criteria are clearly insufficient and limited. Recent studies have identified distinct molecular variants of medulloblastoma that correspond with different clinical presentations, transcriptional profiles, genetic abnormalities and clinical outcomes (Eberhart, 2011;Ellison et al, 2011;Northcott et al, 2010;Pfister et al, 2010). Thus, a better understanding of the molecular biology of this tumor will have significant diagnostic, prognostic and therapeutic value.…”

Molecular diagnostics of brain tumors

“…Combined assessment of these markers allows for a greatly improved risk stratification of medulloblastoma patients that will likely be implemented into upcoming clinical trials. Moreover, characteristic molecular alterations have been identified for certain less common embryonal tumor entities, including mutation and loss of expression of SMARCB1 (INI1/ hSNF5) in atypical teratoid/rhabdoid tumors as well as focal amplification of a micro-RNA cluster at chromosome 19q13.42 in ependymoblastoma/embryonal tumor with abundant neuropil and true rosettes, respectively [2].…”

“…The review articles clustered in this edition of Acta Neuropathologica are meant to give an update on the state of the art of molecular diagnostics for the two main categories of CNS tumors in which recent developments in this respect are most striking, that is the gliomas [1] and the embryonal CNS tumors [2]. Brain tumor diagnostics and therapy nowadays is a multidisciplinary task that requires close collaboration of colleagues from neurosurgery, radiation oncology, pediatric and medical oncology, neuroradiology, neuropathology and others.…”