Translational Study Identifies BRAF V600E Mutation And CDKN2A Deletion As Markers For Malignant Transformation In Low-Grade Paediatric Gliomas

  • Date: 01 Apr 2015

BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGGG 

The Journal of Clinical Oncology published a study on 20 March 2015, about the genetic transformations that lead a paediatric low-grade glioma (PLGG) to transform into a malignant secondary high-grade glioma (sHGG). Malignant transformation is rare in children.

Past studies have uncovered clinical and molecular transformations in adult gliomas, but little was known about genetic determinants of PLGG transformation in children. Canadian researchers performed a population-based, long-term, retrospective outcome study of 866 patients with PLGG in Southern Ontario, tracking patients for over 30 years. They analysed genomic and genetic alterations that transformed to sHGG and correlated these findings with multiple parameters, including outcomes. This study enabled them to define a subgroup of sHGG patients for which early diagnosis and intervention could improve outcome. It also allowed them to determine both genetic and molecular differences between childhood and adult gliomas.

Malignant transformation was observed in 26 out of the 866 patients (2.9%). Patients with sHGG presented a high frequency of nonsilent somatic mutations. Chromatin-modifying genes and telomere-maintenance pathways showed alterations. The most recurrent alterations were BRAF V600E mutation and CDKN2A deletion in 39% and 57% of sHGGs, respectively. All BRAF V600E alterations and 80% of CDKN2A modifications could be traced back to their PLGG counterparts. Both BRAF V600E and CDKN2A alterations were early events in PLGG undergoing transformation.

The median age at PLGG diagnosis was 7.0 years (range from 0.39 to 15.6 years). The median age at sHGG diagnosis was 12.5 years (range 0.57 to 33.7 years).

Common alterations found in adult LGGs such as ATRX, IDH1 and ALT were rare in this study’s cohort, whereas BRAF V600E, H3.3 and hTERT promoter mutations (which are uncommon in adult sHGG) were more frequent.

Another clinically important parameter for risk assessment highlighted by researchers was the complete lack of the BRAF-KIAA1549 gene fusion observed in sHGG.

Potential pitfalls of studies investigating PLGG transforming into sHGG involve instances where tumours are diagnosed as PLGGs following the biopsy, but behave as HGGs. This may involve two scenarios: the biopsy may have missed malignant regions in the tumour, or tumours with low-grade histology behave as high grade. In both these scenarios, the addition of the molecular markers described in this study may help to establish or refute the PLGG diagnosis.

Researchers concluded that BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The long time lapse it takes for PLGGs to become malignant provides an opportunity for surgical interventions, surveillance and targeted therapies to mitigate the outcome of sHGG.

Further studies are needed to validate these results in a larger cohort of patients.

Rare cancers perspective:

Translational research in tumour tissues collected during a period of over three decades reveals molecular findings that are important for understanding some of the mechanisms in malignant transformation of low-grade paediatric glioma. For some of these alterations there already are techniques to determine them at molecular level in routine use, but only for adult populations, as well as targeted treatments approved again for use in adult patients but with different cancer types. Although these findings should be further validated, the rarity of these tumours and specificities around drug testing in paediatric population underline the importance of regulatory action, so that medical advances reach the clinic and benefit patients with rare cancers. However, tumour heterogeneity may further complicate strategies to address rare molecular events in rare cancers, making further molecular analyses the only way to understand other biological mechanisms and processes of malignant transformation. 

 

Notes
Study supported by b.r.a.i.n.child Canada, the JPA Foundation, and the Canadian Institute of Health Research Grant No. MOP-123268. Research was also supported by The Hospital for Sick Children RESTRACOMP fund and Alex's Lemonade Stand Foundation; the Society of Neuro-Oncology (International Research Development Fellowship Program); the National Institutes of Health Grant No. P01CA142536 and the Pediatric Low-Grade Astrocytoma Foundation.

Reference:
BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma.  Mistry M, et al. J Clin Oncol. 2015 Mar 20;33(9):1015-22. doi: 10.1200/JCO.2014.58.3922. Epub 2015 Feb 9.

The study abstract can be found here: http://www.ncbi.nlm.nih.gov/pubmed/25667294

The full study can be found here (requires subscription)
http://jco.ascopubs.org/content/33/9/1015.full