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Brain Tumor Molecular Features Characterized in Individuals With Tumor Predisposition Condition

NEW YORK (GenomeWeb) – An international team led by investigators at Columbia University has documented genetic and epigenetic features found in the glioma tumors that form in individuals with the tumor predisposition syndrome neurofibromatosis 1 (NF1), which stems from germline alterations affecting the tumor suppressor gene NF1.

"The NF1 tumor-predisposing syndrome is associated with a heterogeneous pattern of glioma in children and adults," co-senior authors Antonio Iavarone and Anna Lasorella, cancer genetics researchers at Columbia, and their colleagues explained. "Therefore, the dissection of the molecular landscape of glioma in NF1 patients required a comprehensive molecular study of brain tumors that could not be limited to a particular age and/or glioma grade."

For their analyses, the researchers did exome sequencing on matched tumor and normal peripheral blood samples from dozens of NF1 patients with glioma. Together with RNA sequence data and array-based methylation profiles, the exomes suggested that the mutational landscape of gliomas in individuals with NF1 often resembled those found in tumors that form spontaneously, for example, although the somatic mutations varied somewhat depending on an individual's age and tumor grade.

The team's findings, appearing online yesterday in Nature Medicine, highlighted molecular features that distinguished low-grade gliomas that tend to occur in children from the high-grade gliomas that are more common in adults with NF1, for example.

"Although the predisposition to develop central nervous system tumors in patients with NF1 is well recognized," the authors wrote, "the molecular features of gliomas occurring in patients with NF1 have remained obscure, preventing development and application of novel therapeutic approaches."

With that in mind, the researchers used Illumina HiSeq instruments to sequence protein-coding portions of the genome isolated with Agilent SureSelect kits in 59 frozen glioma tumor and matched blood samples from 56 NF1 patients treated in France, Italy, the US, and elsewhere, including 22 children, 33 adults, and one individual for whom age information was not available.

Along with germline and somatic variants and copy number changes identified in the patients, the team used RNA sequencing and Infinium Methylation BeadChip methylation array analyses to profile gene expression in 29 of the cases and methylation patterns in 31 tumors, respectively.

On the germline mutation side, for example, the researchers uncovered new or known inactivating NF1 mutations in 51 of the patients. In the tumors, meanwhile, they found that the high-grade tumors frequently contained TP53 and CDKN2 alterations, ATRX loss-of-mutations, and mutations affecting the genes in regulatory or PI3 kinase pathway.

In the low-grade tumors, on the other hand, their analysis unearthed fewer somatic mutations, particularly in tumors from children. Those mutations were largely centered on the MAP kinase pathway, and the available gene expression analyses indicated that low-grade tumors were marked by T lymphocyte infiltration, neoantigen formation, and immune activity.

"Taken together, our findings suggest that the long indolent course of low-grade NF1-gliomas that rarely progress to high-grade disease may be preserved by the checks imposed by the adaptive immunity acquired by some low-grade tumors," the authors noted.

Unlike sporadic glioma cases, the team did not detect IDH1 gene or TERT promoter mutations or alterations affecting specific histone genes, although some of the NF1 cases did involve glioma tumors with TERT copy number gains. And, in general, the genetic and epigenetic profiles suggested that gliomas forming in individuals with NF1 shared features with a specific subgroup identified with Cancer Genome Atlas data from sporadic glioma cases.

The authors noted that "a comprehensive analysis of the complete spectrum of glioma grades throughout the lifespan of NF1 patients has allowed us to follow NF1 gliomagenesis and identify the genetic modules and the expression signatures that distinguish low- from high-grade tumors."