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Study Finds Distinct Genes Driving Two Benign Brain Tumor Subtypes

NEW YORK (GenomeWeb News) – In a study published online yesterday in Nature Genetics, researchers at Harvard University, the Broad Institute, the Dana-Farber Cancer Center, and other centers in Massachusetts reported on findings from an effort to track down mutations driving the development of brain tumors known as craniopharyngiomas.

Starting with exome sequencing on samples from a dozen individuals with the so-called adamantinomatous craniopharyngioma and three individuals with the papillary craniopharyngioma, the team tracked down predominant — and mutually exclusive — mutations in each of the two subtypes.

In particular, the adamantinomatous subtype was marked by mutations to the beta-catenin gene CTNNB1, while almost all of the papillary tumors in the discovery exomes and follow-up samples assessed by genotyping had mutations in the BRAF gene.

"[O]ur discovery of frequent and clonal mutations in adamantinomatous and papillary craniopharyngioma in CTNNB1 and BRAF, respectively, offers valuable opportunities for testing molecularly guided therapeutics for the treatment of these formidable brain tumors," co-senior authors Mark Kieran, Gad Getz, and Sandro Santagata, based at Harvard and other centers, and their colleagues wrote.

Both adamantinomatous and papillary craniopharyngiomas are benign tumors that typically affect epithelial tissue in a part of the brain known as the suprasellar region near the pituitary gland and optic nerves, the researchers noted. Though non-cancerous, the tumors can expand into to the hypothalamus and vision-related systems at the brain's base, causing a wide range of visual, hormonal, and other complications.

Generally speaking, papillary tumors are more common in adults, while tumors from the adamantinomatous subtype tend to occur in children. Past studies have pointed to mutations in the third exon of the beta-catenin gene CTNNB1 as a contributor to the latter form of the disease. But less is known about the molecular drivers behind papillary craniopharyngioma.

In the hopes of identifying driver mutations — and potential treatment targets — in each form of the disease, authors of the new study used Agilent SureSelect kits to nab protein-coding sequences from tumor and normal samples from 12 individuals with adamantinomatous craniopharyngiomas and three individuals with papillary tumors. They then sequenced these exomes on Illumina's HiSeq 2500.

Because they were dealing with benign tumor cells that were intermingling with nearby normal cells, the researchers reasoned that driver mutations might be few and far between. That prompted them to analyze their exome sequencing data using a classifier method called MuTect, which turned up BRAF alterations in all three papillary tumors and mutations to exon 3 of CNTNNB1 in all but one of the adamantinomatous tumors.

Although non-synonymous somatic mutations are relatively rare in craniopharyngioma tumors compared to the rates of such mutations in tumors from adults with cancer, the group did uncover instances of craniopharyngioma tumors carrying mutations to genes implicated in cancer.

In the adamantinomatous craniopharyngioma tumors, for example, the group saw glitches in genes from DNA repair pathways and pathways regulating transcriptional or epigenetic process. That tumor type was also prone to changes in non-cancer-associated genes from cell cycle, DNA repair, cell adhesion, and chromatin related pathways.

While some of these potential passenger mutations appeared in only a subset of tumor cells, both the CNTBB1 and BRAF mutations were clonal, turning up consistently across cells from the adamantinomatous or papillary tumors, respectively.

Those two drivers did not overlap, researchers reported. Rather, the CNTBB1 alterations were found only in the adamantinomatous tumors, while the papillary tumors alone harbored the activating mutation to BRAF.

"Our whole-exome sequencing data of craniopharyngiomas demonstrates that the adamantinomatous and papillary sub-types have distinct molecular underpinnings, each driven principally by mutations in a single well-established oncogene: CTNNB1 in the adamantinomatous form and BRAF in the papillary form, independent of age," the study's authors wrote.

The group confirmed those findings with the help of targeted genotyping in samples from 59 more individuals with adamantinomatous craniopharyngioma and 36 papillary craniopharyngioma patients.

The mutually exclusive CTNNB1 and BRAF mutations in adamantinomatous and papillary tumors may help to distinguish the two craniopharyngioma subtypes at the time of an individual's diagnosis, the researchers noted.

The genetic findings could conceivably prove useful on the treatment front, too. In particular, because BRAF inhibitors are already being developed to treat cancer types stemming from aberrant WNT signaling, those involved in the study noted that individuals with papillary craniopharyngioma might one day benefit from similar treatments.

"From a clinical perspective, identifying the BRAF mutation in the papillary tumors is really wonderful, because we have drugs that get into the brain and inhibit this pathway," Santagata said in a statement. "Previously, there were no medical treatments — only surgery and radiation — and now we may be able to go from this discovery right to a well-established drug therapy."