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With Omics Tools, Researchers Describe Mutational Landscape of Rare Childhood Brain Cancer

NEW YORK (GenomeWeb) — Using a combination of omics techniques, a team led by Baylor College of Medicine researchers described the mutational landscape of intercranial germ cell tumors, a rare type of childhood brain cancer.

By analyzing some 60 intercranial germ cell tumor cases using next-generation sequencing along with SNP and expression array analysis, the researchers found that signaling pathways, especially the KIT/RAS pathway, are affected by mutations in IGCTs, findings they reported in the online advanced edition of Nature today. Many of the mutations uncovered further suggested possible treatment routes.

"This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway," the researchers led by Baylor's Ching Lau wrote.

IGCTs are rare, though they are more common in Japan and other East Asian countries. The tumors typically affect the pineal region of the brain, arise around puberty, and are more common in boys than in girls. They can also be split into pure germinoma and non-germinomatous germ cell tumors.

By sequencing the whole exomes of 28 cases to a mean 139x coverage on the Illumina HiSeq 2000 platform, Lau and his colleagues uncovered an average six non-silent mutations per sample. To validate their findings, the researchers performed targeted deep sequencing using a custom AmpliSeq array to about 1,000x coverage on 34 additional IGCT cases.

More than half of the tumors, they found, had mutations in at least one gene involved in the KIT/RAS or AKT/mTOR pathways.

KIT, they noted, was mutated in 16 IGCT tumors, though not in any NGGCT tumors. When those mutations were present, they clustered mostly in exon 17 and exon 11. Additionally, the researchers reported that KIT was overexpressed in the majority of pure germinomas and infrequently in NGCCTs.

KRAS or NRAS mutations, meanwhile, appeared in some 19 percent of IGCT cases, but were not present alongside KIT mutations. And mutations in CBL, a gene encoding a RING finger ubiquitin E3 ligase, were also common in IGCT cases.

The researchers further reported focal amplifications of 14q32.33 in five tumors in the discovery set. Only one oncogene — AKT1 — is located within that 2 megabase region.

Using qPCR, the researchers confirmed an increase in AKT1 copy number in those five cases and in seven additional cases from the validation set. Those copy-number gains were linked to increased mRNA expression of AKT1 but not of other genes in the region.

Other recurrent mutations appeared in BCORL1, MTOR, TP53, SPTA1, KDM2A, and LAMA4, they reported.

As this tumor is so rare, Lau and his colleagues also sought to uncover germline mutations that may predispose someone to developing IGCT, and compared germline sequence data for genes enriched in novel functional variants from patients in the IGCT discovery cohort and to controls.

Of the top genes enriched in functional germline variants, just JMJD1C is a chromatin modifier gene and is thought to have a role in both mouse and human germinal tissue development.

In the combined cohort of 62 IGCT cases, 10 patients harbored a rare germline variant in JMJD1C, and three of those patients, though unrelated, had a rare dinucleotide polymorphism. Nine of those 10 patients were from Japan, and one was from Hong Kong, the researchers noted.

Additionally, they calculated an odds ratio of 4.8 between mutations in JMJD1C and the risk of developing IGCT.

JMJD1C, Lau and his colleagues added, interacts with the thyroid hormone receptor and likely also with the androgen receptor in humans. Expression array analysis revealed high JMJD1C and AR expression in the 37 cases the researchers tested.

"It is intriguing that both histone-modifying genes discovered in this study are implicated in the interaction with nuclear receptor proteins," the researchers said. "It suggests the possibility that JMJD1C and BCORL1 might be associated with the male preponderance and age of peak incidence of IGCTs through interaction with AR triggered by elevated levels of androgen hormones at puberty."

The mutations in these tumors also suggested possible IGCT treatment avenues, notably by inhibiting the KIT/RAS and AKT/mTOR signaling pathways.

For instance, the researchers noted that there currently are eight approved tyrosine kinase inhibitors that target KIT and that the MEK inhibitor selumetinib has been effective against KRAS-mutated non-small-cell lung cancer cells and may also work in IGCT cases.