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Researchers Link TCF12 Mutations to Aggressive Form of Anaplastic Oligodendrogliomas

NEW YORK (GenomeWeb) – An exome-sequencing study has linked variants in TCF12 to a more aggressive form of the relatively rare brain cancer anaplastic oligodendrogliomas.

Researchers from the UK's Institute of Cancer Research and elsewhere performed whole-exome sequencing on 51 anaplastic oligodendrogliomas and matched germline samples. As they reported today in Nature Communications, the investigators identified known somatic mutations associated with the disease like the hallmark IDH and 1p/19q co-deletions, but also recurrent mutations in the oligodendrocyte-related transcription factor TCF12.

"Our in-depth study has set out many of the genetic defects that cause this rare, but highly aggressive form of brain cancer — including identifying a gene mutation that appears in particularly fast-growing forms," senior author Richard Houlston from the ICR in London said in a statement.

Houlston and his colleagues performed whole-genome sequencing on 51 anaplastic oligodendroglioma tumors, targeting more than 318,000 exons in 18,900 genes.

In this study, the researchers divvied the tumors up based on whether they contained IDH mutations and 1p/19q co-deletions; IDH mutations, but not 1p/19q co-deletions; or were wild-type IDH.

Using MutSigCV, they homed in on genes with more non-synonymous mutations than would be expected by chance in each of the tumor subtypes.

These included mutations not only in IDH1 and IDH2, but also in the tumor suppressors FUBP1 and CIC, located on chromosomes 1p and 19q, respectively. These mutations, the researchers noted, had been previously reported in the context of 1p/19q co-deletions.

In addition, the researchers uncovered significant mutations in TCF12, which encodes the basic helix-loop-helix transcription factor 12 and mediates transcription by forming homodimers or heterodimers with other bHLH transcription factors. Heterozygous TCF12 were found in five of the 46 IDH-mutated, 1p/19q co-deletion samples.

The Cancer Genome Atlas low-grade glioma dataset — reported on yesterday in the New England Journal of Medicine — included exome data from 43 additional oligodendrogliomas, two of which harbored a TCF12 mutation. There, too, the researchers noted the TCF12 mutations were restricted to IDH-1p/19q co-deletion tumors.

In a combined analysis, the researchers found that mutations in PI3KCA, NOTCH1, and TP53 were also overrepresented, among others.

Further, a gene ontology analysis revealed that the most significantly altered pathways were associated with the tricarboxylic acid cycle and isocitrate metabolism, which they noted is consistent with the presence of IDH mutations.

The researchers validated the presence of TCF12 mutations in a further set of 83 anaplastic oligodendrogliomas, finding it in five additional tumors.

Based on their combined set of 134 tumors, they estimated that TCF12 is mutated in 7.5 percent of anaplastic oligodendrogliomas.

The various mutations the researchers uncovered in TCF12 — like the frameshift mutations M260fs*5 and E548fs*13, the missense R602M mutation, and the premature stop codon S682fs*14 mutation, among others — affected the activity of the TCF12 protein.

The M260fs*5 and E548fs*13 mutations, for instance, abolished the bHLH domain, eliminating TCF12.

As compared to 45 wild-type tumors, tumors with TCF12 mutations were enriched for immune response pathways, based on gene expression data. When the researchers restricted their analysis to tumors with TCF12-altered bHLH domains, they noted a downregulation of known TCF12 partners like TCF21, EZH2 and BMI1, and a decreased activity of gene sets related to E-cadherin, which is a TCF12 target gene. This, they noted, suggests that the effects of TCF12 may be mediated through an E-cadherin-related pathway.

A loss of TCF12 transcriptional activity, the researchers added, was linked to a more aggressive tumor phenotype. Tumors with TCF12 mutations had a significant increase in palisading necrosis and a trend toward a higher mitotic index, and tumors with TCF12 mutations that disrupted the bHLH domain had the highest proportion of palisading necrosis and mitotic figures, they reported.

"Anaplastic oligodendrogliomas are difficult to remove by surgery and don't respond well to other forms of treatment," Houlston said. "We hope this new information might be used to discover new targeted therapies, offering patients a better chance at survival from this aggressive cancer."