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Abstract Details

Germline Fumarate Hydratase Mutations May be Associated with High-grade Gliomas and Mimic the Methylation Profile of IDH-mutant Gliomas
Neuro-oncology
P4 - Poster Session 4 (11:45 AM-12:45 PM)
5-002

FH enzyme is responsible for converting fumarate to malate in the Krebs cycle. Autosomal dominant FH mutations, which result in the accumulation of the oncometabolite fumarate, have been implicated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Gliomas are not  considered part of the HLRCC syndrome.

We report two cases of germline fumarate hydratase (FH) mutation associated with wild-type isocitrate dehydrogenase (IDH-WT) gliomas, as well as the frequency of FH mutations in gliomas. 
The medical records of two patients with FH mutations and gliomas were retrospectively reviewed. Foundation Medicine genetic testing database was subsequently queried to identify glioma patients with mutated FH gene and associated genomic profile.

 Patient A is a 24-year-old woman with history of resected FH-deficient uterine leiomyoma and a subsequent diagnosis of cerebellar high-grade glioma with IDH-WT and methylated MGMT.  Subsequent germline testing revealed gene mutations in FH (R233C) and p53 (T125M).

Patient B is a 55-year-old woman with resected stage 1B cutaneous melanoma and pathogenic germline FH-mutation (p.Lys477dup), who subsequently developed a right frontal glioblastoma, (IDH-WT, methylated MGMT).

Compared to patient B, patient A’s high-grade astrocytoma had an earlier age of onset and demonstrated a significant element of pseudoprogression. Patient A’s DNA methylation profiling classified the tumor as a high-grade IDH-mutant astrocytoma, even though no IDH mutation was detected by sequencing from two separate reference laboratories. Analysis of FH mutations in gliomas from Foundation Medicine testing database will be reported.

We report a novel association of high grade gliomas in patients with HLRCC. Germline FH mutations may cause the accumulation of the oncometabolite fumarate and promote glioma oncogenesis, a phenomenon similar to the buildup of 2-hydroxyglutarate as a result of somatic IDH mutations.  Moreover, FH mutation appears to produce methylation changes which mimic IDH-mutant tumors.  
Authors/Disclosures
Sasmit Sarangi, MD, MBBS (Rhode Island Hospital/Brown University)
PRESENTER
The institution of Dr. Sarangi has received research support from Fore biotherapeutics.
Hetal Mistry, MD (Rhode Island Hospital) An immediate family member of Dr. Mistry has received personal compensation for serving as an employee of Regeneron.
Eric T. Wong, MD, FAAN (Rhode Island Hospital) Dr. Wong has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novocure. Dr. Wong has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ZaiLab. Dr. Wong has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Turning Point Therapeutics. The institution of Dr. Wong has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novocure. The institution of Dr. Wong has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Turning Point Therapeutics. The institution of Dr. Wong has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cancer Commons. The institution of Dr. Wong has received research support from Novocure. Dr. Wong has received intellectual property interests from a discovery or technology relating to health care. Dr. Wong has received publishing royalties from a publication relating to health care.