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Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations

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Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations Published OnlineFirst July 13, 2018; DOI: 10.1158/1541-7786.MCR-17-0507 Genomics Molecular Cancer Research Desmoplastic Infantile Ganglioglioma/ Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations Anthony C. Wang1, David T.W. Jones2, Isaac Joshua Abecassis3, Bonnie L. Cole4, Sarah E.S. Leary5, Christina M. Lockwood6, Lukas Chavez2, David Capper7, Andrey Korshunov7, Aria Fallah1, Shelly Wang8, Chibawanye Ene3, James M. Olson5, J. Russell Geyer5, Eric C. Holland3, Amy Lee3, Richard G. Ellenbogen3, and Jeffrey G. Ojemann3 Abstract Desmoplastic infantile ganglioglioma (DIG) and desmo- transformation were found, and sequencing of the recurrence plastic infantile astrocytoma (DIA) are extremely rare tumors demonstrated a new TP53 mutation in one case, new ATRX that typically arise in infancy; however, these entities have not deletion in one case, and in the third case, the original tumor been well characterized in terms of genetic alterations or harbored an EML4–ALK fusion, also present at recurrence. clinical outcomes. Here, through a multi-institutional collab- DIG/DIA are distinct pathologic entities that frequently harbor V600 oration, the largest cohort of DIG/DIA to date is examined BRAF mutations. Complete surgical resection is the ideal using advanced laboratory and data processing techniques. treatment, and overall prognosis is excellent. While, the small Targeted DNA exome sequencing and DNA methylation sample size and incomplete surgical records limit a definitive profiling were performed on tumor specimens obtained from conclusion about the risk of tumor recurrence, the risk appears different patients (n ¼ 8) diagnosed histologically as DIG/ quite low. In rare cases with wild-type BRAF, malignant DIGA. Two of these cases clustered with other tumor entities, progression can be observed, frequently with the acquisition and were excluded from analysis. The remaining 16 cases were of other genetic alterations. confirmed to be DIG/DIA by histology and by DNA methyl- ation profiling. Somatic BRAF gene mutations were discovered Implications: DIG/DIA are a distinct molecular entity, with a V600E in 7 instances (43.8%); 4 were BRAF mutations, and 3 subset frequently harboring either BRAFV600E or BRAFV600D V600D were BRAF mutations. Three instances of malignant mutations. Mol Cancer Res; 1–8. Ó2018 AACR. Introduction (DIG) together as one diagnosis, among grade I "neuronal and mixed neuronal-glial" entities (1). In 1978, Friede reported a The World Health Organization's classification of central ner- desmoplastic glial tumor of the medulla with leptomeningeal vous system (CNS) neoplasms categorizes desmoplastic infantile metastases, proposing the terms "gliofibroma" or "desmoplastic astrocytoma (DIA) and desmoplastic infantile ganglioglioma glioma" (2). DIA was introduced by Taratuto, describing 6 infants with "superficial cerebral astrocytoma attached to dura" (3). 1Department of Neurosurgery, University of California Los Angeles, Los Angeles, Vandenberg reported 11 infants with DIG in 1987, noting mixed California. 2Division of Pediatric Neurooncology, German Cancer Research glial and neuronal histology (4). The typically large size, nodular Center (DKFZ), Heidelberg University, Heidelberg, Germany. 3Department of contrast enhancement pattern, cellular pleomorphism and atypia, Neurological Surgery, University of Washington and Seattle Children's Hospital, frequent mitoses, and undifferentiated small-cell component, all 4 Seattle, Washington Department of Anatomic Pathology, University of conjure the visage of an aggressive malignancy. Yet, complete 5 Washington and Seattle Children's Hospital, Seattle, Washington. Department resection is expected to yield an excellent prognosis (5). DIG/DIA of Pediatrics, Division of Hematology/Oncology, University of Washington and Seattle Children's Hospital, Seattle, Washington. 6Department of Laboratory most frequently occur in patients under 24 months of age, and fi Medicine, University of Washington and Seattle Children's Hospital, Seattle, accounts for a signi cant proportion of intracranial neoplasms Washington. 7Department of Neuropathology, German Cancer Research Center seen in the first year of life (6, 7). Mitotic figures, primitive- (DKFZ), Heidelberg University, Heidelberg, Germany. 8Division of Neurosurgery, appearing cells, and cellular pleomorphism are common histo- Hospital for Sick Children and Toronto Western Hospital, Toronto, Ontario, logic features of DIGs and DIAs. Yet, such high-grade character- Canada. istics have repeatedly failed to correlate with worse clinical out- Note: Supplementary data for this article are available at Molecular Cancer comes in DIGs and DIAs, regardless of location (8, 9). Research Online (http://mcr.aacrjournals.org/). DIG/DIAs commonly present in the periphery of the supra- Corresponding Author: Jeffrey G. Ojemann, Department of Neurological tentorial compartment, consisting of a large cystic component Surgery, Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA with a contrast-enhancing solid nodule attached to the overlying 98115. Phone: 206-987-4240; Fax: 206-987-3925; E-mail: dura. Even without a significant cystic portion at presentation, [email protected] this can develop over time (Fig. 1A; ref. 10). Rarely, DIG/DIA doi: 10.1158/1541-7786.MCR-17-0507 presents as an intraventricular lesion (Fig. 1B), or a mostly solid Ó2018 American Association for Cancer Research. sellar/hypothalamic mass (Fig. 1C). Histologically, desmoplasia www.aacrjournals.org OF1 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst July 13, 2018; DOI: 10.1158/1541-7786.MCR-17-0507 Wang et al. Figure 1. A, Solid dura-based DIG. B, Multicystic intraventricular DIG. C, Suprasellar DIA with leptomeningeal metastases. D, Suprasellar and cisternal DIA is prominent within dense stroma, with fibroblastic and desmoplastic and involve the leptomeninges, are often cystic, and neuroepithelial elements. Neoplastic cells are limited to the solid have a generally benign prognosis. PXA tends to present at an nodule and adjacent leptomeninges (5, 10–13). Neuroepithelial older age, and the pleomorphic, xanthomatous appearance of its elements vary in proportions of astrocytic and neuronal cells, astrocytes differentiate the two tumor types. Vandenberg notes a and as the names suggest, presence of neuronal differentiation basal lamina seen in DIG/DIA that is also typical of PXA (9). distinguishes DIG from DIA. DIGs, but not DIAs, commonly Little in the way of genetic and molecular characterization of involve rests of primitive ganglion cells suggesting anaplasia, giving DIG/DIA has been published, and no clonal chromosomal abnor- them an appearance such that the term "desmoplastic neuroblas- malities have been found in DIA or DIG (22, 30–33). While toma" was previously used to described this entity (14). Presence of various nonclonal aberrations have been reported, no specific primitive neuronal components does not seem to imply more locus has consistently appeared. Gessi and colleagues, performed aggressive biology in DIG/DIA (9, 15–17). Craniospinal seeding a genome-wide DNA copy number analysis in combination with a or metastasis (Fig. 1D) has been reported (15–19), as have few multiplex analysis of candidate genes in 4 DIAs and 10 DIGs, instances of malignant transformation (20–22). observing inconsistent focal recurrent genomic losses in chromo- A common origin of DIG/DIA has been suggested, as has a some regions 5q13.3, 21q22.11, and 10q21.3 in both DIA and relationship with PXA and GG (23–28). The argument for diver- DIG (34). Principal component analysis did not show any sig- gence along a common ancestral lineage accounting for the nificant differences; however, in 6 of these cases, gain of genomic similarities and differences between these tumor types has been material at 7q31, which corresponds to the MET gene, was found. made entirely on histopathologic findings thus far (29). PXA A total of 7 cases of BRAFV600E mutations have been found shares many features with DIA in particular—both are frequently previously in DIG/DIA (34–38). Hypermethylated alleles in the OF2 Mol Cancer Res; 2018 Molecular Cancer Research Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst July 13, 2018; DOI: 10.1158/1541-7786.MCR-17-0507 Genomics of DIG/DIA Reveal Distinct Features ARF P14 gene were seen in one case (32). Lonnrot and colleagues, previously (43, 44). Analysis of tumor subgroups was performed identified MYCN amplifications in 2 cases and EGFR amplifica- using a t-SNE-based approach taking the 5,000 most variably tions in 3 cases (39). Several negative TP53 analyses in patients methylated probes (45). with DIG/DIA have been performed (7, 31, 32, 39, 40), with 1 case report of a TP53 SNV found in both a primary DIG and in its Results and Discussion subsequent malignant transformation (22). Individual molecular and genetic characterization of pediatric With this study, we aimed to more precisely understand the tumors may yield unexpected avenues for treatment genetic underpinnings of DIG and DIA among glial–neuronal Ten primary tumor samples from SCH were examined using CNS tumors. targeted DNA exome sequencing. In 5 tumors (50%), we found no genetic aberrations involving the 262 genes included Materials and Methods in UW-OncoPlex. Within the other five tumors, we discovered SCH cohort 2(20%)BRAFV600E
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