Abstract 484: Molecular profiling identifies a second malignancy in a patient with medulloblastoma
Authors: Schieffer Kathleen M. , Miller Katherine E. , Boue Daniel R. , Koboldt Daniel C. , Brennan Patrick , Kelly Benjamin J. , Wheeler Gregory , Magrini Vincent , Wetzel Amy , Varga Elizabeth , Dishman Devon , Leraas Kristen , Agarwal Vibhuti , AbdelBaki Mohamed S. , Finlay Jonathan L. , Leonard Jeffrey R. , White Peter , Gastier-Foster Julie M. , Cottrell Catherine E. , Mardis Elaine R. , Wilson Richard K. 
Published: August 2019

Abstract
Medulloblastoma is a pediatric embryonal tumor that can be classified into four molecular subgroups, each derived from a different progenitor cell. It is estimated that about 30-40% of patients will relapse, typically with recurrence at the primary site and of the same molecular subgroup. We present paired tumor/normal genomic analysis of an 18 year-old male who presented with non-Wnt/non-SHH medulloblastoma at age 12 and relapsed with metastatic disease of the falx cerebri 3 years later. Combination surgery, chemotherapy, and radiation were used in treatment of the primary and recurrent tumor. At a timepoint 6 years from original diagnosis, the patient presented with a cerebellar tumor histologically described as “consistent with recurrent medulloblastoma” with comment recommending genomics to confirm. The diagnosis was made based on near identifical morphology and retention of Neu-N and Synaptophysin in the tumor (confirmed by subsequent genetic analysis). The primary tumor and the tumor occurring 6 years after the primary diagnosis were analyzed by whole exome sequencing (blood and tumor tissues) to assess for germline variants, somatic mutation, and copy number variation. We observed no pathogenic germline variants in cancer predisposition genes. The tumor mutational profiles were distinct, with only 6 (1.8%) shared somatic variants between tumors. Specimen provenance was verified by germline variation and SRY coverage. Two targetable mutations within the RAS-MAPK pathway (PTPN11 p.Glu76Lys and PIK3CA p.Gly1007Arg) were present only in the new CNS tumor. Although the primary tumor harbored isochromosome 17q and a gain of chromosome 4, these somatic chromosomal aberrations were not detected in the new CNS tumor. RNA-seq was performed on both tumors and compared to pediatric CNS tumors from the University of California Santa Cruz Treehouse Initiative (n=434). The primary tumor clustered with the medulloblastoma patients by principal component analysis while the new CNS tumor clustered with a group of gliomas and non-medulloblastoma embryonal tumors. The primary tumor displayed evidence of overexpression of Group 4 medulloblastoma genes (e.g. EOMES, RBM24, SNCAIP, and UNC5D). These genes were not overexpressed in the new CNS tumor. Enrichment of genes commonly found in gliomas (e.g. BCAN, CHI3L2, PDGFRA, and SOX2) were noted in the new CNS tumor only. In summary, tumor genomic profiling of a primary medulloblastoma and the new CNS tumor arising 6 years later revealed two distinct sets of somatic mutations suggestive of second malignancy rather than recurrence in this patient. While second malignancy in the setting of medulloblastoma is a rare event, it has been documented, both in a time period consistent with that described in our patient and in the form of glioma. Thus, tumor profiling refined diagnosis in this patient allowing for a more accurate assessment of treatment and management options.
Citation Format: Kathleen M. Schieffer, Katherine E. Miller, Daniel R. Boue, Daniel C. Koboldt, Patrick Brennan, Benjamin J. Kelly, Gregory Wheeler, Vincent Magrini, Amy Wetzel, Elizabeth Varga, Devon Dishman, Kristen Leraas, Vibhuti Agarwal, Mohamed S. AbdelBaki, Jonathan L. Finlay, Jeffrey R. Leonard, Peter White, Julie M. Gastier-Foster, Catherine E. Cottrell, Elaine R. Mardis, Richard K. Wilson. Molecular profiling identifies a second malignancy in a patient with medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 484.