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Case Report and Novel Findings of DNA Sequencing

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Case Report and Novel Findings of DNA Sequencing 683 Molecular Insights in Patient Care Metachronous Medulloblastoma in a Child With Successfully Treated Neuroblastoma: Case Report and Novel Findings of DNA Sequencing Agda Karina Eterovic, PhDa; Ossama M. Maher, MDb; Joya Chandra, PhDc; Ken Chen, PhDd; Jason Huse, MD, PhDe; and Wafik Zaky, MDc Abstract Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month- old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequenc- ing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor sup- pression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail. J Natl Compr Canc Netw 2018;16(6):683–691 doi: 10.6004/jnccn.2018.7009 Embryonal neoplasms of the central nervous system cers have mostly occurred many years after long-term (CNS) represent nearly one-third of brain tumors in surveillance.5–7 This report presents a case of medullo- children aged <3 years.1,2 Medulloblastoma with its dif- blastoma in a child 5 months after successful treatment ferent histologic variants belongs to this group, repre- of stage IV neuroblastoma, and discusses the findings in senting up to 20% of pediatric CNS tumors. Cerebellar the DNA sequencing results of both the resected poste- neuroblastoma is an extremely uncommon entity of this rior fossa tumor and the germline mutations. group with few published reports on primary cerebellar neuroblastoma.3,4 A number of second neoplasms have been reported in patients with neuroblastoma, including Methods CNS tumors (gliomas and meningioma), but no prior Approval was obtained from The University of Texas reports of medulloblastoma. These second primary can- MD Anderson Cancer Center Institutional Review aInstitute for Personalized Cancer Therapy, The University of Texas MD The authors have disclosed that they have no financial interests, Anderson Cancer Center, Houston, Texas; bNicklaus Children’s Hospital, arrangements, affiliations, or commercial interests with the manufacturers Pediatric Hematology and Oncology, Miami, Florida; and the Departments of any products discussed in this article or their competitors. c d e of Pediatrics, Bioinformatics and Computational Biology, and Pathology, Correspondence: Wafik Zaky, MD, Department of Pediatrics, The University The University of Texas MD Anderson Cancer Center, Houston, Texas. of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 87, Submitted May 27, 2017; accepted for publication January 24, 2018. Houston, TX 77030. Email: [email protected] © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 16 Number 6 | June 2018 684 Molecular Insights in Patient Care Eterovic et al Board for this study (Clearing House protocol by Dr. Case Description Funda Meric-Bernstam), and informed consent was A 10-month-old girl presented with 2-month history obtained. Separate consent for the molecular studies of proptosis and progressive periorbital ecchymosis. and analysis was also obtained. Pathologic diagno- She was born full-term via vaginal delivery and has an insignificant past medical history, and her family sis and review of the suprarenal and posterior fossa history was negative for cancer. A CT scan revealed masses was performed by members of the Division of a right retro-orbital mass measuring 2.7 x 1.2 x 1.8 Pathology and Laboratory Medicine. Immunohisto- cm. A CT of the abdomen showed a calcified right chemical studies that are pertinent to neuroblastoma adrenal mass measuring 6.5 x 5.5 x 5.5 cm with liver and medulloblastoma tumors were used, including metastasis. Evaluation studies for staging including CD57 and neurofilaments. metaiodobenzylguanidine (MIBG) revealed disease at the anterior mediastinum, liver, bone marrow, DNA Sequencing and Analysis skull, and third lumber vertebra. Brain MRI revealed Genomic DNA was quantified by PicoGreen (Invit- disease in the right orbital fossa extending to the rogen, Ltd.) and quality was assessed using Genomic middle cranial fossa, with no intracranial or cer- DNA ScreenTape for the 2200 TapeStation (Agi- ebellar disease. The patient underwent fine-needle lent Technologies). Library preparation, targeted aspiration biopsy of the orbital mass, and neuroblas- capture, and data analysis were completed as previ- toma was diagnosed. A urine catecholamine test was ously described.8 For data analysis, the T200 target- performed initially and reported to be unremarkable; capture deep-sequencing data was aligned to human however, upon patient transfer to a tertiary facility reference assembly hg19 using the Burrows-Wheeler with a pediatric oncology floor, this test was repeated and found to be elevated (91 ng/mL vs a normal in- Alignment tool9 and duplicated reads were removed stitutional laboratory reference range of 15.7–17.0 using Picard.10 Single nucleotide variants and small ng/mL). Further staging evaluation was performed, insertions/deletions were detected using an in- including spine MRI and spinal tap, and found to be 11 house–developed analysis pipeline, which classified negative for disease. variants into 3 categories: somatic, germline, and Chemotherapy with vincristine, cyclophospha- loss of heterozygosity based on variant allele frequen- mide, cisplatin, and doxorubicin was initiated. Af- cies in the tumor and the matched normal tissues. ter the first 2 cycles of chemotherapy, the patient Copy number alterations were determined using a underwent disease evaluation. Laparotomy and previously published algorithm,12 which reports gain resection of the right adrenal mass and adjacent or loss status of each exon. To understand the poten- lymph nodes were performed, and pathology con- tial functional consequence of detected variants, we firmed the diagnosis of neuroblastoma with poor compared them with the SNP Database, Catalogue differentiation and extensive treatment-related of Somatic Mutations in Cancer,13 and The Cancer changes (necrosis and calcification) (Figure 1A). Genome Atlas database, and annotated them using No NMYC amplification or 1p or 17q deletion were seen, and her karyotype was unremarkable. The pa- VEP,14 ANNOVAR,15 CanDrA,16 and other pro- tient was classified as having intermediate-risk dis- grams. Translation consequence of the alteration, ease and resumed chemotherapy consisting of vin- such as nonsynonymous, missense, stop-gain, frame- cristine, cyclophosphamide, cisplatin, dacarbazine, shift, and others, follows Sequence Ontology (http:// ifosfamide, and doxorubicin, followed by 5 main- www.sequenceontology.org). All aberrations that are tenance cycles of 13-cis retinoic acid. Surveillance nonsynonymous were shown. The software used for MIBG during maintenance chemotherapy revealed predicting consequences and clinical implications no residual disease. has been previously described: PolyPhen (the higher Five months after completing treatment, the pa- the score, the more damaging the aberration),17 SIFT tient presented with repeated vomiting and new onset (the lower the score, the more deleterious the aber- of difficulty walking after experiencing head trauma. ration),18 and CanDrA16 to identify whether the mu- MRI of the brain showed a mass in the right cerebel- tation is the driver versus the passenger. lar hemisphere with hydrocephalus (Figure 1E). Com- © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 16 Number 6 | June 2018 Molecular Insights in Patient Care 685 Medulloblastoma in Child With History of Neuroblastoma A B C D E F G H Figure 1. (A) Posttherapy calcification of adrenalectomy and rare viable neuroblastoma cells showing good therapeutic response to adjuvant che- motherapy (hematoxylin-eosin, original magnification x100). (B) Small round blue cell tumor with anaplastic medulloblastoma features in a section of the brain (hematoxylin-eosin, original magnification x400). Immunohistochemical study (C) positive for anti-CD57 and (D) negative for neurofila- ment (original magnification x100, for both). (E) Axial T1 MRI of the brain with contrast
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