Genomic characterization of metastatic ultra-hypermutated interdigitating dendritic cell sarcoma through rapid research autopsy
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Hui-Zi Chen1,2,*, Russell Bonneville1,3,*, Lianbo Yu4, Michele R. Wing1, Julie W. Reeser1, Melanie A. Krook1, Jharna Miya1, Eric Samorodnitsky1, Amy Smith1, Dorrelyn Martin1, Thuy Dao1, Qishan Guo1, David Liebner1,4, Aharon G. Freud5, Patricia Allenby6 and Sameek Roychowdhury1
1Department of Internal Medicine, Division of Medical Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
2Department of Internal Medicine, Hematology and Oncology Fellowship Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
3Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, USA
4Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA
5Department of Pathology, Division of Hematopathology, The Ohio State University, Columbus, Ohio, USA
6Department of Pathology, Division of Autopsy Services, The Ohio State University, Columbus, Ohio, USA
*These authors contributed equally to this work
Sameek Roychowdhury, email: Sameek.Roychowdhury@osumc.edu
Keywords: tumor heterogeneity; research autopsy; hypermutation
Received: October 24, 2018 Accepted: October 31, 2018 Published: January 08, 2019
Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare cancer of dendritic cell origin that lacks a standardized treatment approach. Here, we performed genomic characterization of metastatic IDCS through whole exome sequencing (WES) of tumor tissues procured from a patient who underwent research autopsy. WES was also performed on a treatment-naïve tumor biopsy sample obtained from prior surgical resection. Our analyses revealed ultra-hypermutation, defined as >100 mutations per megabase, in this patient's cancer, which was further characterized by the presence of three distinct mutational signatures including UV radiation and APOBEC signatures. To characterize clonal heterogeneity, we used the bioinformatics tool Canopy to leverage single nucleotide and copy number variants to catalog six subclones across various metastatic tumors. Truncal alterations, defined as being present in all clonal tumor cell populations, in this patient's cancer include point mutations in TP53 and CDKN2A and amplifications of c-KIT and APOBEC3A-H, which are likely driver mutations. In summary, we have performed genomic characterization evaluating tumor mutational burden (TMB) and heterogeneity in a patient with metastatic IDCS. Despite ultra-hypermutation, this patient's cancer was not responsive to treatment with PD-1 inhibition. Our results underscore the importance of characterizing clonal heterogeneity in TMB-high cancers.
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