Exploratory genomic analysis of high-grade neuroendocrine neoplasms across diverse primary sites

in Endocrine-Related Cancer
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Thomas Yang SunDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Lan ZhaoDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Paul Van HummelenDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Brock MartinDepartment of Pathology, Stanford University School of Medicine, Stanford, California, USA

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Kathleen HornbackerClinical Trials Office, Stanford University, Stanford, California, USA

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HoJoon LeeDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Li C XiaDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
Division of Biostatistics, Department of Epidemiology and Public Health, Albert Einstein College of Medicine, Bronx, New York, USA

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Sukhmani K PaddaCedars-Sinai Medical Center, Department of Medical Oncology, Los Angeles, California, USA

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Hanlee P JiDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
Stanford Genome Technology Center, Stanford, California, USA

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Pamela KunzYale School of Medicine, Smilow Cancer Hospital, Yale Cancer Center, New Haven, Connecticut, USA

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Correspondence should be addressed to P Kunz: pamela.kunz@yale.edu
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High-grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n  = 46), whole exome (n  = 40), and gene copy number (n  = 43) sequencing on G3 NEN formalin-fixed, paraffin-embedded samples from diverse organs (in total, 17 were lung, 16 were gastroenteropancreatic, and 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1, and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; P = 0.034) and arm amplification 19q (HR, 4.82; P = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

 

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