The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets
| Autor: | Harmen J.G. van de Werken, Linde M. van Veenendaal, Job van Riet, Martijn P. Lolkema, Edwin Cuppen, Heinz-Josef Klümpen, Margot Tesselaar, Bianca Mostert, Ferry A.L.M. Eskens, Stefan Sleijfer, Marcus W. Dercksen, Gerlof D. Valk |
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| Přispěvatelé: | Oncology, CCA - Cancer biology and immunology, Medical Oncology, Urology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Proliferation index Somatic cell Science General Physics and Astronomy Biology Neuroendocrine tumors medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine medicine Cancer genomics Humans MEN1 ATRX Aged Neoplasm Staging Multidisciplinary Whole Genome Sequencing Genetic heterogeneity General Chemistry Oncogenes Middle Aged medicine.disease Prognosis Primary tumor Neuroendocrine Tumors 030104 developmental biology Neuroendocrine cancer 030220 oncology & carcinogenesis Mutation Cancer research Next-generation sequencing Female KRAS Genes Neoplasm |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature communications, 12(1):4612. Nature Publishing Group Nature Communications, 12(1):4612. Nature Publishing Group |
| ISSN: | 2041-1723 |
| Popis: | Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This landscape reveals distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; we observe relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53, KRAS, RB1, CSMD3, APC, CSMD1, LRATD2, TRRAP and MYC as major drivers versus an overall low TMB in neuroendocrine tumors (1.09). Furthermore, we observe distinct drivers which are enriched in somatic aberrations in pancreatic (MEN1, ATRX, DAXX, DMD and CREBBP) and midgut-derived neuroendocrine tumors (CDKN1B). Finally, 49% of aNEN patients reveal potential therapeutic targets based upon actionable (and responsive) somatic aberrations within their genome; potentially directing improvements in aNEN treatment strategies. Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) display heterogeneous clinical and genetic characteristics. Here, the authors investigate the mutational landscape of 85 aNEN by whole genome sequencing and identify distinct subpopulations, tumour mutational burden patterns, drivers and actionable somatic alterations. |
| Databáze: | OpenAIRE |
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