TY - JOUR
T1 - The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets
AU - van Riet, Job
AU - van de Werken, Harmen J G
AU - Cuppen, Edwin
AU - Eskens, Ferry A L M
AU - Tesselaar, Margot
AU - van Veenendaal, Linde M
AU - Klümpen, Heinz-Josef
AU - Dercksen, Marcus W
AU - Valk, Gerlof D
AU - Lolkema, Martijn P
AU - Sleijfer, Stefan
AU - Mostert, Bianca
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7/29
Y1 - 2021/7/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85111516817&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-24812-3
DO - 10.1038/s41467-021-24812-3
M3 - Article
C2 - 34326338
SN - 2041-1723
VL - 12
SP - 1
EP - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4612
ER -