TY - JOUR
T1 - Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1
AU - Noë, Michaël
AU - Pea, Antonio
AU - Luchini, Claudio
AU - Felsenstein, Matthäus
AU - Barbi, Stefano
AU - Bhaijee, Feriyl
AU - Yonescu, Raluca
AU - Ning, Yi
AU - Adsay, N. Volkan
AU - Zamboni, Giuseppe
AU - Lawlor, Rita T.
AU - Scarpa, Aldo
AU - Offerhaus, G. Johan A.
AU - Brosens, Lodewijk A.A.
AU - Hruban, Ralph H.
AU - Roberts, Nicholas J.
AU - Wood, Laura D.
N1 - Funding Information:
Acknowledgements We acknowledge the following sources of support:NIH/NCI P50 CA62924; NIH/NIDDK K08 DK107781; Sol Goldman Pancreatic Cancer Research Center; Buffone Family Gastrointestinal Cancer Research Fund; Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention; AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award; AACR-Incyte Corporation Career Development Award for Pancreatic Cancer Research; Rolfe Pancreatic Cancer Foundation; Joseph C Monastra Foundation; The Gerald O Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); Lisa Waller Hayes Foundation; Nijbakker Morra Foundation; Dutch Digestive Foundation (CDG 14-02); German Research Foundation (DFG); Associazione Italiana Ricerca Cancro (grant number: 12182); FP7 European Community Grant Cam-Pac (no: 602783); Italian Ministry of University (FIRB RBAP10AHJB); NIH/NCI R00 CA190889.
Publisher Copyright:
© 2018, United States & Canadian Academy of Pathology.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by frequent cutaneous and nervous system abnormalities. Patients with NF1 also have an increased prevalence of multiple gastrointestinal and peripancreatic neoplasms—neuroendocrine tumors of the ampulla that express somatostatin are particularly characteristic of NF1. In this study, we characterize the genetic alterations of a clinically well-characterized cohort of six NF1-associated duodenal neuroendocrine tumors using whole-exome sequencing. We identified inactivating somatic mutations in the NF1 gene in three of six tumors; the only other gene altered in more than one tumor was IFNB1. Copy number analysis revealed deletion/loss of heterozygosity of chromosome 22 in three of six patients. Analysis of germline variants revealed germline deleterious NF1 variants in four of six patients, as well as deleterious variants in other tumor suppressor genes in two of four patients with deleterious NF1 variants. Taken together, these data confirm the importance of somatic inactivation of the wild-type NF1 allele in the formation of NF1-associated duodenal neuroendocrine tumors and suggest that loss of chromosome 22 is important in at least a subset of cases. However, we did not identify any genes altered in the majority of NF1-associated duodenal neuroendocrine tumors that uniquely characterize the genomic landscape of this tumor. Still, the genetic alterations in these tumors are distinct from sporadic neuroendocrine tumors occurring at these sites, highlighting that unique genetic alterations drive syndromic tumors.
AB - Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by frequent cutaneous and nervous system abnormalities. Patients with NF1 also have an increased prevalence of multiple gastrointestinal and peripancreatic neoplasms—neuroendocrine tumors of the ampulla that express somatostatin are particularly characteristic of NF1. In this study, we characterize the genetic alterations of a clinically well-characterized cohort of six NF1-associated duodenal neuroendocrine tumors using whole-exome sequencing. We identified inactivating somatic mutations in the NF1 gene in three of six tumors; the only other gene altered in more than one tumor was IFNB1. Copy number analysis revealed deletion/loss of heterozygosity of chromosome 22 in three of six patients. Analysis of germline variants revealed germline deleterious NF1 variants in four of six patients, as well as deleterious variants in other tumor suppressor genes in two of four patients with deleterious NF1 variants. Taken together, these data confirm the importance of somatic inactivation of the wild-type NF1 allele in the formation of NF1-associated duodenal neuroendocrine tumors and suggest that loss of chromosome 22 is important in at least a subset of cases. However, we did not identify any genes altered in the majority of NF1-associated duodenal neuroendocrine tumors that uniquely characterize the genomic landscape of this tumor. Still, the genetic alterations in these tumors are distinct from sporadic neuroendocrine tumors occurring at these sites, highlighting that unique genetic alterations drive syndromic tumors.
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U2 - 10.1038/s41379-018-0082-y
DO - 10.1038/s41379-018-0082-y
M3 - Article
C2 - 29849115
AN - SCOPUS:85047818386
SN - 0893-3952
VL - 31
SP - 1532
EP - 1538
JO - Modern Pathology
JF - Modern Pathology
IS - 10
ER -