Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1

Abstract

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.

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

“…Somatostatin-producing D cell tumors may also occur in MEN1 where they show LOH at the site of the MEN1 gene [114], but they are more characteristic of neurofibromatosis type 1 in which they are due to inactivating germline mutations in the NF1 gene [115]; somatic mutations have also been described [116]. Another gene identified as altered in more than one tumor of this type was IFNB1 [116]. Loss of chromosome 22 has also been described [116].…”

“…Another gene identified as altered in more than one tumor of this type was IFNB1 [116]. Loss of chromosome 22 has also been described [116]. Mutations of hypoxia-inducible factor 2 alpha (HIF2A) have been implicated in the development of a syndrome of multiple paragangliomas (PGLs) and duodenal somatostatin-producing D cell NETs associated with polycythemia that occurs only in females (Pacak-Zhuang syndrome) [117,118] Gangliocytic paragangliomas are unusual tumors with triphasic differentiation including epithelial neuroendocrine cells, neuronal ganglion cells, and Schwann cells [119]; the term "paraganglioma" is a misnomer as there is no evidence of such differentiation.…”

Clinical and Molecular Risk Factors for Recurrence Following Radical Surgery of Well-Differentiated Pancreatic Neuroendocrine Tumors

“…Pancreatic involvement in NF1 and TSC is less common. In patients with NF1 syndrome, pancreatic tumors are described in 10% of cases; however, these neoplasms are often somatostatinomas that often arise in the duodenum rather than in the pancreas and are characterized by distinct genomic alterations (76,77). Finally, TSC patients present with pancreatic involvement in only 1%, with both functional and non-functional PanNETs reported (78).…”

Duodenal Neuroendocrine Neoplasm

“…A subset (15-40%) of somatostatin-producing tumors are observed in the context of neurofibromatosis type 1 (NF-1) (Stamm et al 1986;Garbrecht et al 2008); in such NF1-associated d-NETs somatic inactivation of the wild-type NF1 allele has been reported, coupled with loss of chromosome 22 in at least a subset of cases (Noë et al 2018). Moreover, a small number of "duodenal somatostatinomas" have been reported secondary to mosaic mutations of the hypoxiainducible factor (HIF) gene HIF2A (Zhuang et al 2012).…”