GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Abstract

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…The vast majority of pNETs are sporadic, and genes involved in the hereditary disorders have also been attributed to sporadic pNET (Crona & Skogseid 2016). Two studies using nextgeneration sequencing (NGS) revealed alterations; among those, MEN1 and ATRX/DAXX alterations were the most frequent ones ( (Tang et al 2016).…”

Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases

“…6 Epitope prediction on peptides containing these SNVs and on neoORF peptides generated by frameshift indels, revealed 28 epitopes that bind with high to intermediate affinity to one of the patient's HLA allele. We then synthesized these predicted neoantigens together with the corresponding wildtype peptides and conducted IFNg ELISpot assays using the patient's peripheral blood to asses if there are T cells that are reactive against them.…”

“…A wide range of somatic genetic alterations have also been described for various NETs, hindgut NETs however remain poorly characterized. 4,6,7 Generally, NET genomes harbor relatively few somatic mutations when compared with adenocarcinomatous tumors. 6 NETs present a wide spectrum of malignancies from relatively indolent to highly aggressive variants.…”

“…4,6,7 Generally, NET genomes harbor relatively few somatic mutations when compared with adenocarcinomatous tumors. 6 NETs present a wide spectrum of malignancies from relatively indolent to highly aggressive variants. The prognosis for high-grade poorly differentiated neuroendocrine carcinomas however is generally poor, as most patients have metastatic disease at the time of diagnosis, whereas patients with low-grade NETs have a rather favorable prognosis.…”

“…10 and 11 ), and it has been suggested, that immunotherapy in NETs provides opportunities for future advances. 1,6 However, it is largely unclear how the setup of the immunological microenvironment in metastatic NET is and especially how diverse these mutations and immunological setups can be between different metastatic lesions.…”