Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases

Koşaloğlu, Zeynep; Zörnig, Inka; Halama, Niels; Kaiser, Iris; Buchhalter, Ivo; Grabe, Niels; Eils, Roland; Schlesner, Matthias; Califano, Andrea; Jäger, Dirk

doi:10.1080/2162402x.2016.1213931

Cited by 15 publications

(12 citation statements)

References 55 publications

(64 reference statements)

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“…The same study showed mutual association between lymph node invasion, CpG island methylation, and miR-885-5p expression (92). Finally, whole-genome sequencing on six liver metastases from the same patient showed that 11 of 18 somatic mutations were identified in all samples, including known tumor-related genes HSPG2 , SERPINF2 (extracellular matrix remodeling), and SMARCA1 (chromatin remodeling) (93).…”

Section: Basic Histology and Biology Of Gep-nensmentioning

confidence: 99%

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

2019

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Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.

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Section: Basic Histology and Biology Of Gep-nensmentioning

confidence: 99%

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

2019

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“…However, a mutual association between lymph node invasion, CpG island methylation, and miR-885-5p expression, has been described [142]. Interestingly, wholegenome sequencing of six liver metastases from a rectal NET showed that 11 of 18 somatic mutations were identified in all samples, including known tumor-related genes HSPG2, SERPINF2 (extracellular matrix remodeling), and SMARCA1 (chromatin remodeling) [143]. Recently, repetitive mutations in five genes including TP53, PTEN, CDKN2A, FBXW7, and AKT1 have been described in rectal NETs, the mutational burden seeming to increase with tumor grade [141].…”

Section: Large Bowel and Rectummentioning

confidence: 99%

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

et al. 2021

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Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.

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“…One possible reason is the lack of messages about mechanistic alterations underlying the development of RNET. To date, apart from a handful of studies focusing on the genetic and epigenetic changes in such neoplasms 36 , comprehensive mechanistic characterization is still urgently needed for therapeutic and diagnostic improvement for patients with RNET. To this end, we hereby presented a comprehensive and in-depth study by performing shotgun metagenomic and untargeted metabolomic profiling of faecal samples from RNET and healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Faecal microbiome and metabolic signatures in rectal neuroendocrine tumors

Hu¹,

Chen²,

Li³

et al. 2022

Theranostics

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Background: The prevalence of rectal neuroendocrine tumors (RNET) has increased substantially over the past decades. Little is known on mechanistic alteration in the pathogenesis of such disease. We postulate that perturbations of human gut microbiome-metabolome interface influentially affect the development of RNET. The study aims to characterize the composition and function of faecal microbiome and metabolites in RNET individuals. Methods: We performed deep shotgun metagenomic sequencing and untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomic profiling of faecal samples from the discovery cohort (18 RNET patients, 40 controls), and validated the microbiome and metabolite-based classifiers in an independent cohort (15 RNET participants, 19 controls). Results: We uncovered a dysbiotic gut ecological microenvironment in RNET patients, characterized by aberrant depletion and attenuated connection of microbial species, and abnormally aggregated lipids and lipid-like molecules. Functional characterization based on our in-house and Human Project Unified Metabolic Analysis Network 2 (HUMAnN2) pipelines further indicated a nutrient deficient gut microenvironment in RNET individuals, evidenced by diminished activities such as energy metabolism, vitamin biosynthesis and transportation. By integrating these data, we revealed 291 robust associations between representative differentially abundant taxonomic species and metabolites, indicating a tight interaction of gut microbiome with metabolites in RNET pathogenesis. Finally, we identified a cluster of gut microbiome and metabolite-based signatures, and replicated them in an independent cohort, showing accurate prediction of such neoplasm from healthy people. Conclusions: Our current study is the first to comprehensively characterize the perturbed interface of gut microbiome and metabolites in RNET patients, which may provide promising targets for microbiome-based diagnostics and therapies for this disorder.

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Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases

Cited by 15 publications

References 55 publications

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

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

Faecal microbiome and metabolic signatures in rectal neuroendocrine tumors

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