Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms.
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ABSTRACT:
SUBMITTER: Bulloni M
PROVIDER: S-EPMC8508355 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pancreatic neuroendocrine neoplasms (panNENs) are a rare yet diverse type of neoplasia whose precise clinical-pathological classification is frequently challenging. Since incorrect classifications can affect treatment decisions, additional tools which support the diagnosis, such as machine learning (ML) techniques, are critically needed but generally unavailable due to the scarcity of suitable ML training data for rare panNENs. Here, we demonstrate that a multi-step ML framework predicts clinically relevant panNEN characteristics while being exclusively trained on widely available data of a healthy origin. The approach classifies panNENs by deconvolving their transcriptomes into cell type proportions based on shared gene expression profiles with healthy pancreatic cell types. The deconvolution results were found to provide a prognostic value with respect to the prediction of the overall patient survival time, neoplastic grading, and carcinoma versus tumor subclassification. The performance with which a proliferation rate agnostic deconvolution ML model could predict the clinical characteristics was found to be comparable to that of a comparative baseline model trained on the proliferation rate-informed MKI67 levels. The approach is novel in that it complements established proliferation rate-oriented classification schemes whose results can be reproduced and further refined by differentiating between identically graded subgroups. By including non-endocrine cell types, the deconvolution approach furthermore provides an in silico quantification of panNEN dedifferentiation, optimizing it for challenging clinical classification tasks in more aggressive panNEN subtypes.
| S-EPMC9913692 | biostudies-literature
Project description:Lung neuroendocrine neoplasms (LNENs) are rare solid cancers, with most genomic studies including a limited number of samples. Recently, generating the first multi-omic dataset for atypical pulmonary carcinoids and the first methylation dataset for large-cell neuroendocrine carcinomas led us to the discovery of clinically relevant molecular groups, as well as a new entity of pulmonary carcinoids (supra-carcinoids). To promote the integration of LNENs molecular data, we provide here detailed information on data generation and quality control for whole-genome/exome sequencing, RNA sequencing, and EPIC 850K methylation arrays for a total of 84 patients with LNENs. We integrate the transcriptomic data with other previously published data and generate the first comprehensive molecular map of LNENs using the Uniform Manifold Approximation and Projection (UMAP) dimension reduction technique. We show that this map captures the main biological findings of previous studies and can be used as reference to integrate datasets for which RNA sequencing is available. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (https://tumormap.ucsc.edu/?p=RCG_lungNENomics/LNEN). The data, source code, and compute environments used to generate and evaluate the map as well as the raw data are available, respectively, in a Nextjournal interactive notebook (https://nextjournal.com/rarecancersgenomics/a-molecular-map-of-lung-neuroendocrine-neoplasms/) and at the EMBL-EBI European Genome-phenome Archive and Gene Expression Omnibus data repositories. We provide data and all resources needed to integrate them with future LNENs transcriptomic studies, allowing meaningful conclusions to be drawn that will eventually lead to a better understanding of this rare understudied disease.
| S-EPMC7596803 | biostudies-literature
Project description:This review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future.
| S-EPMC8695375 | biostudies-literature
Project description:Lung well-to-moderately differentiated neuroendocrine tumors (also known as carcinoids) and large cell neuroendocrine lung carcinoma (poorly differentiated neuroendocrine tumor) are rare neuroendocrine neoplasms, which account for less than 4% of all lung neoplasms. Due to their low incidence, their systemic treatment is greatly influenced by therapeutic evidence derived from the more frequent gastroenteropancreatic neuroendocrine neoplasms and/or small cell lung carcinoma leading to significant bias. Currently, employed systemic therapies for lung carcinoids, aiming at controlling tumor growth include long acting somatostatin analogues (SSAs), peptide receptor radionuclide therapy, chemotherapy and molecular-targeted therapy. In this review, each of those treatments is presented based upon available clinical evidence from retrospective and prospective studies particularly focused on the role of everolimus in the advanced setting and on ongoing clinical trials reflecting our expectations in the near future. In addition, we critically analyse currently employed treatment of large cell neuroendocrine carcinoma where the appropriate chemotherapeutic regimen is still a matter of debate.
| S-EPMC5952021 | biostudies-literature
Project description:B-cell responses are emerging as critical regulators of cancer progression. In this study, we investigated the role of B lymphocytes in the microenvironment of human pancreatic ductal adenocarcinoma (PDAC), in a retrospective consecutive series of 104 PDAC patients and in PDAC preclinical models. Immunohistochemical analysis revealed that B cells occupy two histologically distinct compartments in human PDAC, either scatteringly infiltrating (CD20-TILs), or organized in tertiary lymphoid tissue (CD20-TLT). Only when retained within TLT, high density of B cells predicted longer survival (median survival 16.9 mo CD20-TLT(hi) vs. 10.7 mo CD20-TLT(lo); p = 0.0085). Presence of B cells within TLT associated to a germinal center (GC) immune signature, correlated with CD8-TIL infiltration, and empowered their favorable prognostic value. Immunotherapeutic vaccination of spontaneously developing PDAC (Kras(G12D)-Pdx1-Cre) mice with ?-enolase (ENO1) induced formation of TLT with active GCs and correlated with increased recruitment of T lymphocytes, suggesting induction of TLT as a strategy to favor mobilization of immune cells in PDAC. In contrast, in an implanted tumor model devoid of TLT, depletion of B cells with an anti-CD20 antibody reinstated an antitumor immune response. Our results highlight B cells as an essential element of the microenvironment of PDAC and identify their spatial organization as a key regulator of their antitumor function. A mindfully evaluation of B cells in human PDAC could represent a powerful prognostic tool to identify patients with distinct clinical behaviors and responses to immunotherapeutic strategies.
| S-EPMC4839336 | biostudies-other
Project description:Lung neuroendocrine neoplasms (NENs) can be challenging to classify due to subtle histologic differences between pathological types. MicroRNAs (miRNAs) are small RNA molecules that are valuable markers in many neoplastic diseases. To evaluate miRNAs as classificatory markers for lung NENs, we generated comprehensive miRNA expression profiles from 14 typical carcinoid (TC), 15 atypical carcinoid (AC), 11 small cell lung carcinoma (SCLC), and 15 large cell neuroendocrine carcinoma (LCNEC) samples, through barcoded small RNA sequencing. Following sequence annotation and data preprocessing, we randomly assigned these profiles to discovery and validation sets. Through high expression analyses, we found that miR-21 and -375 are abundant in all lung NENs, and that miR-21/miR-375 expression ratios are significantly lower in carcinoids (TC and AC) than in neuroendocrine carcinomas (NECs; SCLC and LCNEC). Subsequently, we ranked and selected miRNAs for use in miRNA-based classification, to discriminate carcinoids from NECs. Using miR-18a and -155 expression, our classifier discriminated these groups in discovery and validation sets, with 93% and 100% accuracy. We also identified miR-17, -103, and -127, and miR-301a, -106b, and -25, as candidate markers for discriminating TC from AC, and SCLC from LCNEC, respectively. However, these promising findings require external validation due to sample size.
| S-EPMC7564332 | biostudies-literature
Project description:BackgroundThe clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features.MethodsWe evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN.ResultsWe detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients' progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.ConclusionsWe propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.
| S-EPMC8430927 | biostudies-literature
Project description:Malnutrition and sarcopenia affect clinical outcomes and treatment response in cancer patients. Patients with neuroendocrine neoplasms (NENs) may present with additional symptoms related to tumor localization in the gastrointestinal tract and hormone secretion, increasing the risk and effects of sarcopenia. To explore the presence of malnutrition and sarcopenia in gastroenteropancreatic (GEP)-NEN patients, their relation to tumor characteristics, patient outcomes, survival and the molecular expression of ghrelin system components in the tumor. One-hundred-and-four patients were included. Anthropometric, biochemical and CT-scans at diagnosis were evaluated. The expression levels of key ghrelin system components were assessed in 63 tumor samples. Nutritional parameters were similar in GEP-NEN tumors of different origin. Relapsed disease was associated with decreased BMI. Patients who presented with weight loss at diagnosis had significantly lower overall survival (108 (25-302) vs. 263 (79-136) months). Ghrelin O-acyltransferase (GOAT) enzyme expression was higher in these patients. The prevalence of sarcopenia using CT images reached 87.2%. Mortality was observed only in patients with sarcopenia. Muscle evaluation was correlated with biochemical parameters but not with the expression of ghrelin system components. Survival is related to the nutritional status of patients with GEP-NENs and also to the molecular expression of some relevant ghrelin system components. Routine nutritional evaluation should be performed in these patients, in order to prescribe appropriate nutritional support, when necessary, for increasing quality of life and improving clinical outcomes.
| S-EPMC8750458 | biostudies-literature
Project description:DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051-0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance.
| S-EPMC7352978 | biostudies-literature
Project description:PurposeNeuroendocrine neoplasia (NEN) has been displaying an incremental trend along the last two decades. This phenomenon is poorly understood, and little information is available on risk factor for neuroendocrine neoplasia development. Aim of this work is to elucidate the role of potentially modifiable risk factors for pancreatic and pulmonary NEN.MethodsWe conducted a case-control study on 184 patients with NEN (100 pancreas and 84 lung) and 248 controls. The structured questionnaire included 84 queries on socio-demographic, behavioral, dietary and clinical information.ResultsIncreased risk was associated with history of cancer ("other tumor", lung OR = 7.18; 95% CI: 2.55-20.20 and pancreas OR = 5.88; 95% CI: 2.43-14.22; "family history of tumor", lung OR = 2.66; 95% CI: 1.53-4.64 and pancreas OR = 1.94; 95% CI: 1.19-3.17; "family history of lung tumor", lung OR = 2.56; 95% CI: 1.05-6.24 and pancreas OR = 2.60; 95% CI: 1.13-5.95). Type 2 diabetes mellitus associated with an increased risk of pancreatic NEN (OR = 3.01; 95% CI: 1.15-7.89).ConclusionsBesides site-specific risk factors, there is a significant link between neuroendocrine neoplasia and cancer in general, pointing to a shared cancer predisposition.
| S-EPMC7835148 | biostudies-literature