scholarly journals The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Author(s):  
Andreas Venizelos ◽  
Hege Elvebakken ◽  
Aurel Perren ◽  
Oleksii Nikolaienko ◽  
Wei Deng ◽  
...  
Keyword(s):  
Copy Number ◽  
Primary Tumour ◽  
Treatment Strategies ◽  
Morphological Differentiation ◽  
Molecular Characteristics ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Braf Mutations ◽  
Molecular Features ◽  
Net G3

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on sequencing of 360 cancer related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 8/152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicates a high potential for better personalized treatments.

scholarly journals Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
K. Lithgow ◽  
H. Venkataraman ◽  
S. Hughes ◽  
H. Shah ◽  
J. Kemp-Blake ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Treatment Strategies ◽  
Biological Behavior ◽  
Queen Elizabeth Hospital ◽  
Neuroendocrine Neoplasms ◽  
Single Centre ◽  
Net G3 ◽  
Well Differentiated

AbstractNeuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Surgery of the primary tumour in 201 patients with high‐grade gastroenteropancreatic neuroendocrine and mixed neuroendocrine‐non‐neuroendocrine neoplasms

2021 ◽  
Author(s):  
Hans‐Christian Pommergaard ◽  
Kirstine Nielsen ◽  
Halfdan Sorbye ◽  
Birgitte Federspiel ◽  
Elizaveta M. Tabaksblat ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Neuroendocrine Neoplasms ◽  
High Grade

scholarly journals Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study

2021 ◽  
Author(s):  
Roel Bogie ◽  
Chantal MC le Clercq ◽  
Quirinus JM Voorham ◽  
Martijn Cordes ◽  
Daoud Sie ◽  
...  
Keyword(s):  
Copy Number ◽  
Case Control Study ◽  
Case Control ◽  
Colorectal Cancers ◽  
Molecular Characteristics ◽  
Molecular Features ◽  
Serrated Lesions ◽  
Copy Number Changes ◽  
Nested Case Control ◽  
Control Study

Background: Post-colonoscopy colorectal cancers (PCCRCs) pose a challenge in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. Specific features of lesions may contribute for this. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). Methods: PCCRCs were defined according to the WEO 2018 classification, as cancers occurring after a complete index colonoscopy, which excluded CRC. CRCs in patients without colonoscopy or with colonoscopy >10 years before were defined as DCRCs. Whole genome chromosomal copy number changes and mutation status of genes commonly affected in CRC (including APC, KRAS, BRAF, FBXW7, PIK3CA, NRAS, SMAD4 and TP53) were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status were also determined. Results: In total, 122 PCCRCs and 98 DCRCs with high quality DNA were examined. PCCRCs were more often located proximally in the colon (p<0.001), non-polypoid appearing (p=0.004), early stage (p=0.009), and poorly differentiated (p=0.006). PCCRCs showed similar patterns of DNA copy number changes typical of CRC, although significantly less 18q loss (FDR <0.2), compared to DCRCs. No significant differences in mutations were detected between PCCRCs and DCRCs. PCCRCs were more commonly CIMP-high (p=0.014) and MSI (p=0.029). After correction for tumour location, the only molecular difference between PCCRCs and DCRCs that remained significant was less frequent loss of 18q chromosome in PCCRCs (p=0.005). Conclusion: Although PCCRCs show molecular characteristics that are common to the canonical CIN, MSI and hypermethylation pathways, molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. This and the clinical features observed in PCCRCs support the hypothesis that sessile serrated lesions and non-polypoid CRNs are contributors to the development of these cancers. In order to further reduce the occurrence of PCCRCs, the focus should be directed at improving the detection, determination and endoscopic removal of these non-polypoid CRN and SSLs. Clinical Trial Registration: NTR3093 in the Dutch trial register (www.trialregister.nl)

scholarly journals Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

2021 ◽  
Author(s):  
Alok K. Tewari ◽  
Alexander T.M. Cheung ◽  
Jett Crowdis ◽  
Jake R. Conway ◽  
Sabrina Y. Camp ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Localized Prostate Cancer ◽  
Copy Number Loss ◽  
Molecular Features ◽  
Pre Treatment

ABSTRACTHigh-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and prostate cancer-specific mortality1. Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we performed whole exome (WES) and whole transcriptome sequencing (RNA-seq) on pre-treatment multi-regional tumor biopsies from exceptional responders (ER: pCR and MRD patients) and non-responders (NR: pathologic T3 or lymph node positive disease) treated with intensive anti-androgen therapies prior to prostatectomy. SPOP mutation and SPOPL copy number loss were exclusively observed in ER, while TP53 mutation and PTEN copy number loss were exclusively observed in NR. These alterations were clonal in all tumor phylogenies per patient. Additionally, transcriptional programs involving androgen signaling and TGFβ signaling were enriched in ER and NR, respectively. The presence of these alterations in routine biopsies from patients with HRLPC may inform the prospective identification of responders to neoadjuvant anti-androgen therapies to improve clinical outcomes and stratify other patients to alternative biologically informed treatment strategies.

scholarly journals Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

2018 ◽  
Vol 108 (1) ◽  
pp. 54-62 ◽  
Author(s):  
Halfdan Sorbye ◽  
Eric Baudin ◽  
Ivan Borbath ◽  
Martyn Caplin ◽  
Jie Chen ◽  
...  
Keyword(s):  
Patient Group ◽  
Unmet Needs ◽  
Proliferation Rate ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
High Grade ◽  
Primary Tumor Site ◽  
Net G3 ◽  
Well Differentiated

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

scholarly journals Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 233
Author(s):  
Cristian Perna ◽  
Antonia Navarro ◽  
Ignacio Ruz-Caracuel ◽  
Tamara Caniego-Casas ◽  
Eva Cristóbal ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Tumor Infiltrating Lymphocytes ◽  
Copy Number Variations ◽  
Molecular Heterogeneity ◽  
Separate Analysis ◽  
High Grade ◽  
Gene Fusions ◽  
Colorectal Carcinomas ◽  
Braf Mutations ◽  
Molecular Features

High grade colorectal carcinomas (HG-CRCs), which comprise 15% of colorectal carcinomas, are underrepresented in reported molecular studies. Clinicopathological, immunohistochemical, and molecular features of 40 HG-CRCs are described. Moreover, glandular and solid areas of 25 tumors were separately analyzed. The expression of MLH1, PMS2, MSH2, MSH6, p53, E-cadherin, CDX2, CK20, CD8, PDL1, PAN-TRK, c-MET, SMARCB1, ARID1A, SMARCA2, and SMARCA4 was analyzed by immunohistochemistry. Promoter MLH1 methylation was analyzed in tumors with MLH1/PMS2 loss. Next-generation sequencing was used to screen 161 genes for hotspot mutations, copy number variations and gene fusions. In this series, 72.5% of HG-CRCs showed mismatch repair deficiency (MMRd). MMR deficient tumor and MMR proficient (MMRp) tumors showed striking molecular differences. Thus, whereas BRAF mutations were only observed in MMRd tumors, mutations in KRAS and TP53 were more frequent in MMR proficient tumors. Moreover, gene fusions (NTRK1 and MET) were detected only in MMRd tumors, whereas gene amplification (MYC, CCND1 and EGFR) predominated in MMRp/TP53-mutated tumors. Loss of expression of proteins involved in chromatin remodeling, such as ARID1A, was observed only in MMRd HG-CRCs, which also showed more frequently PD-L1 expression and a higher number of tumor infiltrating lymphocytes. The separate analysis of glandular and solid areas indicated that the clonal or subclonal nature of the molecular alterations also depended on MMR status. Mutations in genes such as TP53 and KRAS were always clonal in MMRp-CRCs but occurred as subclonal events in MMRd-CRCs. Gene amplification was implicated in the progression of MMRp tumors, but not in MMRd tumors, in which clonal diversity was due to accumulation of mutations in genes of different pathways such as NOTCH, MMR, or PIK3CA. In summary, intertumor and intratumor molecular heterogeneity in HG-CRCs is mainly due to MMR status.

scholarly journals INNV-04. CONGENITAL SPINAL GLIOBLASTOMA WITH SUSTAINED RESPONSE TO TROPOMYOSIN RECEPTOR KINASE (TRK) INHIBITION: A CASE REPORT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii117-ii117
Author(s):  
Christina Coleman Abadi ◽  
Peter Sun ◽  
Caroline Hastings
Keyword(s):  
Targeted Therapy ◽  
Gene Fusion ◽  
Large Scale ◽  
Response To Treatment ◽  
Molecular Characteristics ◽  
Molecular Testing ◽  
High Grade ◽  
Molecular Features ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Large scale genomic efforts have shown that a significant percentage of infant high-grade gliomas (HGG) carry targetable gene fusions. Given the rarity of congenital spinal HGGs, little is known about the molecular features of these tumors and their response to treatment. We describe a case of a patient with congenital spinal glioblastoma. A full-term female infant with symmetric IUGR was noted to have weakness with little movement of her upper extremities. MRI of the spine showed an infiltrative and hemorrhagic intraspinal cervicothoracic neoplasm with a large hemorrhagic intramedullary component. A biopsy was done and revealed a high-grade glial neoplasm with pan-TRK expression. Next generation sequencing (NGS) confirmed a MEF2D-NTRK1 gene fusion. Prior to the result of her molecular testing, the patient clinically deteriorated with decreased movement and increased apneic episodes despite steroid treatment. She was then started on treatment with carboplatin and etoposide per Macy et al 1. After one cycle of chemotherapy and given the results of NGS, targeted therapy with larotrectinib was added to her treatment. The patient showed a response (clinical and imaging) following cycle 1 with chemotherapy, and a marked response following cycle 2 with both chemotherapy and targeted TRK inhibition. The patient completed six cycles of chemotherapy and has continued on daily oral larotrectinib. She continues to tolerate the targeted therapy well and currently is 8 months old, growing and developing well. She has regained much of her movement and is eating and growing with apparent normal development. This case provides an example of a patient with congenital glioblastoma with TRK gene fusion that showed an impressive response to targeted therapy combined with more conventional chemotherapy. 1Macy M, et al. Clinical and molecular characteristics of congenital glioblastoma. Neuro Oncol. Jul;14 (7) 931–941, 2012).

scholarly journals Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences With the Adult Disease

2010 ◽  
Vol 28 (18) ◽  
pp. 3061-3068 ◽  
Author(s):  
Barbara S. Paugh ◽  
Chunxu Qu ◽  
Chris Jones ◽  
Zhaoli Liu ◽  
Martyna Adamowicz-Brice ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
De Novo ◽  
Molecular Genetic ◽  
High Grade Glioma ◽  
Cranial Irradiation ◽  
High Grade ◽  
Copy Number Alterations ◽  
Molecular Features ◽  
Diffuse Intrinsic Pontine Gliomas

Purpose To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). Patients and Methods We conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors. Results Significant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFRα signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes. Conclusion Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFRα may be a useful target for pediatric HGG, including diffuse pontine gliomas.

scholarly journals Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

2021 ◽  
Vol 10 (8) ◽  
pp. 1741
Author(s):  
Giovanni Centonze ◽  
Vincenzo Lagano ◽  
Giovanna Sabella ◽  
Alessandro Mangogna ◽  
Giovanna Garzone ◽  
...  
Keyword(s):  
T Cell ◽  
Multivariable Analysis ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Immune Markers ◽  
Cancer Specific Survival ◽  
Ki 67 ◽  
Clinical Databases ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Net G3

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.

scholarly journals Update on Endometrial Stromal Tumours of the Uterus

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 429
Author(s):  
Iolia Akaev ◽  
Chit Cheng Yeoh ◽  
Siavash Rahimi
Keyword(s):  
Late Recurrence ◽  
Malignant Potential ◽  
Molecular Techniques ◽  
Molecular Characteristics ◽  
Low Grade ◽  
High Grade ◽  
Endometrial Stromal Cells ◽  
Molecular Features ◽  
Therapeutic Decisions

Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories according to the mitotic count. In the most recent classification by the WHO (2020), ESTs have been divided into four categories: Endometrial Stromal Nodules (ESNs), Low-Grade Endometrial Stromal Sarcomas (LG-ESSs), High-Grade Endometrial Stromal Sarcomas (HG-ESSs) and Undifferentiated Uterine Sarcomas (UUSs). ESNs are clinically benign. LG-ESSs are tumours of low malignant potential, often with indolent clinical behaviour, with some cases presented with a late recurrence after hysterectomy. HG-ESSs are tumours of high malignant potential with more aggressive clinical outcome. UUSs show high-grade morphological features with very aggressive clinical behavior. With the advent of molecular techniques, the morphological classification of ESTs can be integrated with molecular findings in enhanced classification of these tumours. In the future, the morphological and immunohistochemical features correlated with molecular categorisation of ESTs, will become a robust means to plan therapeutic decisions, especially in recurrences and metastatic disease. In this review, we summarise the morphological, immunohistochemical and molecular features of ESTs with particular reference to the most recent molecular findings.

Sign in / Sign up

Export Citation Format

Share Document