Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

Wu, Huanwen; Yu, Zicheng; Liu, Yueping; Guo, Lei; Teng, Lianghong; Guo, Lingchuan; Li, Liang; Wang, Jing; Gao, Jie; Li, Ruiyu; Yang, Ling; Nie, Xiu; Su, Dan; Zeng, Liang

doi:10.1002/cac2.12372

Cited by 10 publications

(18 citation statements)

References 48 publications

(87 reference statements)

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“…Genetically engineered mouse models demonstrated that inactivation of Trp53 and Rb1 induced lineage plasticity by converting from an epithelial phenotype to a NEC phenotype [ 5 , 48 , 51 ]. Genomic aberrations in TP53 and RB1 have also been observed in GEP-NEC at frequencies ranging from 57 to 89% and 9 to 46%, respectively [ 10 – 12 , 29 , 52 – 57 ], thus supporting the idea that the NEC phenotype shares part of the genetic processes of tumor evolution, regardless of the anatomic site of tumor origin [ 5 , 30 ]. Chromothripsis is a single catastrophic event in the genome that is associated with TP53 mutation in GEP-NEC [ 10 ].…”

Section: Clinicopathological and Molecular Features Of Gep-necmentioning

confidence: 90%

“…In addition to the mutations of TP53 and RB1 , other frequently mutated genes in GEP-NECs are KRAS , BRAF , adenomatosis polyposis coli ( APC ), CCNE1 , CDKN2A , Notch receptor 1 (NOTCH1 ), F-box and WD repeat domain containing-7 ( FBXW7 ), catenin beta 1 ( CTNNB1 ), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA )/phosphatase and tensine homolog ( PTEN ) [ 10 – 12 , 29 , 54 , 55 , 57 ] (Table 3 ). The ataxia telangiectasia-mutated ( ATM ) gene was subject to frequent copy number losses, whereas the MYC gene was frequently amplified [ 12 ].…”

Section: Clinicopathological and Molecular Features Of Gep-necmentioning

confidence: 99%

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Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Ooki

Osumi

Fukuda

et al. 2023

Cancer Metastasis Rev

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Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.

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Section: Clinicopathological and Molecular Features Of Gep-necmentioning

confidence: 90%

Section: Clinicopathological and Molecular Features Of Gep-necmentioning

confidence: 99%

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Ooki

Osumi

Fukuda

et al. 2023

Cancer Metastasis Rev

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“…While data pertaining to comprehensive genomic sequencing in pancreatic NECs has traditionally been sparse, a number of recent series have demonstrated enrichment for alterations in TP53 , RB1 , APC , KRAS , BRAF 18 , 19 , copy number losses in ARID1A, ATM and ESR1 , in addition to amplifications/gains in MYC and KDM5A 19 . Recent studies in both pancreatic and non-pancreatic gastrointestinal NECs have demonstrated the presence of potentially actionable alterations 19 , 20 . Specific to BRCA alterations, one series demonstrated that 25% of patients with neuroendocrine cancer of the prostate had detectable biallelic BRCA2 alterations 16 , underpinning a critical need to recommend genomic testing to detect potentially actionable targets and is applicable across solid tumor types.…”

Section: Discussionmentioning

confidence: 99%

Dramatic, durable response to therapy in gBRCA2-mutated pancreas neuroendocrine carcinoma: opportunity and challenge

et al. 2023

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Poorly differentiated pancreatic neuroendocrine tumors (PDNEC), are a subtype of pancreatic cancer encompassing both small cell and large cell neuroendocrine carcinoma subtypes, and are characterized as distinct in terms of biology and prognosis compared to the more common pancreatic adenocarcinoma. Until recently, there has been a paucity of data on the genomic features of this cancer type. We describe a male patient diagnosed with PDNEC and extensive metastatic disease in the liver at diagnosis. Genomic analysis demonstrated a germline pathogenic variant in BRCA2 with somatic loss-of-heterozygosity of the BRCA2 wild-type allele. Following a favorable response to platinum-based chemotherapy (and the addition of immunotherapy), the patient received maintenance therapy with olaparib, which resulted in a further reduction on follow-up imaging (Fig. 1). After seventeen months of systemic control with olaparib, the patient developed symptomatic central nervous system metastases, which harboured a BRCA2 reversion mutation. No other sites of disease progression were observed. Herein, we report an exceptional outcome through the incorporation of a personalized management approach for a patient with a pancreatic PDNEC, guided by comprehensive genomic sequencing.

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“…DNA-and RNA-based next-generation sequencing. Whole exome and transcriptome sequencing were performed in Geneplus-Beijing (Beijing, China) as previously described [27][28][29] . Brie y, genomic DNA and RNA were extracted from the tumor samples using FirePureTM FFPE gDNA Extraction Kit for genomic DNA and RNeasy FFPE Kit for RNA or AllPrep DNA/RNA FFPE Kit for both DNA and RNA (QIAGEN, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

Genomic and Transcriptomic Characterization of Pre-operative Chemotherapy Response in Patients with Osteosarcoma

Yang

Huang

Yuan³

et al. 2023

Preprint

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Osteosarcoma is a heterogeneous disease with regard to its chemotherapy response and clinical outcomes. This study aims to investigate the genomic and transcriptomic characteristics related to pre-operative chemotherapy response. Samples from 25 osteosarcoma patients were collected to perform both whole exome and transcriptome sequencing. Osteosarcoma had the relatively high level of chromosomal copy number variant (CNV) burden. Chemotherapy responders showed the higher chromosomal CNV burden than non-responders (p = 0.0775). The percentage of COSMIC signature 3, associated with homologous recombination repair deficiency, was higher in responders (56%) than in non-responders (45%). Transcriptomic analysis suggested that 11 genes were significantly up-regulated in responders and 18 genes were up-regulated in non-responders. Both GSEA and KEGG enrichment analysis indicted that four pathways related to cardiomyopathy were up-regulated in responders, while neuroactive ligand−receptor interaction was up-regulated in non-responders. Finally, a random forest-based classifier was developed to classify chemotherapy response using 23 differentially expressed genes, with the area under the curve of 0.843 (95% CI, 0.654-1.000). Osteosarcoma had the heterogeneous mutational profile with frequent occurrence of CNVs. Transcriptomic analysis identified several signaling pathways associated with chemotherapy responsiveness to osteosarcoma. Transcriptomic characteristics classifier provides a potential research direction for predicting the chemotherapy response.

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Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

Cited by 10 publications

References 48 publications

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Dramatic, durable response to therapy in gBRCA2-mutated pancreas neuroendocrine carcinoma: opportunity and challenge

Genomic and Transcriptomic Characterization of Pre-operative Chemotherapy Response in Patients with Osteosarcoma

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