Treatment of neuroendocrine carcinoma of the cervix with a PARP inhibitor based on next generation sequencing.
Ontology highlight
ABSTRACT:
SUBMITTER: Rose PG
PROVIDER: S-EPMC6804835 | biostudies-other | 2019 Nov
REPOSITORIES: biostudies-other
Publications
Treatment of neuroendocrine carcinoma of the cervix with a PARP inhibitor based on next generation sequencing.
Gynecologic oncology reports 20190912
•This case reports the treatment of neuroendocrine carcinoma of the cervix with a PARPi based on NGS.•NGS reports have demonstrated somatic mutations BRCA in neuroendocrine carcinoma of the cervix.•The use of a PARPi in neuroendocrine carcinoma of the cervix has not been previously reported. ...[more]
Similar Datasets
Project description:Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.
| S-EPMC5943084 | biostudies-literature
Project description:Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that span from well-differentiated neuroendocrine tumors (NETs) to highly aggressive neoplasms classified as neuroendocrine carcinomas (NECs). The genomic landscape of NENs has not been well studied. The aim of this study is to confirm the feasibility of next generation sequencing (NGS) testing circulating tumor DNA (ctDNA) in patients with NENs and characterize common alterations in the genomic landscape. Results: Of the 320 NEN patients, 182 (57%) were male with a median age of 63 years (range: 8-93) years. Tumor type included pancreatic NET (N = 165, 52%), gastrointestinal NEC (N = 52, 16%), large cell lung NEC (N = 21, 7%), nasopharyngeal NEC (N = 16, 5%) and NEC/NET not otherwise specified (N = 64, 20%). ctDNA NGS testing was performed on 338 plasma samples; 14 patients had testing performed twice and 2 patients had testing performed three times. Genomic alterations were defined in 280 (87.5%) samples with a total of 1,012 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Of the 280 samples with alterations, TP53 associated genes were most commonly altered (N = 145, 52%), followed by KRAS (N = 61, 22%), EGFR (N = 33, 12%), PIK3CA (N = 30, 11%), BRAF (N = 28, 10%), MYC (N = 28, 10%), CCNE1 (N = 28, 10%), CDK6 (N = 22, 8%), RB1 (N = 19, 7%), NF1 (N = 19, 7%), MET (N = 19, 7%), FGFR1 (N = 19, 7%), APC (N = 19, 7%), ERBB2 (N = 16, 6%) and PTEN (N = 14, 5%). Conclusions: Evaluation of ctDNA was feasible among individuals with NEN. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in NEN patients. Patients and Methods: Molecular alterations in 338 plasma samples from 320 patients with NEN were evaluated using clinical-grade NGS of ctDNA (Guardant360®) across multiple institutions. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.
| S-EPMC7233805 | biostudies-literature
Project description:NGPS is a method for de-novo, full-length protein sequencing in high throughput. The method is based on cleavage of the protein at semi-random sites by microwave-assisted acid hydrolysis (MAAH), enrichment of LC-MS/MS amenable peptides from the hydrolysate by solid-phase-extraction, LC-MS/MS analysis, de-novo long peptide tag sequencing of resulting peptides and assembly of peptide tags into consensus contigs.
2017-04-03 | PXD003804 | Pride
Project description:PurposePulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.Experimental designLCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242).ResultsCommonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation.ConclusionsLCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618-29. ©2016 AACR.
| S-EPMC4995776 | biostudies-literature
Project description:BackgroundPrimary small cell neuroendocrine carcinomas of the cervix and endometrium are rare gynecological malignancies with limited treatment options. This study aimed to improve the understanding of the carcinogenesis process and identify potential therapeutic targets for these two tumor types by constructing the mutational landscape at the whole exome level.MethodsPrimary tumor tissues and their matched blood samples were obtained from 10 patients with small cell cervical neuroendocrine carcinoma (NECC) and five patients with small cell endometrial neuroendocrine carcinoma (NECE). Whole exome sequencing was performed to construct the somatic mutation profiles. Mutational signature and recurrent mutated gene analysis were used to identify tumor subtypes and common carcinogenesis processes.ResultsBased on the burden of different mutational signatures, the NECCs in this work can be divided into two subtypes, including the mismatch repair deficiency like (dMMR-like) type (4/10) and the high spontaneous deamination type (6/10). Components of the PI3K/AKT signaling and RAS signaling were exclusively mutated in these two subtypes, respectively. The integration of human papillomavirus made a limited contribution to tumorigenesis in NECC (20%). The dysfunction of the mismatch repair system and microsatellite instability are the major features of NECE. PI3K/AKT, JAK/STAT signaling, and chromatin remodeling activity were the common mutated pathways in NECE. PIK3CA, WNK2, and KMT2B underwent mutations in both the dMMR-like subtype of NECC (50% - 75%) and in NECE (60% - 80%) specimens, while exhibiting infrequent mutational occurrences in publicly available data pertaining to neuroendocrine carcinomas of the lung or bladder (< 10%).ConclusionWe identified the two subtypes of NECC with distinct mutated pathways and potential therapy targets. The dMMR-like type NECC and NECE may share a similar carcinogenesis process that include dysfunction of PI3K/AKT signaling, cell cycle, antiapoptotic processes, and chromatin remodeling activity.
| S-EPMC10618670 | biostudies-literature
Project description:Pancreatic neuroendocrine tumor (PNET), a heterogenous type of neoplasm with limited treatment options, is relatively rare and to date, the genetic background has remained to be fully elucidated. The present study aimed to determine the mutational landscape of PNET with and without liver metastasis, as well as its clinical application value for treatment. Fresh tumor tissues were collected from 14 patients with PNET following surgery, 4 of whom had developed liver metastasis. Subsequently, targeted next-generation sequencing of 612 cancer-associated genes and comprehensive analysis were performed on the tumor tissues. The results identified 63 somatic mutations in 53 genes in the 14 patients with PNET, amongst which menin 1 was identified as the most recurrently mutated gene. The analysis also identified several novel recurrently mutated genes, including adrenoceptor alpha 2B, ARVCF delta catenin family member, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase and neuregulin 1. Among the 53 mutated genes, 11 were enriched in the PI3K/AKT signaling pathway (adjusted P=7.12x10-5). In addition, 4 patients with PNET with liver metastasis had distinctly different mutational profiles compared with those without liver metastasis; 13 genes were discovered to be exclusively mutated in the liver metastasis group of the patients with PNET, including ATRX chromatin remodeler, thioredoxin reductase 2, anus kinase 3, ARVCF delta catenin family member, integrin subunit alpha V and RAD50 double strand break repair protein. In addition, two potentially actionable alterations in BRCA2 DNA repair-associated (p.Q548Q) and neurofibromin 1 (p.Q1188X) were identified using the OncoKB database. In conclusion, the present study generated a comprehensive mutational profile of 14 patients with PNET and further described the features of patients with liver metastasis, which highlights potential targets for drug development of PNET.
| S-EPMC7967861 | biostudies-literature
Project description:Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of target therapy has not been established in these tumors. This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, and explore the possibility of target therapy using next-generation sequencing. In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. The case harboring EGFR mutation showed response to EGFR-tyrosine kinase inhibitor. However, there are no clinicopathological features associated with therapeutically targetable cases. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types. In conclusion, although patients with SCLC and LCNEC may benefit from target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.
| S-EPMC5752493 | biostudies-literature
Project description:The purpose of this study is to determine the proportion of patients diagnosed with Lynch syndrome in colorectal cancer patients with the loss of staining by immunohistochemistry (IHC) of any of the mismatch repair (MMR) proteins. Besides, this study aims to test the specificity and the sensitivity of detecting microsatellite instability (MSI) by next-generation sequencing, and to find out the consistency between IHC and MSI in colorectal cancer patients in China. In addition, researchers want to analyze the clinical characteristics and germline mutation of Lynch syndrome in Chinese population.
| 2236244 | ecrin-mdr-crc
Project description:Whole genome sequences are ideally suited for deriving evolutionary relationship among organisms. With the availability of Next Generation sequencing (NGS) datasets in an unprecedented scale, it will be highly desirable if phylogenetic analysis can be carried out using short read NGS data. We described here an anchor based approach NexABP for phylogenetic construction of closely related strains/isolates from NGS data. This approach can be used even in the absence of a fully assembled reference genome and works by reducing the complexity of the datasets without compromising results. NexABP was used for constructing phylogeny of different strains of some of the common pathogens, such as Mycobacterium tuberculosis, Vibrio cholera and Escherichia coli. In addition to classification into distinct lineages, NexABP could resolve inner branches and also allow statistical testing using bootstrap analysis. We believe that there are some clear advantages of using NexABP based phylogenetic analysis as compared to other methods.
| S-EPMC3769656 | biostudies-literature
Project description:Name of the disease (synonyms) See Table 1, Column 1-"Name of disease" and Column 2-"Alternative names". OMIM# of the disease See Table 1, Column 3-"OMIM# of the disease". Name of the analysed genes or DNA/chromosome segments and OMIM# of the gene(s) Core genes (irrespective of being tested by Sanger sequencing or next-generation sequencing): See Table 1, Column 4-"Cytogenetic location", Column 5-"Associated gene(s)" and Column 6-"OMIM# of associated gene(s)". Additional genes (if tested by next-generation sequencing, including Whole exome/genome sequencing and panel sequencing): See Table 2, Column 1-"Gene", Column 2-"Alternative names", Column 3-"OMIM# of gene" and Column 4-"Cytogenetic location". Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the gene(s) in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
| S-EPMC7029013 | biostudies-literature