Prediction of Core Signaling Pathway by Using Diffusion- and Perfusion-based MRI Radiomics and Next-generation Sequencing in Isocitrate Dehydrogenase Wild-type Glioblastoma

Radiology ◽  
2020 ◽  
Vol 294 (2) ◽  
pp. 388-397 ◽  
Author(s):  
Ji Eun Park ◽  
Ho Sung Kim ◽  
Seo Young Park ◽  
Soo Jung Nam ◽  
Sung-Min Chun ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Isocitrate Dehydrogenase ◽  
Next Generation ◽  
Wild Type ◽  
Generation Sequencing

Therapeutic impact and timing of gastrointestinal malignancy genomic profiling: A single-institution experience.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 584-584
Author(s):  
Kristin Lynn Koenig ◽  
Jarred Burkart ◽  
Sameh Mikhail ◽  
Christina Sing-Ying Wu ◽  
Anne M. Noonan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Targeted Therapies ◽  
Clinical Care ◽  
Comprehensive Cancer Center ◽  
Genomic Profiling ◽  
Next Generation ◽  
Wild Type ◽  
Genomic Alterations ◽  
Generation Sequencing

584 Background: Tumor genomic profiling has become critical in the identification of targeted therapeutic options for patients (pts) with advanced malignancies. Mutational frequencies and their therapeutic importance vary among tumor types. This analysis was undertaken to characterize the landscape of genomic alterations in gastrointestinal (GI) malignancies found in a large academic institutional practice, and to determine the frequency of alteration-specific targeted therapy selection based on genomic profiling. Methods: Adult pts with GI malignancies presenting to the Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing through FoundationOne testing as part of routine clinical care. Institutional review board approval was obtained to retrospectively analyze results from FoundationOne testing performed between 2012 and 2015. Results: 265 pts with GI malignancies underwent successful genomic profiling. 1205 genomic alterations were found, with an average of 4.5 per tumor (range 0-20); 365 (30%) of these were potentially actionable and most often found in colorectal or gastroesophageal tumors. 14 pts (5.3%) had actionable alterations in MET, CDKN2A/B, FGFR2, KRAS, BRAF, or NF2 that led to enrollment in genotype-directed clinical trials or off label use of targeted therapies beyond standard of care. Pt performance status at the time of genomic alteration identification was a significant factor in precluding genotype-directed therapy. One variant of unknown significance involving FGFR2 identified at initial testing subsequently became actionable and led to pt enrollment on a clinical trial. One pt with rectal cancer was found to have a KRAS wild-type and BRAF mutant primary but KRAS mutant and BRAF wild-type liver metastasis. Conclusions: Genomic profiling of GI malignancies through next generation sequencing is feasible and can lead to genotype-directed therapy selection; however, it should be considered early in the pt’s course to optimize use of targeted therapies through clinical trials. Consideration should be given to serial tumor testing to identify emerging genomic alterations for optimal therapy selection.

Somatic POLE proofreading domain mutations by next generation sequencing to predict outcomes in stage II colorectal cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 559-559
Author(s):  
Shaobo Mo ◽  
Yaqi Li ◽  
Junjie Peng
Keyword(s):  
Next Generation Sequencing ◽  
Microsatellite Instability ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Molecular Heterogeneity ◽  
Next Generation ◽  
Wild Type ◽  
Mutation Status ◽  
Pathologic Features ◽  
Generation Sequencing

559 Background: Stage II colorectal cancers (CRC) exhibit unique molecular heterogeneity and patients with somatic POLE mutations are defined as a distinct tumor subgroup. The aim of this study was to clarify the characteristics and prognostic effect of somatic POLE proofreading domain mutations by Next Generation Sequencing in stage II CRC. Methods: Recurrent patients were 1:1 matched to patient with no recurrence for stage II CRC patients diagnosed between 2008 and 2013 in Fudan University Shanghai Cancer Center (FUSCC). All patients were pathologically confirmed and received radical resection. Microsatellite instability status and POLE mutation status were determined by NGS using ColonCore panel (Burning Rock, Guangzhou, China). Groups based on NGS-POLE mutation status were compared in terms of patient demographics and pathologic features using chi-squared tests. Survival curves were plotted using the Kaplan-Meier method. Results: In total, 245 stage II CRC patients were enrolled. POLE mutations were detected in 25 (10.2%) of 245 stage II CRC, while only 9 (3.7%) was located in proofreading domain (NGS-POLE EDM-mutations) and other 16 were found in non-proofreading domain (non-NGS-POLE mutations). Compared to cases with wild-type POLE, cases with NGS-POLE EDM-mutations were more prone to be microsatellite instability-high (MSI-H) (3 of 9 [33.3%] vs. 23 of 236 [9.7%], p = 0.024), younger at diagnosis (median 46 years vs. 62 years, p < 0.001), and more frequently with right-sided tumor location (6 of 9 [66.7%] vs. 54 of 236 [22.9%]; p = 0.003). All tumors with NGS-POLE EDM-mutations presented with a surprisingly high tumor mutation burden (TMB) (median 145.2 per Mb). Patients with NGS-POLE EDM-mutations have favorable 5-year disease-free survival (DFS) compared with those with non-NGS-POLE EDM-mutations and wild-type POLE (100% vs. 62.5% vs. 52.5%, p = 0.037). Though there is DFS difference between patients with non-NGS-POLE EDM-mutations and wild-type POLE, the difference was not statistically significant (p = 0.412). Conclusions: Stage II CRC patients with NGS-POLE EDM-mutation identify a special cancer subset with better immune environment predicting excellent outcomes.

scholarly journals Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

2019 ◽  
Vol 9 (4) ◽  
pp. e01272 ◽  
Author(s):  
Vanesa Pytel ◽  
Jordi A. Matías‐Guiu ◽  
Laura Torre‐Fuentes ◽  
Paloma Montero‐Escribano ◽  
Paolo Maietta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Next Generation ◽  
Whole Exome ◽  
Vitamin D Signaling ◽  
Generation Sequencing

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2020 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
JunZhao Cui ◽  
Zi-Qi Meng ◽  
YueLi Zou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Circulating Tumor Dna ◽  
Akt Signaling ◽  
Neoplastic Meningitis ◽  
Next Generation ◽  
Akt Signaling Pathway ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background: This study profiled the somatic genes mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). Methods: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software. Results: The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway. Conclusions: This study identified genes mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

scholarly journals SUN-032 Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yun Kyung Cho ◽  
Sang-Wook Kim
Keyword(s):  
Next Generation Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Missense Mutations ◽  
Next Generation ◽  
Wild Type ◽  
Hypogonadotrophic Hypogonadism ◽  
Digenic Inheritance ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Chd7 Gene ◽  
Generation Sequencing

Abstract Background: Normosmic congenital hypogonadotropic hypogonadism denotes Kallmann syndrome not associated with anosmia or hyposmia. Over the past few years, the availability of next-generation sequencing has started to unravel the complex molecular basis of congenital hypogonadotrophic hypogonadism including digenic or oligogenic pathogenecity in addition to classic monogenic causality (1). Clinical Case: A 22-year-old male patient was referred to the endocrine clinic in 2018 with recent -onset hyperglycemia. His weight was 82.2 kg with a height of 180 cm (BMI of 25.3 kg/m2). Physical examination revealed small testes, micropenis, and no axillary and pubic terminal hair. His smell sense was intact. His hormonal test reveals low testosterone (0.10 ng/mL) and low free testosterone (0.65 pg/mL) levels with inappropriately low gonadotrophins levels. Secretion of LH and FSH increased 2-fold after GnRH stimulation. His bone age was 13-years 6-months old, and brain magnetic resonance imaging showed the presence of olfactory bulbs, and unremarkable findings except for small size of the pituitary gland. There were no signs associated with CHARGE syndrome (coloboma ocular, heart defects, atresia or stenosis of the choanae, retardation of growth and/or development, genitourinary anomalies, and ear abnormalities). Biochemical investigation demonstrated high serum glucose level and high HbA1c (13.8%). To identify variants to cause the phenotype of the proband, we adopted trio-based whole exome sequencing (WES) and candidate gene approach. Candidate genes was listed from the orphanet (https://www.orpha.net). WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C&gt;T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G&gt;A, p.Arg80Gln, rs1799904). The missense variants were predicted to have a damaging effect on the encoded protein, by SIFT and PolyPhen-2 analyses. Genetic analyses of his family revealed that his father had the same heterozygote missense mutations of the CHD7 gene, but wild type of PCSK1. Proband’s mother had the same heterozygote missense mutations of PCSK1, but wild type of CHD7. Furthermore, the proband had homozygote missense mutation of PAX4 (c.575G&gt;A, p.Arg192His, rs2233580) known as maturity-onset diabetes of the young (MODY) 9 gene. Both parents have the same but heterozygous mutation of PAX4 p.Arg192His, and pre-diabetic range of hyperglycemia. Conclusion: This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male. Reference: (1) Maione L, et al. Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55-R80.

Comprehensive Analysis of Oncogenic Fusions in Mismatch Repair Deficient Colorectal Carcinomas by Sequential DNA and RNA Next Generation Sequencing

2021 ◽  
Author(s):  
Jing Wang ◽  
Ruiyu Li ◽  
Junjie Li ◽  
Yuting Yi ◽  
Xiaoding Liu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Mismatch Repair ◽  
Comprehensive Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Next Generation ◽  
Wild Type ◽  
College Hospital ◽  
Ras Pathway ◽  
Dna And Rna ◽  
Generation Sequencing

Abstract Background: Colorectal carcinoma (CRC) harboring oncogenic fusions has been reported to be highly enriched in mismatch repair deficient (dMMR) tumors with MLH1 hypermethylation (MLH1me+) and wild-type BRAF and RAS. In this study, dMMR CRCs were screened for oncogene fusions using sequential DNA and RNA next generation sequencing (NGS). Results: Comprehensive analysis of fusion variants, genetic profiles and clinicopathological features in fusion-positive dMMR CRCs was performed. Eighteen fusion-positive cases were identified by DNA NGS in 193 consecutive dMMR CRCs in Peking Union Medical College Hospital, all of which were MLH1me+ and BRAF/RAS wild-type. RNA NGS was sequentially conducted in 21 MLH1me+ BRAF/RAS wild-type dMMR CRCs lacking oncogenic fusions by DNA NGS, and revealed four additional fusions, increasing the proportion of fusion-positive tumors from 46% (18/39) to 56% (22/39) in MLH1me+ BRAF/RAS wild-type dMMR cases. All 22 fusions were found to involve RTK-RAS pathway. Most fusions affected targetable receptor tyrosine kinases, including NTRK1(9/22, 41%), NTRK3(5/22, 23%), ALK(3/22, 14%), RET(2/22, 9%) and MET(1/22, 5%), whilst only two fusions affected mitogen-activated protein kinase cascade components BRAF and MAPK1, respectively. RNF43 was identified as the most frequently mutated genes, followed by APC, TGFBR2, ATM, BRCA2 and FBXW7. The vast majority (19/22, 86%) displayed alterations in key WNT pathway components, whereas none harbored additional mutations in RTK-RAS pathway. In addition, fusion-positive tumors were typically diagnosed in elder patients and predominantly right-sided, and showed a significantly higher preponderance of hepatic flexure localization (P<0.001) and poor differentiation (P=0.019), compared to fusion-negative MLH1me+ CRCs. Conclusions: We proved that sequential DNA and RNA NGS was highly effective for fusion detection in dMMR CRCs, and proposed an optimized practical fusion screening strategy. We further revealed that dMMR CRCs harboring oncogenic fusion was a genetically and clinicopathologically distinctive subgroup, and justified more precise molecular subtyping for personalized therapy.

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