Peritoneal mesotheliomas characterized by less cell-cycle alterations and more TRAF7 alterations than malignant pleural mesotheliomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9059-9059
Author(s):  
Michael Offin ◽  
Jacklynn V. Egger ◽  
Andrea Cercek ◽  
Garrett Michael Nash ◽  
Marc Ladanyi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genetic Alterations ◽  
Time Interval ◽  
Clinicopathologic Characteristics ◽  
Targeted Next Generation Sequencing ◽  
Molecular Alterations ◽  
Pathogenic Variants ◽  
Mutation Burden ◽  
Well Differentiated ◽  
Next Generation Sequencing Ngs

9059 Background: While peritoneal mesotheliomas (PM) are clinically distinct from malignant pleural mesotheliomas (MPM) it is unknown if genetic alterations reflect these differences. Here we report the molecular alterations and clinicopathologic characteristics of a prospectively collected PM cohort as compared to MPM. Methods: Patients with PM (n = 59) and targeted next generation sequencing (NGS; MSK-IMPACT) from January 2014 to January 2019 were assessed and followed through February 2020. Germline variants were analyzed in consented patients. NGS was compared to patients with MPM (n = 194) assessed in the same time interval. Results: Median age at diagnosis was 61 (range: 20-77), 56% were women (n = 33), and 92% had epithelioid histology (n = 54). 66% had ascites (n = 39) and 24% developed extra-abdominal metastases (n = 14; including lung, pleura, and mediastinum). 68% (n = 40) underwent surgical debulking and 80% (n = 47) had infusional therapy (median lines: 3) including platinum/pemetrexed (n = 38), EPIC (n = 22), HIPEC (n = 15), and immunotherapy (n = 16). The median overall survival (OS) from diagnosis was 5.4 years (median follow up 3.5 years). The median tumor mutation burden (TMB) was 1.8 mut/Mb (range: 0-14.9) in PM vs 2.0 mut/Mb (range: 0-31.5) in MPM (p = 0.049). More patients with PM had TRAF7 alterations than in MPM (5/59 vs 3/194; p = 0.02) while fewer had CDKN2A/ CDKN2B (4 vs 55; p = 0.0004). All patients with TRAF7 altered PM had well-differentiated papillary epithelioid histology. There was no difference in the prevalence of other common alterations such as BAP1 (32 vs 98; p = 0.66), NF2 (12 vs 55, p = 0.24), SETD2 (11 vs 24; p = 0.28), and TP53 (9 vs 28; p = 0.84) in PM vs MPM respectively. Patients with BAP1-altered PM had shorter OS (4.6 vs 9.8 years; HR 2.6, 95% CI 1.1-6.4; p = 0.04) while TRAF7-altered PM had improved OS (not reached vs 4.8 years; HR 0.3, 95% CI 0.1-0.9; p = 0.04) compared to wild type. 13% (4/30) of patients with PM had pathogenic variants on germline NGS ( POT1 I78T, MUTYH R109Y, BAP1 E402*, APC I1037K). Conclusions: NGS confirms the distinct biology of PM compared to MPM. Specifically, the former shows fewer cell cycle ( CDKN2) alterations compared to MPM. In contrast to MPM, BAP1 alteration was associated with shorter survival. As previously described, we found enrichment of TRAF7 in well differentiated papillary epithelioid PM associated with improved survival but notably some TRAF7 alterations were identified in poorly differentiated MPM. Consistent with other reports, the prevalence of germline alterations was 13%.

scholarly journals HGG-21. GERMLINE MUTATIONS IN MSH2 GENE IN PEDIATRIC PATIENTS WITH CONGENITAL AND SPORADIC GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii348-iii348
Author(s):  
Maria Ejmont ◽  
Małgorzata Rydzanicz ◽  
Wiesława Grajkowska ◽  
Marta Perek-Polnik ◽  
Agnieszka Sowińska ◽  
...  
Keyword(s):  
Germline Mutations ◽  
Response To Therapy ◽  
Msh2 Gene ◽  
Illumina Hiseq ◽  
Adult Type ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
New Treatment ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data

Abstract INTRODUCTION Glioblastoma (GBM) remains one of the biggest therapeutic challenges in neuro-oncology. In spite of multimodal treatment approaches the prognosis of GBM is extremely poor, median survival is estimated about 12–16 months. Although GBM is one of the most common and malignant primary brain tumors, pediatric glioblastoma, including congenital is a very rare tumor, with an incidence of about 1.1–3.4 per million live births. Moreover, the mode of presentation, behavior, response to therapy and molecular background of pediatric glioblastomas differs from adult type of GBM. Until now, about ten patients with congenital glioblastoma have been described and in none of them germline markers were examined. Here we report two patients with GBM, one with congenital tumor with germline mutations in MSH2 gene. METHODS Targeted Next-Generation Sequencing (NGS) of the probands DNA extracted from leucocytes was performed using the TruSight One sequencing panel on an Illumina HiSeq 1500. Applied gene panel investigated the coding sequence and splice sites of 4813 genes associated with known disease phenotypes. The NGS data were analyzed using an in-house procedure. Identified variants were validated by Sanger sequencing. RESULTS NGS analysis of patients constitutional DNA revealed know, pathogenic variants c.940C>T and c.942 + 3A>T in MSH2 gene (NM_000251.3) associated with MMR-dependent hereditary cancer syndromes. CONCLUSION Molecular analysis are heavily needed for better understanding of pediatric GBM etiology and new treatment modality implementation. Identification of this oncogenic driver may provide insight into the pathogenesis of GBM, including congenital cases. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064 and 2016/21/B/NZ2/01785).

scholarly journals Genetic Variants Detected Using Cell-Free DNA from Blood and Tumor Samples in Patients with Inflammatory Breast Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1290
Author(s):  
Jennifer S. Winn ◽  
Zachary Hasse ◽  
Michael Slifker ◽  
Jianming Pei ◽  
Sebastian M. Arisi-Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Triple Negative ◽  
Genetic Profile ◽  
Cell Free Dna ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Free Dna ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

We studied genomic alterations in 19 inflammatory breast cancer (IBC) patients with advanced disease using samples of tissue and paired blood serum or plasma (cell-free DNA, cfDNA) by targeted next generation sequencing (NGS). At diagnosis, the disease was triple negative (TN) in eleven patients (57.8%), ER+ Her2- IBC in six patients (31.6%), ER+ Her2+ IBC in one patient (5.3%), and ER- Her2+ IBC in one other patient (5.3%). Pathogenic or likely pathogenic variants were frequently detected in TP53 (47.3%), PMS2 (26.3%), MRE11 (26.3%), RB1 (10.5%), BRCA1 (10.5%), PTEN (10.5%) and AR (10.5%); other affected genes included PMS1, KMT2C, BRCA2, PALB2, MUTYH, MEN1, MSH2, CHEK2, NCOR1, PIK3CA, ESR1 and MAP2K4. In 15 of the 19 patients in which tissue and paired blood were collected at the same time point, 80% of the variants detected in tissue were also detected in the paired cfDNA. Higher concordance between tissue and cfDNA was found for variants with higher allele fraction in tissue (AFtissue ≥ 5%). Furthermore, 86% of the variants detected in cfDNA were also detected in paired tissue. Our study suggests that the genetic profile measured in blood cfDNA is complementary to that of tumor tissue in IBC patients.

scholarly journals Characterization of novel genetic alterations in salivary gland secretory carcinoma

2019 ◽  
Vol 33 (4) ◽  
pp. 541-550 ◽  
Author(s):  
Kiyong Na ◽  
Juan C. Hernandez-Prera ◽  
Jae-Yol Lim ◽  
Ha Young Woo ◽  
Sun Och Yoon
Keyword(s):  
Salivary Gland ◽  
Fusion Gene ◽  
Salivary Gland Tumor ◽  
Treatment Strategies ◽  
Chromosomal Translocation ◽  
Genetic Alterations ◽  
Secretory Carcinoma ◽  
Clinicopathologic Characteristics ◽  
Pathogenic Variants ◽  
Tumorigenesis And Progression

AbstractSecretory carcinoma is a salivary gland tumor with a characteristic chromosomal translocation that results in an ETV6-NTRK3 fusion gene. Secretory carcinoma shows relatively frequent rates of lymph-node metastasis and tumor recurrence and has a characteristic histology. Except for the ETV6 translocation, genomic alterations in secretory carcinoma have not been reported. In the present study, we characterized the novel recurrent genetic mutations of secretory carcinoma. On the basis of histology, immunohistochemistry, and ETV6 gene break-apart fluorescence in situ hybridization assays, 22 tumors were classified as secretory carcinomas (19 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) and their clinicopathologic characteristics were reviewed. Targeted deep sequencing analyses were performed on 20 secretory carcinomas (17 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) to investigate their genetic alterations. The A16V (C→T) mutation in PRSS1, which encodes a cationic trypsinogen and has a mutation associated with hereditary pancreatitis and pancreatic adenocarcinoma, was observed in 40% (8/20) (7/17 of ETV6 translocation-positive and 1/3 of ETV6 translocation-negative secretory carcinomas). Pathogenic variants of MLH1, MUTYH, and STK11 were also identified. Variants of uncertain significance included mutations in KMT5A. These novel characteristic genetic alterations may advance current understandings of secretory carcinoma tumorigenesis and progression, leading to improved diagnoses and treatment strategies.

scholarly journals Molecular profiling of congenital glioblastoma using a next-generation sequencing panel

2021 ◽  
Author(s):  
Débora Cabral de Carvalho Corrêa ◽  
Francine Tesser-Gamba ◽  
Nasjla da Silva ◽  
Andrea Capellano ◽  
Maria Teresa Alves ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Next Generation ◽  
Congenital Brain Tumor ◽  
Molecular Alterations ◽  
Pathogenic Variants ◽  
Pediatric Neoplasms ◽  
Tumor Entity ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background Congenital GBM (cGBM), presenting prenatally or within the first months of life, is among the rarest type of congenital brain tumor, with approximately 120 cases reported. Due to its infrequent occurrence, few studies have focused on the molecular and genetic aspects of this tumor, and the mutational events involved in the pathogenesis and progression of cGBM still remains poorly understood. This study aimed to investigate molecular alterations, with a potential prognostic marker and therapeutic target in cGBM using the next-generation sequencing (NGS) strategy. Methods We selected seven tumor samples from patients diagnosed with cGBM and treated at Pediatric Oncology Institute-GRAACC/UNIFESP. NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay panel, from ThermoFisher Scientific, designed specifically for pediatric neoplasms. Results Of all seven patients analyzed, three patients exhibited tumors with genetic variants, which include two pathogenic variants in NF1 and SUZ12 genes that have not been reported in cGBM yet, an increase in the number of copies of ALK gene, and two gene fusions, PPP1CB-ALK and TPM3-NTRK1. Also, none of the cases showed variants in H3F3A, TP53 and ATRX genes, alterations which are frequently seen in pediatric and adolescent GBM. Conclusions Our results suggest that cGBM may comprise a unique tumor entity and alterations in ALK and NTRK genes provide a potential target for therapy. Therefore, identification of genetic variants in cGBM is highly relevant in order to define prognosis and therapeutic strategies.

scholarly journals Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1364 ◽  
Author(s):  
Diego Carbonell ◽  
Julia Suárez-González ◽  
María Chicano ◽  
Cristina Andrés-Zayas ◽  
Juan Carlos Triviño ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variants ◽  
Genetic Alterations ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Myeloid Neoplasms ◽  
Diagnostic Samples ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient.

Clinico-pathological and genomic features of NRAS- or HRAS-mutated non-small cell lung cancer (NSCLC) identified in large-scale genomic screening project (LC-SCRUM-Asia).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9054-9054
Author(s):  
Yutaro Tamiya ◽  
Shingo Matsumoto ◽  
Takaya Ikeda ◽  
Kiyotaka Yoh ◽  
Terufumi Kato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Large Scale ◽  
Patient Characteristics ◽  
Kras Mutations ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genomic Screening ◽  
Frequent Variant ◽  
Nsclc Patients ◽  
Next Generation Sequencing Ngs

9054 Background: RAS ( KRAS, NRAS and HRAS) is a targetable oncogene family in several cancers, including NSCLC, and the clinical development of various RAS-targeted therapies are ongoing. However, the clinical relevance of uncommon RAS mutations, such as NRAS and HRAS mutations, in NSCLC patients (pts) remains unclear. Methods: In a large-scale genomic screening project (LC-SCRUM-Asia), we have prospectively analyzed lung cancer pts for genomic alterations by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay. We evaluated clinico-pathological and genomic characteristics in NRAS- or HRAS-mutated NSCLC pts comparing with those in KRAS-mutated pts based on the LC-SCRUM-Asia database. Results: Since March 2015 to December 2020, 9131 NSCLC pts were enrolled in the LC-SCRUM-Asia, and 8374 of them (92%) were successfully analyzed by NGS. The RAS mutation frequencies were 1134 KRAS (14%), 50 NRAS (0.6%), and 15 HRAS (0.2%). The most frequent variant of NRAS and HRAS mutations was Q61X (78%) and G13X (80%), respectively, whereas that of KRAS was G12X (84%). Patient characteristics were summarized in Table. Male was significantly frequent in NRAS- than in KRAS-group (p=0.03), and smokers were frequent in all the three groups (overall, 79%). The majority of NRAS (70%) and KRAS mutations (89%) were detected in adenocarcinoma (Ad), whereas 60% of HRAS mutations were in squamous cell carcinoma (Sq). Tumor mutation burden (TMB) was significantly higher in NRAS-mutated tumors than in KRAS-mutated tumors (p=0.03). Concomitant TP53 mutations were significantly frequent in HRAS-mutated pts than in KRAS-mutated pts (53% vs. 30%, p=0.05), and STK11 mutations were also tended to be frequent in HRAS-mutated pts than in KRAS-mutated pts (20 vs. 7%, p=0.10). Therapeutic efficacy of PD-1/PD-L1 inhibitors was not different among the three groups in the current follow-up data, but HRAS-mutated tumors did not respond to PD-1/PD-L1 inhibitors (response rate, 0%; median PFS, 1.6 months). Conclusions: NRAS- or HRAS-mutated NSCLCs were different from KRAS-mutated NSCLCs in clinico-pathological and genomic profiles. In particular, the immunotherapies were not effective for HRAS-mutated NSCLCs.[Table: see text]

Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY)

2018 ◽  
Vol 31 (12) ◽  
pp. 1295-1304 ◽  
Author(s):  
Taha R. Özdemir ◽  
Özgür Kırbıyık ◽  
Bumin N. Dündar ◽  
Ayhan Abacı ◽  
Özge Ö. Kaya ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Maturity Onset Diabetes ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Onset Diabetes ◽  
Frequent Mutations ◽  
Standards And Guidelines ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

scholarly journals Deciphering Genetic Alterations of Taiwanese Pancreatic Adenocarcinoma With Targeted Sequencing

2021 ◽  
Author(s):  
Chi-Cheng Huang ◽  
Chih-Yi Liu ◽  
Chi-Jung Huang ◽  
Yao-Chun Hsu ◽  
Heng-Hui Lien ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Hot Spot ◽  
Genetic Alterations ◽  
Pathogenic Variants ◽  
Metastatic Lesions ◽  
Fresh Frozen ◽  
Next Generation Sequencing Ngs ◽  
Targeted Medicine

Abstract Purpose Pancreatic adenocarcinoma (PAC) is the 8th leading cause of cancer-related death in Taiwan, and its incidence is increasing. The development of PAC involves successive accumulation of multiple genetic alternations. Understanding the molecular pathogenesis and heterogeneity of PAC may facilitate personalized treatment for PAC and identify therapeutic agents.Materials and Methods We performed next-generation sequencing (NGS) with targeted panels to explore the molecular changes underlying PAC in Taiwan. The Ion Torrent Oncomine Comprehensive Panel (OCP) was used for PAC metastatic lesions, and more PAC samples were sequenced with the Ion AmpliSeq Cancer Hot Spot (CHP) v2 panel.ResultsFive fresh-frozen paraffin-embedded (FFPE) specimens were successfully assayed with the OCP, and KRAS was the most prevalent alternation, which might contraindicate the use of anti-EGFR therapy. One PAC patient harbored a FGFR2 p.C382R mutation, who might derive benefit from FGFR tyrosine kinase inhibitor. Additional 38 samples assayed with CHP v2 showed 113 hotspot variants, corresponding to 54 COSMID IDs. The most frequently mutated genes were TP53, KRAS, HRAS, and PDGFRA, (29, 23, 14, 10 hotspot variants), impacting 11, 23, 14, and 10 PAC patients. Highly pathogenic variants including COSM22413 (PDGFRA, FATHMM predicted score: 0.88), COSM520, COSM521, COSM518 (KRAS, FATHMM predicted score: 0.98) were reported.ConclusionsBy using NGS with targeted panel, somatic mutations with therapeutic potential were identified. The combination of clinical and genetic information is useful for decision making and precise selection of targeted medicine.

scholarly journals Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4816
Author(s):  
Andrea P. Espejo-Freire ◽  
Andrew Elliott ◽  
Andrew Rosenberg ◽  
Philippos Apolinario Costa ◽  
Priscila Barreto-Coelho ◽  
...  
Keyword(s):  
Head And Neck ◽  
Genetic Alterations ◽  
Design And Optimization ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Mutation Burden ◽  
Biomarker Analysis ◽  
Next Generation Sequencing Ngs ◽  
Response Biomarkers ◽  
Ngs Data

We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.

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