P04.14 Sporadic wild-type multiple meningiomas harbor distinct driver mutations

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii21-ii21
Author(s):  
T Juratli ◽  
I Prilop ◽  
F Saalfeld ◽  
M Meinhardt ◽  
G Schackert ◽  
...  
Keyword(s):  
Hot Spot ◽  
Low Frequency ◽  
Neurofibromatosis Type ◽  
Driver Mutations ◽  
Wild Type ◽  
Driver Genes ◽  
Who Grade ◽  
Genetic Changes ◽  
Histologic Subtype ◽  
Multiple Meningiomas

Abstract BACKGROUND Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding of the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM. MATERIAL AND METHODS We identified eight patients with MM (n=17) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using a next generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter. RESULTS Most of MM were WHO grade 1 (n= 14, 82.3%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 3), AKT1 (n= 3) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 7/8 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2). CONCLUSION Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.

PATH-40. SPORADIC NF2 WILD-TYPE MULTIPLE MENINGIOMAS HARBOR DISTINCT DRIVER MUTATIONS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi124-vi124
Author(s):  
Insa Prilop ◽  
Thomas Pinzer ◽  
Daniel Cahill ◽  
Priscilla Brastianos ◽  
Gabriele Schackert ◽  
...  
Keyword(s):  
Hot Spot ◽  
Low Frequency ◽  
Neurofibromatosis Type ◽  
Driver Mutations ◽  
Wild Type ◽  
Driver Genes ◽  
Who Grade ◽  
Genetic Changes ◽  
Histologic Subtype ◽  
Multiple Meningiomas

Abstract OBJECTIVE Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM. METHODS We identified nine patients with MM (n=19) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using next-generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter. RESULTS Most of MM were WHO grade 1 (n= 16, 84.2%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 4), AKT1 (n= 3), POLR2A (n=1) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 8/9 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2). CONCLUSIONS Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.

High-throughput scanning of breast tumor surgical specimens for low-level mutations

2005 ◽  
Vol 43 (8) ◽  
Author(s):  
Fengfei Wang ◽  
Manjit Kaur ◽  
Wei-Hua Liu ◽  
Penny Zhu ◽  
Jin Li ◽  
...  
Keyword(s):  
Driving Force ◽  
Low Frequency ◽  
Human Tumors ◽  
Wild Type ◽  
Potential Influence ◽  
Genetic Changes ◽  
Low Level ◽  
Multistage Carcinogenesis ◽  
Large Numbers ◽  
Potential Use

AbstractLarge numbers of mutations are postulated to occur as early events in carcinogenesis. For certain types of human tumors (mutator phenotypes) these mutations can be a driving force in generating clonogenic, causative genetic changes leading to multistage carcinogenesis. These low-level mutational events are highly significant due to their potential use as molecular markers for early identification of genomic instability that can lead to cancer and to their potential influence on the ability of tumors to resist drug treatment and/or metastasize. Detecting the presence and diversity of such genetic changes in human tumors is desirable due to their potential prognostic value. However, identification of these low-frequency genetic changes is difficult, since most mutations exist at mutant/wild-type ratios of <10

scholarly journals Management of multiple meningiomas

2018 ◽  
Vol 128 (5) ◽  
pp. 1403-1409 ◽  
Author(s):  
Georgios Tsermoulas ◽  
Mazda K. Turel ◽  
Jared T. Wilcox ◽  
David Shultz ◽  
Richard Farb ◽  
...  
Keyword(s):  
Active Treatment ◽  
Significant Proportion ◽  
Neurofibromatosis Type ◽  
Consecutive Series ◽  
Management Options ◽  
Cross Sectional ◽  
Who Grade ◽  
Delayed Treatment ◽  
Multiple Meningiomas ◽  
Treatment Data

OBJECTIVEMultiple meningiomas account for 1%–10% of meningiomas. This study describes epidemiological aspects of the disease and its management, which is more challenging than for single tumors.METHODSA consecutive series of adult patients with ≥ 2 spatially separated meningiomas was reviewed. Patients with neurofibromatosis Type 2 were excluded. The authors collected clinical, imaging, histological, and treatment data to obtain information on epidemiology, management options, and outcomes of active treatment and surveillance.RESULTSA total of 133 consecutive patients were included over 25 years, with a total of 395 synchronous and 53 metachronous meningiomas, and a median of 2 tumors per patient. One hundred six patients had sporadic disease, 26 had radiation-induced disease, and 1 had familial meningiomatosis. At presentation, half of the patients were asymptomatic. In terms of their maximum cross-sectional diameter, the tumors were small (≤ 2 cm) in 67% and large (> 4 cm) in 11% of the meningiomas. Fifty-four patients had upfront treatment, and 31 had delayed treatment after an observation period (mean 4 years). One in 4 patients had ≥ 2 meningiomas treated. Overall, 64% of patients had treatment for 142 tumors—67 with surgery and 18 with radiotherapy alone. The mean follow-up was 7 years, with 13% of treated patients receiving salvage therapy. Approximately 1 in 4 patients who underwent surgery had ≥ 1 WHO Grade II or III meningioma. Meningiomas of different histological subtypes and grades in the same patient were not uncommon.CONCLUSIONSMultiple meningiomas are often asymptomatic, probably because the majority are small and a significant proportion are induced by radiation. Approximately two-thirds of patients with multiple meningiomas require therapy, but only one-third of all meningiomas need active treatment. The authors recommend surveillance for stable and asymptomatic meningiomas and therapy for those that are symptomatic or growing.

scholarly journals Early and multiple origins of metastatic lineages within primary tumors

2016 ◽  
Vol 113 (8) ◽  
pp. 2140-2145 ◽  
Author(s):  
Zi-Ming Zhao ◽  
Bixiao Zhao ◽  
Yalai Bai ◽  
Atila Iamarino ◽  
Stephen G. Gaffney ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Development ◽  
Evolutionary Process ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Driver Genes ◽  
Genetic Changes ◽  
Primary Tumors ◽  
Multiple Origins

Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases.

scholarly journals A comparative analysis of network mutation burdens across 21 tumor types augments discovery from cancer genomes

2015 ◽  
Author(s):  
Heiko Horn ◽  
Michael S. Lawrence ◽  
Jessica Xin Hu ◽  
Elizabeth Worstell ◽  
Nina Ilic ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Cancer Biology ◽  
Low Frequency ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Sequencing Data ◽  
Driver Genes ◽  
Significance Level ◽  
Cancer Genomes ◽  
Tumor Types

Heterogeneity across cancer makes it difficult to find driver genes with intermediate (2-20%) and low frequency (<2%) mutations, and we are potentially missing entire classes of networks (or pathways) of biological and therapeutic value. Here, we quantify the extent to which cancer genes across 21 tumor types have an increased burden of mutations in their immediate gene network derived from functional genomics data. We formalize a classifier that accurately calculates the significance level of a gene’s network mutation burden (NMB) and show it can accurately predict known cancer genes and recently proposed driver genes in the majority of tested tumours. Our approach predicts 62 putative cancer genes, including 35 with clear connection to cancer and 27 genes, which point to new cancer biology. NMB identifies proportionally more (4x) low-frequency mutated genes as putative cancer genes than gene-based tests, and provides molecular clues in patients without established driver mutations. Our quantitative and comparative analysis of pan-cancer networks across 21 tumour types gives new insights into the biological and genetic architecture of cancers and enables additional discovery from existing cancer genomes. The framework we present here should become increasingly useful with more sequencing data in the future.

scholarly journals DEEPGENTM—A Novel Variant Calling Assay for Low Frequency Variants

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 507
Author(s):  
Bernd Timo Hermann ◽  
Sebastian Pfeil ◽  
Nicole Groenke ◽  
Samuel Schaible ◽  
Robert Kunze ◽  
...  
Keyword(s):  
Cancer Detection ◽  
Genetic Variants ◽  
Liquid Biopsy ◽  
Hot Spot ◽  
Treatment Success ◽  
Low Frequency ◽  
Variant Calling ◽  
Subsequent Treatment ◽  
Precision Oncology ◽  
Orthogonal Comparison

Detection of genetic variants in clinically relevant genomic hot-spot regions has become a promising application of next-generation sequencing technology in precision oncology. Effective personalized diagnostics requires the detection of variants with often very low frequencies. This can be achieved by targeted, short-read sequencing that provides high sequencing depths. However, rare genetic variants can contain crucial information for early cancer detection and subsequent treatment success, an inevitable level of background noise usually limits the accuracy of low frequency variant calling assays. To address this challenge, we developed DEEPGENTM, a variant calling assay intended for the detection of low frequency variants within liquid biopsy samples. We processed reference samples with validated mutations of known frequencies (0%–0.5%) to determine DEEPGENTM’s performance and minimal input requirements. Our findings confirm DEEPGENTM’s effectiveness in discriminating between signal and noise down to 0.09% variant allele frequency and an LOD(90) at 0.18%. A superior sensitivity was also confirmed by orthogonal comparison to a commercially available liquid biopsy-based assay for cancer detection.

scholarly journals Sporadic multiple meningiomas harbor distinct driver mutations

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Tareq A. Juratli ◽  
Insa Prilop ◽  
Felix C. Saalfeld ◽  
Sylvia Herold ◽  
Matthias Meinhardt ◽  
...  
Keyword(s):  
Driver Mutations ◽  
Multiple Meningiomas

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

scholarly journals TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Edaise M. da Silva ◽  
Pier Selenica ◽  
Mahsa Vahdatinia ◽  
Fresia Pareja ◽  
Arnaud Da Cruz Paula ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Amplification ◽  
Genetic Alterations ◽  
Wild Type ◽  
Histologic Subtype ◽  
Exact Test ◽  
Fisher's Exact Test ◽  
Fisher’S Exact Test ◽  
Hotspot Mutations ◽  
Or Gene

AbstractMetaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher’s exact test) and were mutually exclusive with TP53 mutations (p < 0.001, CoMEt). In addition, a comparative analysis of the MBCs subjected to WES or targeted cancer gene sequencing (n = 44) revealed that MBCs harboring TERT promoter hotspot mutations or gene amplification (n = 6) more frequently harbored PIK3CA than TERT wild-type MBCs (n = 38; p = 0.001; Fisher’s exact test). In conclusion, TERT somatic genetic alterations are found in a subset of TP53 wild-type MBCs with squamous/spindle differentiation, highlighting the genetic diversity of these cancers.

scholarly journals Overexpression of OsABCG48 Lowers Cadmium in Rice (Oryza sativa L.)

Agronomy ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 918
Author(s):  
Xingzhe Cai ◽  
Meng Wang ◽  
Yucong Jiang ◽  
Changhu Wang ◽  
David W. Ow
Keyword(s):  
Oryza Sativa L ◽  
Cost Effective ◽  
Health Issues ◽  
Rna Seq ◽  
Wild Type ◽  
Genetic Changes ◽  
Cd Accumulation ◽  
Lateral Root Development ◽  
Atp Binding Cassette Transporter ◽  
Cost Effective Approach

Cadmium pollution threatens food safety and security by causing health issues and reducing farmland availability. Engineering genetic changes in crop plants to lower Cd accumulation can be a cost-effective approach to address this problem. Previously, we reported that a rice line, 2B, which expresses a truncated version of OsO3L2 had reduced Cd accumulation throughout the plant, including in seed. However, downstream events caused by expression of this gene were not known. In this study, RNA-seq was used to identify differentially expressed genes between the wild type and 2B rice with or without Cd treatment, leading to the study of an ABC transporter gene, OsABCG48 (ATP-Binding Cassette transporter G family member 48). Heterologous expression of OsABCG48 conferred tolerance to Cd in Schizosaccharomyces pombe, Arabidopsis and rice. Moreover, overexpressing OsABCG48 in rice lowered root Cd accumulation that was associated with more extensive lateral root development. These data suggest that OsABCG48 might have applications for engineering low-Cd rice.

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