PATH-34. MOLECULAR AND CLINICAL HETEROGENEITY WITHIN SPINAL EPENDYMOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi122-vi122
Author(s):  
Sina Al-Kershi ◽  
Catena Kresbach ◽  
Lara Pohl ◽  
Mario M Dorostkar ◽  
Abigail K Suwala ◽  
...  
Keyword(s):  
Molecular Data ◽  
Genetic Alterations ◽  
Histological Evaluation ◽  
Molecular Profile ◽  
Clinical Heterogeneity ◽  
Intramedullary Tumors ◽  
Small Series ◽  
Number Variation ◽  
Tumor Types ◽  
Transcriptomic Changes

Abstract Ependymomas encompass multiple clinically relevant tumor types based on localization, genetic alterations, as well as epigenetic and transcriptomic profiles. Distinct global DNA methylation signatures serve as the most powerful diagnostic tool to distinguish these types. The methylation class of spinal ependymomas (SP-EPN) comprises mostly WHO°II tumors with slow progression and incomplete surgical resection rate. Molecular data of SP-EPN are scarce and clear treatment recommendations are lacking although these neoplasms represent the most common intramedullary tumors in children and adults. The only known recurrent genetic events in SP-EPN are the loss of chromosome 22q and mutations of the NF2 gene. However, data on the frequency of NF2 mutations range from 16 % to 71 % and originate from small series that lack epigenetic or transcriptomic characterization. Furthermore, it remains unclear whether SP-EPN with germline or sporadic NF2 mutation or with NF2 wild type status display clinical and other molecular differences. Finally, the underlying genomic and transcriptomic changes of SP-EPN without NF2 mutations are fully unclear. To provide a comprehensive molecular profile of SP-EPN, we integrated genomic and epigenetic analyses and clinical data of 170 cases. Unsupervised hierarchical clustering and t-SNE analyses of methylation data revealed three distinct molecular SP-EPN subtypes. Of the three subtypes, only subtype 1 and subtype 2 contained tumors with NF2 mutations, either as previously known germline mutations or as sporadic mutations without evidence for a syndromic disease (p< 0.0001). Besides the lack of NF2 mutations, subtype 3 tumors showed a higher frequency of MGMT promoter methylation (p= 0.0015) and occurred in significantly older patients compared to tumors of subtypes 1 and 2 (p= 0.0038). Further investigations such as whole-exome sequencing, copy number variation profiling, gene expression analysis, and histological evaluation are ongoing and will add to the picture of molecular and clinical heterogeneity within SP-EPN.

scholarly journals Divergent molecular profile of PIK3CA gene in arsenic-associated bladder carcinoma

Mutagenesis ◽  
2021 ◽  
Author(s):  
Mukta Basu ◽  
Balarko Chakraborty ◽  
Sabnam Ghosh ◽  
Sudip Samadder ◽  
Sankhadeep Dutta ◽  
...  
Keyword(s):  
Bladder Carcinoma ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Molecular Profile ◽  
Strong Impact ◽  
Pik3ca Gene ◽  
Recurrent Mutations ◽  
Number Variation ◽  
Exon 9 ◽  
Impact Of Arsenic

Abstract The activation of PIK3CA in bladder carcinoma (BlCa) with its recurrent mutations in exon 9 and 20 were well reported. But the association of arsenic on the activation of the pathway is not well elucidated. Therefore, we aimed to analyse the effect of arsenic on the genetic (copy number variation/mutation) and expression profiles of PIK3CA in primary BlCa samples. Infrequent amplification (16%) of the PIK3CA locus was observed, with higher frequency among the arsenic-high (AsH) than arsenic-low (AsL) samples. Frequent (54%) tumour-specific mutations in exon 9 and 20 of PIK3CA were observed in the BlCa samples with prevalent (47%) C>T transition mutations. Exon 9 and 20 harboured 48% and 73% of the total mutations, respectively, with 37% in E542K/E545K and 25% of the mutation in H1047Y/R. Though mutation frequency in AsH and AsL was found to be comparable, we observed some arsenic-specific mutation at c.1633G>A, c.1634A>C (E545K) and c.2985C>T and c.3130G>T mutations, as well as prevalent transverse mutations of A>C and G>T in AsH group. Furthermore, 73% of the BlCa samples showed overexpression (mRNA/protein) of PIK3CA with genetic alterations (amplification/mutation), significantly (P = 0.01) higher in AsH group. However, 36% of the samples showed overexpressed PIK3CA, independent of mutation or amplification, signifying a transcriptional upregulation of PIK3CA gene. Therefore, the expression status of NFκB, a transcription factor of PIK3CA, was assessed and found to be significantly correlated with the overexpression of PIK3CA (mRNA/protein) in AsH group. Similarly, the expression pattern of pAKT1 (Thr 308) was also found to be significantly correlated with PIK3CA overexpression. Finally, AsH patients with the overexpression of PIK3CA or NFκB had the worst overall survival, signifying a strong impact of arsenic on this pathway and outcome of the patients. Thus, our study showed that the arsenic-associated differential molecular profile of PIK3CA/AKT1/NFkB in BlCa has an important role in the molecular pathogenesis of the disease.

Receptor tyrosine kinase gene amplification is predictive of intraoperative seizures during glioma resection with functional mapping

2020 ◽  
Vol 132 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
Bryan D. Choi ◽  
Daniel K. Lee ◽  
Jimmy C. Yang ◽  
Caroline M. Ayinon ◽  
Christine K. Lee ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Univariate Analysis ◽  
Tumor Resection ◽  
Tumor Grade ◽  
Molecular Data ◽  
Genetic Alterations ◽  
Functional Mapping ◽  
Chi Square ◽  
Kinase Gene ◽  
Glioma Resection

OBJECTIVEIntraoperative seizures during craniotomy with functional mapping is a common complication that impedes optimal tumor resection and results in significant morbidity. The relationship between genetic mutations in gliomas and the incidence of intraoperative seizures has not been well characterized. Here, the authors performed a retrospective study of patients treated at their institution over the last 12 years to determine whether molecular data can be used to predict the incidence of this complication.METHODSThe authors queried their institutional database for patients with brain tumors who underwent resection with intraoperative functional mapping between 2005 and 2017. Basic clinicopathological characteristics, including the status of the following genes, were recorded: IDH1/2, PIK3CA, BRAF, KRAS, AKT1, EGFR, PDGFRA, MET, MGMT, and 1p/19q. Relationships between gene alterations and intraoperative seizures were evaluated using chi-square and two-sample t-test univariate analysis. When considering multiple predictive factors, a logistic multivariate approach was taken.RESULTSOverall, 416 patients met criteria for inclusion; of these patients, 98 (24%) experienced an intraoperative seizure. Patients with a history of preoperative seizure and those treated with antiepileptic drugs prior to surgery were less likely to have intraoperative seizures (history: OR 0.61 [95% CI 0.38–0.96], chi-square = 4.65, p = 0.03; AED load: OR 0.46 [95% CI 0.26–0.80], chi-square = 7.64, p = 0.01). In a univariate analysis of genetic markers, amplification of genes encoding receptor tyrosine kinases (RTKs) was specifically identified as a positive predictor of seizures (OR 5.47 [95% CI 1.22–24.47], chi-square = 5.98, p = 0.01). In multivariate analyses considering RTK status, AED use, and either 2007 WHO tumor grade or modern 2016 WHO tumor groups, the authors found that amplification of the RTK proto-oncogene, MET, was most predictive of intraoperative seizure (p < 0.05).CONCLUSIONSThis study describes a previously unreported association between genetic alterations in RTKs and the occurrence of intraoperative seizures during glioma resection with functional mapping. Future models estimating intraoperative seizure risk may be enhanced by inclusion of genetic criteria.

scholarly journals Copy Number Variation and Rearrangements Assessment in Cancer: Comparison of Droplet Digital PCR with the Current Approaches

2021 ◽  
Vol 22 (9) ◽  
pp. 4732
Author(s):  
Vincenza Ylenia Cusenza ◽  
Alessandra Bisagni ◽  
Monia Rinaldini ◽  
Chiara Cattani ◽  
Raffaele Frazzi
Keyword(s):  
Digital Pcr ◽  
Genetic Alterations ◽  
Droplet Digital Pcr ◽  
Molecular Oncology ◽  
Therapeutic Choice ◽  
Golden Standard ◽  
Number Variation ◽  
Key Aspects

The cytogenetic and molecular assessment of deletions, amplifications and rearrangements are key aspects in the diagnosis and therapy of cancer. Not only the initial evaluation and classification of the disease, but also the follow-up of the tumor rely on these laboratory approaches. The therapeutic choice can be guided by the results of the laboratory testing. Genetic deletions and/or amplifications directly affect the susceptibility or the resistance to specific therapies. In an era of personalized medicine, the correct and reliable molecular characterization of the disease, also during the therapeutic path, acquires a pivotal role. Molecular assays like multiplex ligation-dependent probe amplification and droplet digital PCR represent exceptional tools for a sensitive and reliable detection of genetic alterations and deserve a role in molecular oncology. In this manuscript we provide a technical comparison of these two approaches with the golden standard represented by fluorescence in situ hybridization. We also describe some relevant targets currently evaluated with these techniques in solid and hematologic tumors.

scholarly journals Explore the Rare—Molecular Identification and Wine Evaluation of Two Autochthonous Greek Varieties: “Karnachalades” and “Bogialamades”

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1556
Author(s):  
Dimitrios Evangelos Miliordos ◽  
Georgios Merkouropoulos ◽  
Charikleia Kogkou ◽  
Spyridon Arseniou ◽  
Anastasios Alatzas ◽  
...  
Keyword(s):  
Molecular Data ◽  
Molecular Profiling ◽  
Scientific Data ◽  
Financial Impact ◽  
Molecular Profile ◽  
Red Wines ◽  
Grape Berries ◽  
Quality Aspects ◽  
Commercial Vineyard ◽  
Of Greece

Wines produced from autochthonous Vitis vinifera varieties have an essential financial impact on the national economy of Greece. However, scientific data regarding characteristics and quality aspects of these wines is extremely limited. The aim of the current study is to define the molecular profile and to describe chemical and sensory characteristics of the wines produced by two autochthonous red grapevine varieties—“Karnachalades” and “Bogialamades”—grown in the wider area of Soufli (Thrace, Greece). We used seven microsatellites to define the molecular profile of the two varieties, and then we compared their profile to similar molecular data from other autochthonous as well as international varieties. Grape berries were harvested at optimum technological maturity from a commercial vineyard for two consecutive vintages (2017–2018) and vilification was performed using a common vinification protocol: the 2017 vintage provided wines, from both varieties, with greater rates of phenolics and anthocyanins than 2018, whereas regarding the sensory analysis, “Bogialamades” wine provided a richer profile than “Karnachalades”. To our knowledge, this is the first study that couples both molecular profiling and exploration of the enological potential of the rare Greek varieties “Karnachalades” and “Bogialamades”; they represent two promising varieties for the production of red wines in the historic region of Thrace.

scholarly journals A computational method for prioritizing targeted therapies in precision oncology: performance analysis in the SHIVA01 trial

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Istvan Petak ◽  
Maud Kamal ◽  
Anna Dirner ◽  
Ivan Bieche ◽  
Robert Doczi ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Progressive Disease ◽  
Genetic Alterations ◽  
Outcome Data ◽  
Computational Method ◽  
Molecular Profile ◽  
Precision Oncology ◽  
Driver Genes ◽  
Oncology Clinical Trial ◽  
Molecularly Targeted Agents

AbstractPrecision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

scholarly journals Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil

2010 ◽  
Vol 54 (8) ◽  
pp. 711-716 ◽  
Author(s):  
Daiane Rodrigues Barbosa Belgini ◽  
Maricilda Palandi de Mello ◽  
Maria Tereza Matias Baptista ◽  
Daniel Minutti de Oliveira ◽  
Fernanda Canova Denardi ◽  
...  
Keyword(s):  
Present Report ◽  
Molecular Data ◽  
The Other ◽  
Renin Activity ◽  
Inguinal Region ◽  
Molecular Profile ◽  
Hydroxylase Deficiency ◽  
Lyase Deficiency ◽  
Frequent Mutations ◽  
Low Levels

In 2004, Costa-Santos and cols. reported 24 patients from 19 Brazilian families with 17α-hydroxylase deficiency and showed that p.W406R and p.R362C corresponded to 50% and 32% of CYP17A1 mutant alleles, respectively. The present report describes clinical and molecular data of six patients from three inbred Brazilian families with 17α-hydroxlyse deficiency. All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C. The finding of p.W406R and p.R362C in the CYP17A1 gene here reported in additional families, confirms them as the most frequent mutations causing complete combined 17α-hydroxylase/17,20-lyase deficiency in Brazilian patients.

scholarly journals Prognostic relevance of Ki-67 and P16/INK4a markers in histological diagnosis of cervical dysplasia

2020 ◽  
Vol 7 (1) ◽  
pp. 8-15
Author(s):  
T. A. Dimitriadi ◽  
D. V. Burtsev ◽  
E. A. Dzhenkova ◽  
T. N. Gudtskova ◽  
K. V. Dvadnenko
Keyword(s):  
Histological Examination ◽  
Initial Diagnosis ◽  
Immunohistochemical Method ◽  
Histological Evaluation ◽  
Molecular Profile ◽  
Childbearing Age ◽  
Severe Injuries ◽  
Biopsy Material ◽  
Ki 67 ◽  
P16 Ink4a

Purpose of the study. To determine the quantitative parameters of the molecular markers Ki‑67 and p16/INK4a at CIN 1–3 and to establish the possibility of using them to improve the quality of diagnosis by histological samples.Patients and methods. Biopsy material of the cervix was studied in 71 patients who were carriers of HPV infection. Immunohistochemical method (IHC) in biopsy specimens determined the expression of Ki‑67 and p16/INK4a markers.Results. According to the results of a standard histological examination, the distribution of patientsinto groups occurred as follows: CIN 1–18, in CIN 2–39, in CIN 3–14 patients. It was found that the expression of the studied markers is associated with the severity of dysplastic changes in the tissue of the cervix. By the studied marker, the most characteristic molecular profiles for the degrees of dysplasia were determined: CIN1 – Ki‑67–15–25%, p16/INK4a 10–15%; CIN2 – Ki‑67–70–80%, p16/INK4a – 65–70%; CIN3 – Ki‑67–85–90%, p16/INK4a – 90–95%. Heterogeneity was revealed in the expression of these markersin the CIN 2 group: in 7 cases (22,6%), the molecular profile corresponded to CIN 1, in 1 case (3,6%) to CIN 3. Clinical examples of using the IHC profile to clarify the degree of CIN are given.Conclusion. The use of an IHC study with Ki‑67 and p16/INK4a, in addition to the standard histological examination, makes it possible to objectify the initial diagnosis of the degree of CIN, as well as to identify patients with a high and low risk of developing severe injuries. This is especially true for the CIN2 group, the most problematic in terms of histological evaluation and tactics of clinical management of patients. The use of IHC in the initial diagnosis will contribute to: improving the information content of multiple aimed and loop excisional biopsies; reduction in relapse due to inadequate treatment; eliminating the unreasonable use of such a traumatic method as conization (especially in women of childbearing age).

Comprehensive Genetic and Histopathologic Study Reveals Three Types of Neuroblastoma Tumors

2001 ◽  
Vol 19 (12) ◽  
pp. 3080-3090 ◽  
Author(s):  
Maria Łastowska ◽  
Catherine Cullinane ◽  
Sadick Variend ◽  
Simon Cotterill ◽  
Nick Bown ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Genetic Alterations ◽  
Good Prognosis ◽  
Mycn Amplification ◽  
Genetic Changes ◽  
Pathology Classification ◽  
Genetic Features ◽  
1P Deletion ◽  
Tumor Types ◽  
Type 3

PURPOSE: To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma. PATIENTS AND METHODS: The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups. RESULTS: Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS. CONCLUSION: Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

scholarly journals Primary squamous cell carcinoma of major salivary gland: “Sapienza Head and Neck Unit” clinical recommendations

Rare Tumors ◽  
2020 ◽  
Vol 12 ◽  
pp. 203636132097352
Author(s):  
Silvia Mezi ◽  
Giulia Pomati ◽  
Andrea Botticelli ◽  
Francesca De Felice ◽  
Daniela Musio ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Salivary Gland ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Salivary Gland Tumor ◽  
Genetic Alterations ◽  
Integrated Treatment ◽  
Molecular Profile ◽  
Major Salivary Gland ◽  
Primary Squamous Cell Carcinoma

Primary squamous cell carcinoma of salivary gland (SCG) is an extremely rare type of malignant salivary gland tumor, which in turn results in scarcity of data available regarding both its treatment and associated genetic alterations. A retrospective analysis of 12 patients with primary SCG was conducted, along with analysis of the association between treatment, clinical/pathological characteristics, and outcomes. Most patients (8) were staged IVa, with the majority of them (10) having G3 fast growing cancer. Local and systemic recurrence were reported in only three out of nine parotid cases (0 out of 2 submandibular SCGs). In two out of eight patients local relapse occurred after integrated treatment, while recurrence occurred in two out of three patients undergoing exclusive surgery. Five patients eventually died. Treatment of resectable disease must be aggressive and multimodal, with achievement of loco-regional control in order to reduce rate of recurrence and improve outcomes. Metastatic disease would require a therapeutic strategy tailored to the molecular profile in order to improve the currently disappointing results.

Abstract 2721: Establishment of a catalog of somatic genetic alterations of Japanese cancer patients across multiple tumor types at Shizuoka Cancer Center

2019 ◽  
Author(s):  
Hirotsugu Kenmotsu ◽  
Masakuni Serizawa ◽  
Takeshi Nagashima ◽  
Keiichi Ohshima ◽  
Keiichi Hatakeyama ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Genetic Alterations ◽  
Cancer Center ◽  
Multiple Tumor ◽  
Tumor Types
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