scholarly journals Comprehensive Analysis of 343 Genes Using Targeted Sequencing Panel By Next-Generation Sequencer in 77 Pediatric AML Patients with Normal and Complex Karyotypes: Jccg Study, JPLSG AML-05

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1530-1530
Author(s):  
Taeko Kaburagi ◽  
Genki Yamato ◽  
Norio Shiba ◽  
Kenichi Yoshida ◽  
Yusuke Hara ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Small Sample ◽  
Targeted Sequencing ◽  
World Health ◽  
Genetic Mutations ◽  
Next Generation ◽  
Next Generation Sequencer ◽  
Epigenetic Factor

Abstract Introduction Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease caused by various genetic alterations. Some prognosis-associated chromosomal aberrations and gene mutations such as t(8;21), inv(16), monosomy 7, and FLT3-ITD have been adopted for risk stratification. Although treatment outcomes have improved via stratification therapy, relapse and mortality are still observed in 40% and 30% patients, respectively. Patients with an intermediate risk with no favorable or recurrent factors are considered to exhibit varied biology and outcomes. Further studies are warranted to evaluate the accuracy of prognosis in these patients. Methods Among 369 patients with de novo AML participated in the Japanese AML-05 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group during 2006-2010, 77 patients including 59 with normal karyotype-AML (NK-AML) and 18 with complex karyotype-AML (CK-AML) were enrolled. Targeted sequencing was performed using a 343-gene custom panel and next-generation sequencer. Reportedly, these 343 genes are associated with hematopoietic malignancy or solid tumor pathogenesis. Correlations among gene mutations, other cytogenetic alterations, and clinical characteristics were investigated. Results In all, 187 mutations in 61 genes (average: 2.42 mutations/patient) were detected, and 72 patients (93%) had at least one genetic mutation. Among patients with NK-AML, 51 (86%) had one of the following driver mutations: FLT3-ITD, KMT2A-PTD, CEBPA, or NPM. Interestingly, internal tandem duplication (ITD) of BCOR (BCOR-ITD) was detected along with several novel ITDs in patients with unclear AML pathogenesis. Among patients with CK-AML, the following mutations regarding myelodysplastic syndrome (MDS) pathogenesis were detected: TP53: 3 (17%), JAK2: 2 (11%), ASXL1: 2 (11%), U2AF1: 1 (7%), SF3A1: 1 (7%), RUNX1: 2 (11%), and BCOR/BCORL1: 3 (17%). Consequently, 15 of 18 (83%) patients with CK-AML had some genetic mutations related to MDS. Eight types of transcription factor mutations and five of epigenetic factor mutations were detected in 10 patients. Eight of these (80%) relapsed or died. Three RUNX1 rearrangements (RUNX1-CBFA2T2, RUNX1-CBFA2T3, and RUNX1-FNBP1) and other fusions (PICALM-MLL10 and MYB-GATA1) were detected in patients with CK-AML. Interestingly, these patients had a low transcription factor or epigenetic factor mutation number; all of them survived without relapse. Discussion We detected several novel ITDs other than FLT3-ITD in patients with NK-AML. KIT-ITD was reported in adult and pediatric patients with AML; BCOR-ITD was linked to the pathogenesis of pediatric clear-cell sarcoma of the kidney. However, the clinical significance of ITDs, other than FLT3-ITD, has not been revealed in AML, for which further studies are being planned. This study identified the characteristic genetic background (i.e., MDS) in patients with CK-AML. Most patients with CK-AML (17/18; 94%) were diagnosed as AML with MDS related changes, according to World Health Organization classification. Fifteen of those (88%) had genetic mutations related to MDS pathogenesis. Furthermore, several RUNX1 rearrangements were detected in patients with CK-AML. Reportedly, RUNX1-CBFA2T2 and RUNX1-CBFA2T3 are recurrent fusions in adult AML. Particularly, RUNX1-CBFA2T3 has a gene expression profile similar to that of RUNX1-RUNX1T1, which may explain the favorable outcome in patients with such rearrangements. Despite the small sample size of this study, the findings indicate two major subgroups of pediatric CK-AML: 1) CK-AML with MDS-related genetic mutations (i.e., transcription factor and epigenetic factor mutations) linked to poor outcomes and 2) CK-AML with few of these mutations and with fusion genes (e.g., RUNX1) linked to favorable outcomes. Disclosures No relevant conflicts of interest to declare.

Targeted Sequencing of a Pediatric Metabolic Bone Gene Panel Using a Desktop Semiconductor Next-Generation Sequencer

2014 ◽  
Vol 95 (4) ◽  
pp. 323-331 ◽  
Author(s):  
Frank Rauch ◽  
Liljana Lalic ◽  
Francis H. Glorieux ◽  
Pierre Moffatt ◽  
Peter Roughley
Keyword(s):  
Gene Panel ◽  
Targeted Sequencing ◽  
Next Generation ◽  
Next Generation Sequencer ◽  
Metabolic Bone

scholarly journals Genetic Mutations in Young Nonsmoking Patients With Oral Cavity Cancer: A Systematic Review

OTO Open ◽  
2020 ◽  
Vol 4 (4) ◽  
pp. 2473974X2097018
Author(s):  
Rohini R. Bahethi ◽  
Katelyn O. Stepan ◽  
Rachel Pinotti ◽  
Ryan Li ◽  
Nishant Agrawal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Oral Cavity ◽  
Similar Rate ◽  
Genetic Alterations ◽  
Small Sample ◽  
Genetic Mutations ◽  
Case Control Studies ◽  
Level Of Evidence ◽  
Tp53 Mutations ◽  
Small Sample Sizes

Objective This investigation aims to review the known genetic mutations associated with oral cavity squamous cell carcinoma (OCSCC) in young adults with limited environmental risk factors (YLERs). Data Sources A comprehensive search strategy was designed to identify studies in MEDLINE (Ovid), Embase (Ovid), and Scopus from database inception to May 2017 that included adults ≤50 years of age with OCSCC and minimal tobacco use history (≤10 pack-years) who had their tumors genetically sequenced or mutational profiles analyzed. Review Methods Identified articles were screened by 2 reviewers. Quality of evidence was graded by the MINORS criteria for case-control studies; other studies were graded by assigning a level of evidence for gene mutation literature. Results Thirteen studies met our inclusion criteria, and 130 patients met our criteria for age and tobacco history. TP53 was the most commonly evaluated gene (10 of 13 studies) and the most frequently observed mutation. One study reported that nonsmokers had significantly fewer TP53 mutations, while 9 studies found no difference in the prevalence of TP53 mutations. No other mutations were found specific to this cohort. Conclusions TP53 mutations may occur at a similar rate in YLERs with OCSCC as compared with older patients or those with risk factors. However, few studies have aimed to characterize the genetic landscape of oral cavity tumors in this population, often with small sample sizes. Future studies are needed to explore unidentified genetic alterations leading to tumor susceptibility or alternative mechanisms of carcinogenesis.

Utilization of Peripheral Blood Cell-Free DNA in Myelodysplastic Syndromes: Clinical and Molecular Characteristics and Utilization for Genetic Analyses Using Conventional and Next-Generation Strategies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4102-4102
Author(s):  
Akihiro Tomita ◽  
Yasuhiro Suzuki ◽  
Fumika Nakamura ◽  
Chisako Iriyama ◽  
Mizuho Shirahata-Adachi ◽  
...  
Keyword(s):  
Research Funding ◽  
Sanger Sequencing ◽  
Disease Status ◽  
Peripheral Blood Cell ◽  
Targeted Sequencing ◽  
Genetic Mutations ◽  
Next Generation ◽  
Genetic Analyses ◽  
Free Dna ◽  
Tumor Dna

Abstract Background: Genetic mutations are detected in over 90% of patients with myelodysplastic syndromes (MDS). Some mutations may be critical not only for the pathogenesis of MDS, but also for disease progression to acute myelocytic leukemia and the acquirement of drug resistance; however, the detailed functions of these mutations remain unclear. To determine the roles of these mutations, genetic analyses using serially harvested tumor DNA are required. To date, genomic DNA from bone marrow (BM) cells has been utilized for genetic analyses of MDS patients, but bone marrow aspiration cannot be performed repeatedly because it causes physical pain in patients. Recently, peripheral blood cell-free DNA (PB-cfDNA) obtained from plasma and/or serum has received much attention as an alternative tumor DNA source, especially for solid tumors. Here, we demonstrate that PB-cfDNA may be used as an alternative DNA source instead of BM cells, that it reflects MDS disease status, and that the mutations in MDS can be successfully detected from PB-cfDNA by Sanger sequencing and next-generation targeted sequencing analyses. Aims: 1) Confirmation of the molecular and clinical basis of PB-cfDNA in MDS; 2) detection of genetic mutations using PB-cfDNA with conventional and next-generation sequencing strategies; and 3) optimization of sequencing conditions using PB-cfDNA. Methods: PB-cfDNA from patients with MDS and other related diseases (N = 33) and normal volunteer donors (N = 19) was analyzed. The concentration of PB-cfDNA was measured and correlations between the PB-cfDNAconcentration and clinical data were analyzed. DNA sequencing was performed using Sanger sequencing and targeted sequencing was performed using a TruSight Myeloid Sequencing Panel (Ilumina). Results: The plasma PB-cfDNA concentration was significantly higher in MDS patients than in normal donors (p = 0.0405), and was significantly higher in those with a higher International Prognostic Scoring System (IPSS) score than in those with a lower score (p = 0.0339). The concentration of plasma and serum PB-cfDNA was significantly correlated with the serum lactate dehydrogenase (LDH)level (both p < 0.0001) and the blast cell count in PB (plasma, p = 0.0373; serum, p = 0.0274). Since PB-cfDNA showed a fragmented pattern reflecting its oligonucleosomal structure, amplification using primers for PCR-based sequencing analyses were optimized when the size of the PCR products were approximately 160 bp. For Sanger and targeted sequencing, 1 and 50 ng of PB-cfDNA, respectively, were required for each assay. Almost all genetic mutations detected by Sanger and targeted sequencing using BM cells from MDS patients (TET2, IDH2, SETBP1, U2AF1, SRSF2, NRAS, TP53) were also detected using the PB-cfDNA, but they were not detected in the germline controls. Serially harvested PB-cfDNA samples from a patient with refractory anemia with excess blasts-1 (RAEB-1) who underwent cord blood transplantation (CBT) after 5-azacytidine treatment were utilized for genetic analyses; they showed a correlation between PB-cfDNA concentration and the clinical course, and that the U2AF1 and SETBP1 mutations detected before CBT were no longer detectable 150 days after CBT. Discussion: These data suggest that PB-cfDNA likely originates from MDS clones, which reflect their disease status, and that they can be utilized as a biomarker and an alternative promising source of tumor DNA instead of BM cells for genetic analyses; including not only conventional Sanger sequencing, but also next-generation targeted sequencing. However, since the PB-cfDNA concentration of some MDS patients was too low (less than 10 ng/1 mL plasma) to be used for targeted sequencing and/or whole exome sequencing, optimization of the sensitivity of sequencing analyses is still required. Disclosures Tomita: Janssen Pharmaceutical K.K.: Consultancy. Ishikawa:GlaxoSmithKline K.K.: Research Funding. Kiyoi:Alexion Pharmaceuticals: Research Funding; Eisai Co., Ltd.: Research Funding; Japan Blood Products Organization: Research Funding; FUJIFILM RI Pharma Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Bristol-Myers Squibb: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; Teijin Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding.

The Significance of the Next Generation Targeted Sequencing in the Precise Diagnosis of Pediatric Acquire Aplastic Anemia and Inherited Bone Marrow Failure Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3908-3908 ◽  
Author(s):  
Wenbin An ◽  
Ye Guo ◽  
Yumei Chen ◽  
Yao Zou ◽  
Xiaojuan Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Family History ◽  
Bone Marrow Failure ◽  
Gene Mutations ◽  
Chromosome Breakage ◽  
Targeted Sequencing ◽  
Genetic Mutations ◽  
Bone Marrow Failure Syndromes ◽  
Precise Diagnosis ◽  
History Of

Abstract Background Diagnosis of inherited bone marrow failure syndromes (IBMFs) depend on classic clinical manifestation including early onset, physical anomalies, family history of cancer and/or bone marrow failure and chromosome breakage testing (MMC and/or DEB), mutation analyses and bone marrow chromosome analyses. At present, more than 70 pathogenic gene mutations had been identified. However, in some patients, physical anomalies is absent or delayed, and were misdiagnosed as acquired aplastic anemia(AA). Genetic analysis is very important to establish a precise diagnosis, predict cancer risk, direct treatment and genetic counseling. In this study, we focus on the application of next generation targeted sequencing in precise diagnosis of pediatric acquired AA/IBMFs, and the association between genetic abnormalities and clinical and laboratory characteristics. Methods We designed a targeted sequencing assay to test a panel of 417 genes. The panel contain reported gene associated with IBMFs and other diseases need be differentiated. Pediatic patients (≤14 year old) with suspected diagnosis of AA/IBMFs were enrolled. Peripheral blood (PB) DNA was used to genetic analysis and oral epithelia cells or PB DNA from their parents were used to identify somatic mutations and unreported polymorphism. All the results were validated by Sanger sequencing. Results The average coverage of targeted region was 98.15%, and the average sequencing depth was 315.9×. Totally, 283 patients were enrolled, including 176 clinically diagnosed acquired AA, 51 Fanconi anemia (FA), 8 dyskeratosis congenital(DKC), 30 Diamond-Blanckfan anemia(DBA), 15 congenital neutropenia(CN), and 3 congenital thrombocytopenia. Totally, 19% subjects had IBMFs related genetic mutations. In the patients who were clinically diagnosed as acquired AA patients, about 7% had IBMFs related disease-causing genetic mutations. Finally, 7 patients were genetically diagnosed as FA, 2 were DKC, 1 was WAS and 1 was SDS. In patients who were clinically diagnosed as FA, 33.4% had FANC related gene mutations. Telomere associated gene mutations were detected in 75% of clinical diagnosed DKC. For patients clinically diagnosed as DBA and CN, 36.7% and 20% were detected disease-causing mutations. After genetic screening, 2 patients who had been diagnosed as FA were modified as WAS and 1 DBA was modified as SDS. Only 26% genetic diagnosed IBMFs patients had family history of bone marrow failure, leukemia, tumor or physical anomalies. Compared with acquired AA, patients with genetic diagnosed FA were more likely to have physical anomalies of short stature and development retardation, Cafe au lait spots and finger or toe malformation(P<0.001).However, 46% patients with IBMFs did not have any type of physical anomalies. Moreover, there were only 24% patients with genetic diagnosed IBMFs had positive results of MMC induced chromosome breakage test or SCGE, and both the examinations could not differentiate subtype of IBMFs. FANCD2 mono-ubiquitination test were performed recently. However, even in the genetically confirmed FA, the positive rate was only 18% (2/11). And, there were positive results in some acquired AA patients. For FA patients with definitely genetic mutations, 62.5%(15/24) were compound heterozygous mutations,37.5%(9/24) were homozygous mutations. Mutational frequencies of FANC were: FANCA 65%, FANCD2 23%, FANCG 9%, FANCI 9% and FANCB 4%. For the mutated type, the frequencies of missense, frameshift, nonsense, splicing mutation were 42%, 26%, 16%, 16%. In our study, there were 4 undetermined patients met the clinical diagnostic criteria of FA, and having heterozygous damaged mutations in FANC genes. Conclusion In conclusion, our IBMFs associated genes targeted sequencing assay is an effective strategy for precise diagnosis of bone marrow failure diseases, especially for those without family history or physical anomalies. However, nearly half of the clinically diagnosed IBMFs patients in our study were not detected the disease-causing mutations. This may be due to the mutations in the intron area, or large fragment deletion, which cannot be detected by targeted sequencing. And the novel gene involved in IBMFs need further study. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular Profiling of Odontogenic Tumors - Pilot Study

2017 ◽  
Vol 21 (2) ◽  
pp. 112-115
Author(s):  
Sibel Elif Gültekin ◽  
Burcu Sengüven ◽  
Reemitcha Aziz ◽  
Carina Heydt ◽  
Reinhard Buettner
Keyword(s):  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Odontogenic Tumor ◽  
Odontogenic Tumors ◽  
Sequencing Analysis ◽  
Next Generation ◽  
Next Generation Sequencing Analysis ◽  
Epidermal Growth ◽  
Dental Apparatus

Summary Background/Aim: In the pathogenesis of odontogenic tumors which arise from the rests of the dental apparatus in the jaw, several molecular pathways have been shown to play critical roles such as genetic alterations in the hedgehog, BRAF/Ras/MAPK, epidermal growth factor receptor. Next generation genomic sequencing has identified gene mutations in many different tumors. Materials and Methods: Here we report four types of odontogenic tumor including six cases in which five had mutation according to next generation sequencing analysis from archival paraffin blocks that diagnosed previously as ameloblastoma (solid), amloblastoma (unicystic-mural), ameloblastic fibroma, squamous odontogenic tumor, and adenomatoid odontogenic tumor. Results: All ameloblastomatic tumors were shown BRAF mutation and adenomatoid odontogenic tumors were KRAS mutation. Conclusion: This evidence may highlight the poorly understood pathogenesis of odontogenic tumors. Further comparisons need to be made with other benign and malignant odontogenic tumors so that unique odontogenic features may be found.

Discovering the genetic factors in eye disease

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 68-71
Author(s):  
Takeshi Iwata
Keyword(s):  
Visual Impairment ◽  
Gene Mutations ◽  
Eye Diseases ◽  
World Health ◽  
Eye Disease ◽  
Genetic Mutations ◽  
Macular Dystrophy ◽  
Retinal Diseases ◽  
Number Of Patients ◽  
The World

Eye disease is an increasing problem, exacerbated by ageing populations in most countries. The National Eye Institute in the USA predicts that the cases of age-related macular degeneration (AMD) and glaucoma around the world will double by 2050. According to the World Health Organisation, these two diseases account for six per cent of all cases of visual impairment and blindness globally. Visual impairment affects quality of life and productivity and is therefore an important area of research. Professor Takeshi Iwata's laboratory is making ground-breaking discoveries in the specialist area of genetically-influenced retinal diseases. Most eye diseases are partly due to genetics, but the influence of a person's genotype is more profound in hereditary diseases such as retinitis pigmentosa and macular dystrophy. Specific genotypes are less influential, but play a role in AMD and glaucoma. The Iwata laboratory investigates AMD, glaucoma and 36 hereditary retinal diseases, to determine the genetic mutations that cause or predispose a patient towards developing disease. Iwata says: 'Our goal is to develop therapies for retinal eye diseases based on fundamental research into their molecular mechanisms.' Determining the genetic mutations behind each disease is the first step to realising this goal. As many of the hereditary retinal diseases are rare, collaboration is very important to the laboratory's work. To collect samples from a large number of patients, Iwata explains: 'We founded the Japan Eye Genetics Consortium (JEGC), a group comprising 30 ophthalmology departments throughout Japan.' Clinicians enter patients' phenotype information into a national genotype-phenotype database and send saliva or blood samples to the Iwata laboratory for gene analysis. Iwata explains: 'Following analysis, we upload whole exome and genome analysis results to the database to share amongst the collaborators.' The JEGC is already yielding important results. 80 per cent of families studied were found to have previously unidentified mutations. Functional analysis is underway to characterise each of these gene mutations in detail. Over 1366 family pedigrees have been collected, and the consortium aims to gather 5000 in total. In 2014, a more ambitious consortium was launched. The aim of the Asian Eye Genetics Consortium (AEGC), Iwata explains, is: 'to identify all the gene mutations responsible for hereditary eye diseases in the Asian population.' Over 150 scientists from 20 countries have been brought together through the consortium.

Next-Generation Sequencing Screening Reveals Novel Genetic Variants for Dilated Cardiomyopathy in Pediatric Chinese Patients

2021 ◽  
Author(s):  
yan wang ◽  
bo han ◽  
youfei fan ◽  
yingchun yi ◽  
jianli lv ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Dilated Cardiomyopathy ◽  
Clinical Outcomes ◽  
Genetic Alterations ◽  
Left Ventricular ◽  
Cytoskeletal Proteins ◽  
Genetic Mutations ◽  
Next Generation ◽  
Pathogenic Mutations ◽  
Generation Sequencing

Abstract Dilated cardiomyopathy (DCM) is a myocardial disease characterized by bilateral or left ventricular cardiac dilation and systolic dysfunction leading to heart failure and sudden cardiac death in children. Most studies focus on the genetic alterations in DCM-related genes in adult populations; however, it remains enigmatic about the mutational landscape in pediatric DCM patients, especially in the Chinese population. We exploited the next-generation sequencing (NGS) technologies to genetically analyze 46 pediatric patients and to decipher the genotype-phenotype correlation in these patients’ clinical outcomes. Our results indicated DCM-associated pathogenic mutations in 10 genes related to the structure or function of the sarcomere, desmosomal and cytoskeletal proteins. We also identified 6 pathogenic mutations (5 novel) in the titin (TTN) gene leading to the formation of truncated TTN protein variants in 6 (13%) out of 46 patients each. Furthermore, we investigated the correlations between TTN gene mutation and clinical outcomes in these patients. Conclusion: Our data suggest that one-third of cases of pediatric DCM are caused by genetic mutations. The role of TTN variants should not be underestimated in pediatric DCM and age-dependent pathogenic penetrance of these genetic mutations needs to be considered in the case of familial DCM. Thus, NGS analysis can be applied to decode the yet unknown DCM etiological genetic factors in pediatric as well as adult patients.

scholarly journals Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

2019 ◽  
Vol 81 (01) ◽  
pp. 064-070 ◽  
Author(s):  
Nicola Montemurro
Keyword(s):  
Glioblastoma Multiforme ◽  
Dna Methyltransferase ◽  
Expression Profiles ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
World Health ◽  
Genetic Mutations ◽  
Isocitrate Dehydrogenase 1 ◽  
Medline Search ◽  
Key Words Glioblastoma

Abstract Background and Objective Glioblastoma multiforme (GBM) is still a deadly disease with a poor prognosis and high mortality, despite the discovery of new biomarkers and new innovative targeted therapies. The role of genetic mutations in GBM is still not at all clear; however, molecular markers are an integral part of tumor assessment in modern neuro-oncology. Material and Methods We performed a Medline search for the key words “glioblastoma,” “glioblastoma multiforme,” and “genetic” or “genetics” from 1990 to the present, finding an exponential increase in the number of published articles, especially in the past 7 years. Results The understanding of molecular subtypes of gliomas recently led to a revision of the World Health Organization classification criteria for these tumors, introducing the concept of primary and secondary GBMs based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs). Conclusion From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM.

scholarly journals Comprehensive Genetic Analysis in Cases of Juvenile Myelomonocytic Leukemia for Prognostic Estimation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3159-3159
Author(s):  
Norihiro Murakami ◽  
Hideki Muramatsu ◽  
Yusuke Okuno ◽  
Hirotoshi Sakaguchi ◽  
Kenichi Yoshida ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Research Funding ◽  
Survival Rates ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Juvenile Myelomonocytic Leukemia ◽  
Genetic Mutations ◽  
Ras Pathway ◽  
Pathway Gene ◽  
Myelomonocytic Leukemia

Abstract Introduction: Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm (MPN) that occurs during childhood and has a poor prognosis. Somatic or germline mutations in canonical RAS pathway genes, i.e., PTPN11, NF1, NRAS, KRAS, and CBL, are reported be detected in approximately 85% patients. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for JMML. Although spontaneous remission is occasionally observed in others with supportive therapy, some patients show aggressive disease progression despite HSCT. Recent studies have identified several additional genetic events in an array of genes, including SETBP1 and JAK3, but the relationship between genetic alterations and clinical outcomes remains unclear. Patients and Methods: A total of 131 patients (88 boys, 43 girls) with JMML were enrolled in the study. The median age was 15 months (range, 1-160 months). Eighty-two of 131 patients underwent HSCT, and 36 patients died (disease related, n = 27, transplantation-related complications, n = 16, infection, n = 5, unknown, n = 3). We performed comprehensive genetic analyses of the 131 JMML patients using whole-exome sequencing (n = 68, 52%) or targeted deep sequencing (n = 92, 70%), and assessed the impact of genetic alterations on clinical outcomes in 119 patients, excluding 12 patients with Noonan syndrome-related myeloproliferative disorder (NS/MPD). Results: We identified canonical RAS pathway gene mutations in 115 of 131 patients (88%). Although most RAS pathway mutations were mutually exclusive, coexisting secondary RAS pathway mutations were found in nine patients (8%). In addition, 28 patients harbored secondary genetic alterations in other genes, including SETBP1 (n = 10), JAK3 (n = 12), ASXL1 (n = 6), SH3BP1 (n = 1), RRAS2 (n = 2), and SOS1 (n = 3). In total, 34 of 131 patients harbored secondary genetic mutations. In univariate analysis, patients with secondary genetic mutations showed poorer survival rates than patients without these mutations [5-year transplantation-free survival (TFS) (95% CI) = 8.8% (2.3%-21.1%) vs. 24.1% (15.2%-34.1%), p = 0.007; 5-year overall survival (OS) (95% CI) = 49.6% (32.0%-65.0%) vs. 62.3% (50.8%-71.8%), p = 0.135]. On the basis of the dominant canonical RAS pathway mutations classification, patients with PTPN11 and NF1 mutations were significantly associated with the presence of secondary genetic mutations compared to patients with other RAS pathway gene mutations (PTPN11 (20 of 43, 47%), NF1 (5 of 7, 71%), NRAS (2 of 18, 11%), KRAS (4 of 20, 20%), CBL (1 of 17, 6%), p < 0.001). Consistent with previous reports, patients with PTPN11 and NF1 mutations had inferior survival rates than other JMML patients [5-year TFS (95% CI) = 0% vs. 32.7% (21.5%-44.3%), p < 0.001; 5-year OS (95% CI) = 45.3% (31.1%-58.5%) vs. 68.1% (55.2%-78.0%), p = 0.006]. Multivariate survival analysis identified the RAS pathway mutations (i.e., patients with PTPN11 and NF1 mutations vs. others) [TFS: HR (95% CI) = 3.732 (2.382-5.847), p < 0.001; OS: HR (95% CI) = 1.983 (1.117-3.521), p < 0.019] and low platelet count (<33 × 109/L vs. ≥ 33 × 109/L) [TFS: HR (95% CI) = 1.816 (1.160-2.843), p < 0.001] as independent risk factors for TFS and OS. In subgroup analysis of 50 patients with PTPN11 and NF1 mutations, there were no significant survival differences between patients with (n = 25) or without (n = 25) secondary genetic mutations [5-year TFS (95% CI) = 0% vs. 0%, p = 0.753; 5-year OS (95% CI) = 39.6% (20.8%-57.9%) vs. 51.7% (30.9%-69.1%), p = 0.589]. Discussion: Consistent with previous studies, secondary genetic mutations were associated with inferior survival rates, but high correlations were observed in JMML patientswith PTPN11 and NF1 mutations. Our results suggest that comprehensive genetic mutational profiling is essential to estimate prognosis and to stratify JMML patients who require HSCT and/or novel treatment modalities. Disclosures Ogawa: Sumitomo Dainippon Pharma: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Kan research institute: Consultancy, Research Funding. Kojima:SANOFI: Honoraria, Research Funding.

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