scholarly journals The use of PanDrugs to prioritize anticancer drug treatments in a case of T-ALL based on individual genomic data

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Pablo Fernández-Navarro ◽  
Pilar López-Nieva ◽  
Elena Piñeiro-Yañez ◽  
Gonzalo Carreño-Tarragona ◽  
Joaquín Martinez-López ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lymphoblastic Leukaemia ◽  
Large Scale ◽  
Genomic Medicine ◽  
Fusion Transcript ◽  
Sequencing Technologies ◽  
Dna And Rna ◽  
Whole Exome ◽  
New Treatment

Abstract Background Acute T-cell lymphoblastic leukaemia (T-ALL) is an aggressive disorder derived from immature thymocytes. The variability observed in clinical responses on this type of tumours to treatments, the high toxicity of current protocols and the poor prognosis of patients with relapse or refractory make it urgent to find less toxic and more effective therapies in the context of a personalized medicine of precision. Methods Whole exome sequencing and RNAseq were performed on DNA and RNA respectively, extracted of a bone marrow sample from a patient diagnosed with tumour primary T-ALL and double negative thymocytes from thymus control samples. We used PanDrugs, a computational resource to propose pharmacological therapies based on our experimental results, including lists of variants and genes. We extend the possible therapeutic options for the patient by taking into account multiple genomic events potentially sensitive to a treatment, the context of the pathway and the pharmacological evidence already known by large-scale experiments. Results As a proof-of-principle we used next-generation-sequencing technologies (Whole Exome Sequencing and RNA-Sequencing) in a case of diagnosed Pro-T acute lymphoblastic leukaemia. We identified 689 disease-causing mutations involving 308 genes, as well as multiple fusion transcript variants, alternative splicing, and 6652 genes with at least one principal isoform significantly deregulated. Only 12 genes, with 27 pathogenic gene variants, were among the most frequently mutated ones in this type of lymphoproliferative disorder. Among them, 5 variants detected in CTCF, FBXW7, JAK1, NOTCH1 and WT1 genes have not yet been reported in T-ALL pathogenesis. Conclusions Personalized genomic medicine is a therapeutic approach involving the use of an individual’s information data to tailor drug therapy. Implementing bioinformatics platform PanDrugs enables us to propose a prioritized list of anticancer drugs as the best theoretical therapeutic candidates to treat this patient has been the goal of this article. Of note, most of the proposed drugs are not being yet considered in the clinical practice of this type of cancer opening up the approach of new treatment possibilities.

scholarly journals Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 65
Author(s):  
Patricia Haug ◽  
Samuel Koller ◽  
Jordi Maggi ◽  
Elena Lang ◽  
Silke Feil ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Screening ◽  
De Novo ◽  
Efficient Tool ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
Screening And Identification ◽  
High Throughput Dna Sequencing ◽  
New Mutations

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.

Whole Exome Sequencing of Six Chinese Families With Hereditary Non-Syndromic Hearing Loss: A Genetic Etiology Study

2020 ◽  
Author(s):  
Pengfei Liang ◽  
Fengping Chen ◽  
Shujuan Wang ◽  
Qiong Li ◽  
Wei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Large Scale ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Chinese Families ◽  
Whole Exome ◽  
Syndromic Hearing Loss

Abstract Background: Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identified as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families.Methods: After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were verified by Sanger sequencing in all patients and their parents.Results: Biallelic mutations were identified in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identified. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family.Conclusions: Next-generation sequencing (NGS) approach becomes more cost-effective and efficient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current findings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive significance for genetic counseling.

scholarly journals Case Report: An Infant With Kabuki Syndrome, Alobar Holoprosencephaly and Truncus Arteriosus: A Case for Whole Exome Sequencing in Neonates With Congenital Anomalies

2021 ◽  
Vol 12 ◽  
Author(s):  
Rishika P. Sakaria ◽  
Parul G. Zaveri ◽  
Shannon Holtrop ◽  
Jie Zhang ◽  
Chester W. Brown ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
Large Scale ◽  
Heart Diseases ◽  
Truncus Arteriosus ◽  
Kabuki Syndrome ◽  
Whole Exome ◽  
Anomalous Pulmonary Venous Return ◽  
Spectrum Of Patients

Kabuki syndrome is a rare multiple anomalies syndrome associated with mutations in KMT2D or KDM6A. It is characterized by infantile hypotonia, developmental delay and/or intellectual disability, long palpebral fissures with everted lateral third of the lower eyelids and typical facial features. Intracranial anomalies occur infrequently in patients with KS and holoprosencephaly has only been recently described. Additionally, though congenital heart diseases are common in patients with KS, to our knowledge truncus arteriosus has never been reported in a patient with KS. We present an unusual case of KS in an infant with holoprosencephaly and truncus arteriosus with partial anomalous pulmonary venous return. Duo whole exome sequencing in our patient identified a pathogenic nonsense variant in exon 10 of KMT2D (c.2782C > T; p. Gln928*) establishing the diagnosis. This report further expands the phenotypic spectrum of patients with Kabuki syndrome and emphasizes the utility of performing large scale sequencing in neonates with multiple congenital anomalies.

scholarly journals Whole Exome Sequencing Identifies genetic variants in Chinese Han pregnant women with Venous thromboembolism-a case control study

2020 ◽  
Author(s):  
Yupei Shen ◽  
Yan Zhang ◽  
Ying Xiong ◽  
Zhiping Zhang ◽  
Baohua Zhang ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Pregnant Women ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Large Scale ◽  
Single Nucleotide Variants ◽  
Chinese Han ◽  
Whole Exome ◽  
Increased Risk

Abstract Background: Venous thromboembolism (VTE) is a common health problem, causing considerable morbidity and mortality. The incidence of VTE is higher in pregnant women than in those who are not pregnant. However, genetic factors for VTE in pregnant women are largely unknown.Methods: We performed a large-scale prospective cohort study of 65138 pregnancies. Pregnant patients with VTE and pregnant women without VTE were enrolled in the study and sequenced by whole exome sequencing. Functional and enrichment analyses were performed using the DAVID online database. The protein-protein interaction network was constructed using the STRING database. Results: 5810 significant variants were associated with pregnant patients with VTE, including 4874 single nucleotide variants and 936 short deletions which were annotated in 3417 genes (P < 0.05). Fifty-six variants annotated in 46 genes (P < 0.001) and the top 3 variants, including rs2706258 (RNA LOC102724050, p = 1.25 × 10-6), rs17057520 (SCARA3, p = 4.64 × 10-5), and rs3739550 (CAAP1, p = 4.64 × 10-5), were identified. Fourteen low frequency variants had a minor allele frequency (MAF) of less than 1%. Logistic analysis revealed that rs7099478 (GRK5), rs8041208 (WDR72), rs17215792 (KLF7), rs13035688 (KLF7), rs6725221 (KLF7), and rs3214417 (KLF7) were associated with an increased risk of developing VTE (P < 0.05, OR > 1). In addition, combined pathway and PPI analyses revealed that CDC7 and MCM6 involved with DNA replication were associated with VTE in pregnant individuals.Conclusion: The study identified a series of variants and genes that may contribute to VTE in the Chinese pregnant population. Several genes may be risk factors for VTE including KLF7, GRK5, and WDR72. CDC7 and MCM6 may be related to the potential functions of VTE in pregnant women. Notably, the KLF7 gene had 4 genetic variants that were found to be associated with lipid metabolism and cardiovascular diseases. Therefore, further validation is required to reveal the KLF7 mechanism in pregnant women with VTE.

scholarly journals The Application of Whole−Exome Sequencing in Patients With FUO

2022 ◽  
Vol 11 ◽  
Author(s):  
Wanru Guo ◽  
Xuewen Feng ◽  
Ming Hu ◽  
Yanwan Shangguan ◽  
Jiafeng Xia ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Fever Of Unknown Origin ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Unknown Origin ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
Positive Results ◽  
Generation Sequencing

BackgroundFever of unknown origin (FUO) is still a challenge for clinicians. Next-generation sequencing technologies, such as whole exome sequencing (WES), can be used to identify genetic defects in patients and assist in diagnosis. In this study, we investigated the application of WES in individuals with FUO.MethodsWe performed whole-exome sequencing on 15 FUO patients. Clinical information was extracted from the hospital information system.ResultsIn 7/15 samples, we found positive results, including potentially causative mutations across eight different genes: CFTR, CD209, IRF2BP2, ADGRV 1, TYK2, MEFV, THBD and GATA2.ConclusionsOur results show that whole-exome sequencing can promote the genetic diagnosis and treatment of patients with FUO.

Chemoresistant pleomorphic rhabdomyosarcoma: whole exome sequencing reveals underlying cancer predisposition and therapeutic options

2018 ◽  
Vol 57 (2) ◽  
pp. 104-108 ◽  
Author(s):  
Camille Tlemsani ◽  
Karen Leroy ◽  
Anne-Paule Gimenez-Roqueplo ◽  
Audrey Mansuet-Lupo ◽  
Eric Pasmant ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lung Metastases ◽  
Genomic Medicine ◽  
Treatment Decision ◽  
Complete Response ◽  
Tumour Cells ◽  
Therapeutic Options ◽  
Whole Exome

BackgroundRhabdomyosarcoma (RMS) is rare cancer affecting children and adults. Pleomorphic RMS histology is almost exclusive to adult patients and often resistant to chemotherapy.ObjectiveWe report the case of a 19-year-old patient who presented with a metastatic chemoresistant pleomorphic RMS.MethodsConsidering the poor prognosis and the few systemic therapeutic options, we decided to carry out a whole exome sequencing (WES) of the tumour and germline DNA.ResultsWES identified a germline variation (c.1863_1864insT) in the MLH1 gene corresponding to a pathogenic mutation: (p. Leu622Serfs*10), whereas the family history did not fit with classical criteria for Lynch syndrome. Loss-of-heterozygosity at MLH1 locus was found in the tumour. Immunohistochemistry showed loss of MLH1 and PMS2 nuclear expression in the tumour cells. In view of the mismatch repair defects and a high programmed cell death ligand 1 (PD-L1) expression (60% of tumour cells expressed PD-L1), we administrated an anti-PD-1 antibody to the patient. He achieved a rapid complete response of the lung metastases, which appears sustained after a 1-year follow-up.ConclusionThis observation of an RMS revealing an unexpected Lynch syndrome underlines the overlap between tumorous and germline molecular genetics and emphasises the major impact of cancer genomic medicine in clinical practice for guiding treatment decision.

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