scholarly journals Whole-exome Sequencing Reveals Genetic Underpinnings of Tongue Carcinoma in Chinese Population

2020 ◽  
pp. 1-9
Author(s):  
Shuhang Wang ◽  
Ning Jiang ◽  
Zicheng Yu ◽  
Yuan Fang ◽  
Shujun Xing ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Asian Population ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Driver Mutations ◽  
Copy Number Loss ◽  
Asian Patients ◽  
Whole Exome ◽  
Distinct Features

Oral tongue squamous cell carcinoma (OTSCC) is a common malignancy, of which the incidence has increased in China in the last decade. Surprisingly, while multiple studies have revealed the mutational features of OTSCC in Western populations, limited data was shown in Asian patients. Herein, we utilized whole-exome sequencing to profile the genetic alterations in 13 Chinese OTSCC and compared them to those from 40 Western patients published in Cancer Discovery. In result, some key driver mutations were observed in both Chinese and Western cohorts, such as TP53 (Chinese 60.0% vs Western 60.0%), FAT1 (Chinese 7.7% vs Western 30.0%), CASP8 (Chinese 7.7% vs Western 10.0%) and NOTCH1 (Chinese 15.4% vs Western 10.0%), while mutations in CDKN2A (23.1%) and NTRK3 (23.1%) were only observed in Chinese patients, indicating these two novel mutations might play vital roles in OTSCC tumorigenesis specifically in Asian population. Mutational signatures depicted both common and distinct features across cohorts. In addition, significant copy number loss was found in 7q22.1, 9q13.1, and focal regions spanning CDKN2A and CDKN2B. FOXP1-TEX261 (2p13.3:3p13) fusion, reported in various cancer types, was firstly observed in OTSCC. Also, we identified numerous actionable mutations with FDA approved targeted. Taken together, our study revealed the mutational features of Chinese OTSCC patients, either similar or distinct to those of Caucasian patients. CDKN2A and NTRK3 were observed as two novel drivers that might play essential roles in tumorigenesis in Chinese patients, and were found as two potential therapeutic targets, rendering it promising to develop novel therapies.

Whole Exome Sequencing Reveals Clonal Evolution Pattern and Driver Mutations Of Relapsed Pediatric AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1410-1410
Author(s):  
Kenichi Yoshida ◽  
Norio Shiba ◽  
Yuichi Shiraishi ◽  
Akira Shimada ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Pediatric Leukemia ◽  
Term Survival ◽  
Whole Exome ◽  
Pediatric Aml

Abstract Background Pediatric acute myeloid leukemia (AML) comprises ∼20% of pediatric leukemia, representing one of the major therapeutic challenges in pediatric oncology. Nearly 40% of patients still relapse after present first-line therapies and once the relapse occurs, the long-term survival rates decrease, ranging from 21% to 34%. As for the pathogenesis of AML relapse, the recent development of massively parallel sequencing technologies has provided a new opportunity to investigate comprehensive genetic alterations that are involved in tumor recurrence of adult AML. However, little is known about the molecular details of relapsed pediatric AML. Methods In order to reveal the clonal origin and the major mutational events in relapsed pediatric AML, we performed whole exome sequencing of 4 trio samples from diagnostic, relapsed and complete remission phases using Illumina HiSeq 2000. Copy number abnormalities were also detected using whole exome sequencing. Subsequently, deep sequencing of identified mutations was performed to evaluate intra-tumor heterogeneity and the clonolocal history of relapsed clones. Results Whole-exome sequencing of 12 samples from 4 patients were analyzed with a mean coverage of more than x100, and 95 % of the targeted sequences were analyzed at more than x20 depth on average. A total of 98 somatic mutations were identified, where mean number of non-silent mutations was higher at relapsed phase than at the time of diagnosis (14.0/case vs 10.5/case) (p=0.270). Assessment of clonality using variant allele frequencies of individual mutations suggested that some mutations were subclonal mutations, consisting of intra-tumor heterogeneity both at the time of diagnosis and at relapse. In all 4 patients, relapsed AML evolved from one of the subclones at the initial phase, which was accompanied by many additional mutations including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process of leukemia recurrence. Forty-six out of the 98 mutations were specific either at the time of diagnosis (n = 16) or at relapse (n = 30). Relapse-specific mutations and copy number changes were found in several genes including known drivers such as NRAS and CREBBP. These mutations were further investigated in an extended cohort of relapsed pediatric AML samples using targeted sequencing to evaluate their prevalence. In some cases, AML relapse may accompany a dynamic clonal change. For example, some bona fide driver mutations, such as KRAS mutations, that were predominant at the time of diagnosis disappeared in relapsed samples. Discussion Whole exome sequencing unmasked clonal structure of primary and relapsed pediatric AML, which helped to understand the underlying mechanism of relapse in pediatric AML. Our results suggested that pediatric AML has intra-tumor heterogeneity and subclonal mutations such as NRAS and CREBBP occurring in one of the subclones could drive the AML relapse. Disclosures: No relevant conflicts of interest to declare.

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

2021 ◽  
Vol 22 ◽  
Author(s):  
Masoud Heidari ◽  
Hamid Gharshasbi ◽  
Alireza Isazadeh ◽  
Morteza Soleyman-Nejad ◽  
Mohammad Hossein Taskhiri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Polycystic Kidney ◽  
Novel Mutations ◽  
Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

scholarly journals A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

2017 ◽  
Vol 176 (5) ◽  
pp. K9-K14 ◽  
Author(s):  
Sandrine Caburet ◽  
Ronit Beck Fruchter ◽  
Bérangère Legois ◽  
Marc Fellous ◽  
Stavit Shalev ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Polycystic Ovary ◽  
Missense Variant ◽  
Genetic Alterations ◽  
Homozygous Mutation ◽  
Gonadotropin Secretion ◽  
Whole Exome ◽  
A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

Novel ATP13A2 and PINK1 variants identified in Chinese patients with Parkinson’s disease by whole-exome sequencing

2020 ◽  
Vol 733 ◽  
pp. 135075 ◽  
Author(s):  
Hui Chen ◽  
Yu-Hua Jin ◽  
Yan-Yan Xue ◽  
Yu-Lan Chen ◽  
Yi-Jun Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Patients ◽  
Whole Exome

scholarly journals Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations

2016 ◽  
Vol 27 (4) ◽  
pp. 738-744 ◽  
Author(s):  
M. Bousquet ◽  
C. Noirot ◽  
F. Accadbled ◽  
J. Sales de Gauzy ◽  
M.P. Castex ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Alterations ◽  
Whole Exome

Whole-exome sequencing of chondroid hamartoma of lung identified no driver mutations

2018 ◽  
Vol 214 (3) ◽  
pp. 459-462
Author(s):  
Su Hye Choi ◽  
Hyeon-Chun Park ◽  
Min Sung Kim ◽  
Yeun-Jun Chung ◽  
Sug Hyung Lee
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Driver Mutations ◽  
Whole Exome

Exome Sequencing Identifies Recurring DNMT3A Mutations in Adult ETP-ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1377-1377
Author(s):  
Martin Neumann ◽  
Sandra Heesch ◽  
Cornelia Schlee ◽  
Stefan Schwartz ◽  
Nicola Goekbuget ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Somatic Mutations ◽  
Pediatric Patients ◽  
Genetic Alterations ◽  
Whole Exome ◽  
Repressor Complex ◽  
Flt3 Mutations ◽  
Exome Sequence

Abstract Abstract 1377 Introduction: Early T-cell precursor (ETP) ALL accounting for 10% of all T-ALL cases is of special interest because of its proposed origin from early thymic progenitors with multilineage differentiation potential. ETP-ALL is associated with a poorer outcome in pediatric and adult patients. On the molecular level, ETP-ALL is characterized by a specific immunophenotype (CD1-, CD5weak, CD8-, co-expression of stem cell and/or myeloid antigens) and distinct molecular features (expression of stem cell genes, high frequency of FLT3 mutations with absence of NOTCH1 mutations). Whereas a highly heterogeneous genetic pattern was revealed by whole genome sequencing in pediatric patients, the genetic background of adult ETP-ALL remains largely unknown. Here we investigated genetic alterations in adult ETP-ALL by whole exome sequencing and subsequently analyzed specific target genes. Patients and methods: We performed whole exome sequencing of five paired (diagnosis/remission) adult ETP-ALL patients enrolled in German Acute Lymphoblastic Leukemia Multicenter Study Group (GMALL) trials. Using exon capturing from genomic DNA, followed by 76-bp paired-end sequencing on an Illumina Genome Analyzer IIx platform, we generated at least 5 Gb of exome sequence from each ETP-ALL and remission samples. Somatic mutations were identified by comparing the ETP-ALL with the remission exome sequence, excluding all annotated polymorphisms (dbSNP130), non-coding positions and positions with evidence of a variant in the corresponding remission samples. Candidate variants were confirmed by capillary sequencing of genomic DNA. The DNMT3A mutations status was analyzed by Sanger sequencing of exons 11–23 in additional 68 adult ETP-ALL (55 male, 13 female, median age: 38 years) as well as the mutation status of the polycomb repressor complex (PRC) genes EZH2 and SUZ12. For 52 of 68 patients clinical follow-up data were available. Results: Using whole exome sequencing we found a total of 56 non-synonymous somatic mutations or indels in the five ETP-ALL patients (range: 6 to 16 per patient). Eleven mutations/indels affected cancer genes. DNMT3A (2/5) and FAT3 (2/5) were recurrently mutated in the five patients. The DNA-methyl-transferase DNMT3A is a frequent mutational target in acute myeloid leukemia (AML; 20%), whereas FAT3 (FAT, tumor suppressor homolog 3) mutations were recently reported in ovarian carcinoma (TCGA, Nature 2011). Novel mutations identified in adult ETP-ALL involved genes in epigenetic regulation (e.g. MLL2, MLL3, BMI1), and in genes previously reported to be mutated in ETP-ALL (e.g. in JAK1, ETV6, NOTCH1, DNM2). By Sanger sequencing, we screened for DNMT3A mutations in a larger cohort of adult ETP-ALL. DNMT3A mutations were present in 11 of the 68 (16%) patients, a mutation rate similar to AML. Amino acid R882 (exon 23), the most frequently mutated amino acid in AML, was mutated in five ETP-ALL. The remaining six mutations occurred in single spots, with one exception in the ZNF or the MTF domain. Patients with a DNMT3A mutation were significantly older (median: 63 vs 37 years, P=0.016). No correlation was found between DNMT3A and FLT3 mutations (27% in DNMT3A mut pts. vs. 37% in DNMT3A wt pts., P=0.41) or NOTCH1 mutations (10% in DNMT3A mut pts. vs. 16% in DNMT3A wt pts., P=0.47). In addition, we investigated genetic alterations in epigenetic regulators including members of the polycomb repressor complex (PRC). Mutations were seen in EZH2 in 4/68 (6%), SUZ12 in 1/68 (1%) and SH2B3 in 4/69 (6%) of ETP-ALL. Interestingly, patients with at least one mutation in an epigenetic regulator gene (DNMT3A, SUZ12, SH2B3, MLL2, or EZH2) showed a trend towards an inferior survival (one-year-survival: 50% vs. 85%, P=0.08). Conclusion: Adult ETP-ALL patients display a heterogenous spectrum of mutations, particularly affecting genes involved in epigenetic regulation. The spectrum is different to pediatric patients with a lower rate of polycomb repressor complex and a higher rate of DNMT3A mutations. The higher rate of DNMT3A mutations in older patients might point to a different pathogenesis compared to pediatric ETP-ALL. Like in AML, DNMT3A mutations in adult ETP-ALL show a similar frequency, within the same hot spots and are correlated with an adverse prognostic value, underscoring the myeloid character of ETP-ALL. Thus, these data may provide a rationale to use epigenetic therapy in ETP-ALL. Disclosures: Krebs: Illumina: Honoraria. Greif:Illumina: Honoraria.

Whole Exome Sequencing In Relapsed Pediatric T-ALL: Progression Into Relapse Is Characterized By An Increased Number Of Somatic Mutations and a Conservation Of Mutations In Leukemogenic Driver Genes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 228-228
Author(s):  
Joachim Kunz ◽  
Tobias Rausch ◽  
Obul R Bandapalli ◽  
Martina U. Muckenthaler ◽  
Adrian M Stuetz ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Initial Diagnosis ◽  
Driver Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Recurrent Mutations

Abstract Acute precursor T-lymphoblastic leukemia (T-ALL) remains a serious challenge in pediatric oncology, because relapses carry a particularly poor prognosis with high rates of induction failure and death despite generally excellent treatment responses of the initial disease. It is critical, therefore, to understand the molecular evolution of pediatric T-ALL and to elucidate the mechanisms leading to T-ALL relapse and to understand the differences in treatment response between the two phases of the disease. We have thus subjected DNA from bone marrow samples obtained at the time of initial diagnosis, remission and relapse of 14 patients to whole exome sequencing (WES). Eleven patients suffered from early relapse (duration of remission 6-19 months) and 3 patients from late relapse (duration of remission 29-46 months).The Agilent SureSelect Target Enrichment Kit was used to capture human exons for deep sequencing. The captured fragments were sequenced as 100 bp paired reads using an Illumina HiSeq2000 sequencing instrument. All sequenced DNA reads were preprocessed using Trimmomatic (Lohse et al., Nucl. Acids Res., 2012) to clip adapter contaminations and to trim reads for low quality bases. The remaining reads greater than 36bp were mapped to build hg19 of the human reference genome with Stampy (Lunter & Goodson, Genome Res. 2011), using default parameters. Following such preprocessing, the number of mapped reads was >95% for all samples. Single-nucleotide variants (SNVs) were called using SAMtools mpileup (Li et al., Bioinformatics, 2009). The number of exonic SNVs varied between 23,741 and 31,418 per sample. To facilitate a fast classification and identification of candidate driver mutations, all identified coding SNVs were comprehensively annotated using the ANNOVAR framework (Wang et al., Nat. Rev. Genet., 2010). To identify possible somatic driver mutations, candidate SNVs were filtered for non-synonymous, stopgain or stoploss SNVs, requiring an SNV quality greater or equal to 50, and requiring absence of segmental duplications. Leukemia-specific mutations were identified by filtering against the corresponding remission sample and validated by Sanger sequencing of the genomic DNA following PCR amplification. We identified on average 9.3 somatic single nucleotide variants (SNV) and 0.6 insertions and deletions (indels) per patient sample at the time of initial diagnosis and 21.7 SNVs and 0.3 indels in relapse. On average, 6.3 SNVs were detected both at the time of initial diagnosis and in relapse. These SNVs were thus defined as leukemia specific. Further to SNVs, we have also estimated the frequency of copy number variations (CNV) at low resolution. Apart from the deletions resulting from T-cell receptor rearrangement, we identified on average for each patient 0.7 copy number gains and 2.2 copy number losses at the time of initial diagnosis and 0.5 copy number gains and 2.4 copy number losses in relapse. We detected 24/27 copy number alterations both in initial diagnosis and in relapse. The most common CNV detected was the CDKN2A/B deletion on chromosome 9p. Nine genes were recurrently mutated in 2 or more patients thus indicating the functional leukemogenic potential of these SNVs in T-ALL. These recurrent mutations included known oncogenes (Notch1), tumor suppressor genes (FBXW7, PHF6, WT1) and genes conferring drug resistance (NT5C2). In several patients one gene (such as Notch 1, PHF6, WT1) carried different mutations either at the time of initial diagnosis and or in relapse, indicating that the major leukemic clone had been eradicated by primary treatment, but that a minor clone had persisted and expanded during relapse. The types of mutations did not differ significantly between mutations that were either already present at diagnosis or those that were newly acquired in relapse, indicating that the treatment did not cause specific genomic damage. We will further characterize the clonal evolution of T-ALL into relapse by targeted re-sequencing at high depth of genes with either relapse specific or initial-disease specific mutations. In conclusion, T-ALL relapse differs from primary disease by a higher number of leukemogenic SNVs without gross genomic instability resulting in large CNVs. Disclosures: No relevant conflicts of interest to declare.

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