scholarly journals Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes

BMC Cancer ◽  
2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Jean-François Spinella ◽  
Jasmine Healy ◽  
Virginie Saillour ◽  
Chantal Richer ◽  
Pauline Cassart ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Fanconi Anemia ◽  
Rare Case ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Whole Exome

Abstract 2484: Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia

2012 ◽  
Author(s):  
Jasmine Healy ◽  
Virginie Saillour ◽  
Jean-François Spinella ◽  
Ramon Vidal ◽  
Eric Bareke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Case ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Whole Exome

Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing

2018 ◽  
Vol 19 (15) ◽  
pp. 1181-1193 ◽  
Author(s):  
Rachid Abaji ◽  
Francesco Ceppi ◽  
Swati Patel ◽  
Vincent Gagné ◽  
Chang J Xu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Risk ◽  
Lymphoblastic Leukemia ◽  
Genetic Risk Factors ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Whole Exome

Whole‐exome sequencing reveals the subclonal expression of NUP214 ‐ ABL1 fusion gene in T‐cell acute lymphoblastic leukemia

2019 ◽  
Vol 67 (1) ◽  
Author(s):  
Yoshinori Tsurusaki ◽  
Jun‐ichi Nagai ◽  
Sachio Fujita ◽  
Masanaka Sugiyama ◽  
Wataru Nakamura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Whole Exome ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals PB1659 WHOLE EXOME SEQUENCING IN ADULT PATIENT WITH PHILADELPHIA / BCR-ABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 767
Author(s):  
P. Chin Lee ◽  
Z. Zubaidah ◽  
H. Ranjeev ◽  
K. Tsung Fei ◽  
N. Ching Ching
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adult Patient ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Whole Exome

Using Whole Exome Sequencing in Pediatric Acute Lymphoblastic Leukemia Germline, Diagnosis, and Relapse Trios to Discover Novel Relapse Enriched Mutations for Clonal Backtracking By Ddpcr

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4085-4085
Author(s):  
Jason Saliba ◽  
Nikki Ann Evensen ◽  
Julia Meyer ◽  
Igor Dolgalev ◽  
Daniel Newman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Rna Polymerase Ii ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Missense Mutations ◽  
Whole Exome ◽  
Major Clone ◽  
Insight Into

Abstract While the outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically over the last four decades, the prognosis for those who relapse remains dismal, especially for those who relapse while on therapy. In fact, relapsed disease remains a leading cause of cancer related mortality in children. To date, various studies have discovered a number of somatic alterations that contribute to driving relapse and have provided profound insight into the selective forces that lead to clonal outgrowth of drug resistant populations, however these lists are not yet comprehensive. We analyzed 13 pediatric ALL patients treated according to Nordic NOPHO ALL protocols and explored a comprehensive collection of germline, diagnosis, relapse, and maintenance samples. Whole exome sequencing (WES) was performed on all available germline, diagnosis, and relapse samples to find somatic missense mutations enriched in the relapse samples versus the diagnosis and/or germline samples. Sequencing reads were aligned to the human genome (build hg19/GRCh37) using the Burrows-Wheeler Aligner (BWA) and single-nucleotide somatic variants were generated with MuTect. ANNOVAR was used to annotate variants with functional consequences and identify if the variant was contained in dbSNP, ExAC, 1000 Genomes project, and COSMIC databases. Nine of the NOPHO patients were analyzed as trios (WES of germline, diagnosis, and relapse), three of the patients as Diagnosis-Relapse duos and one as a Germline-Relapse duo. Candidate relapse driving mutations were identified as present at high levels in the relapse sample, but were undetectable in germline or low to absent in the diagnosis sample. Missense mutations had to be enriched by ≥5% in the relapse sample versus diagnosis/germline to be included for further consideration. Relapse specific candidates were further prioritized based on tumor percentage (≥ 20%), bioinformatic tools predicting a missense change being deleterious or damaging to protein function, and literature reviews for insight into the biological pathway potentially affected.Eight of the thirteen patients contained mutations in genes previously reported to be enriched and are involved in nucleoside metabolism/synthesis, histone acetylation, transcription regulation, or cell signaling/growth through the Ras pathway. Interestingly, a majority of the patients contained novel relapse specific genes in a major clone that met the criteria for drivers (Table 1). These novel candidates are involved in a wide array of cellular processes such as cell adhesion/migration, RNA polymerase II/transcription, circadian rhythm, the unfolded protein response, RNA transport, epigenetic regulation, DNA methylation, and kinases. Knowing the exact relapse specific mutations for each patient allows use of droplet digital PCR (ddPCR) to track the emergence of specific candidate mutations from peripheral blood samples (range of 2-68 per patient, Table 1) collected from these patients prior to relapse. Thus far, we have successfully backtracked the emergence of the NT5C2 p.R367Q mutation (.2% Minor Allele Frequency (MAF)) just over a month before frank relapse in patient 8142, using ddPCR. Tracking these mutations offers insight into which mutations drive relapse and the speed at which the relapse clones emerge. Probes for ddPCR to detect our top candidates have been developed and are currently being applied. Ultimately, candidate mutations emerging with the major clone will undergo functional testing to understand the mechanism by which the mutation drives relapse. Through these approaches, we will be able to pinpoint what mutation(s) and combinations thereof drive relapse through clonal survival during maintenance therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Whole-exome sequencing exploration of acquired uniparental disomies in B-cell precursor acute lymphoblastic leukemia

Leukemia ◽  
2018 ◽  
Vol 32 (9) ◽  
pp. 2058-2062 ◽  
Author(s):  
Kristina B. Lundin-Ström ◽  
Andrea Biloglav ◽  
Henrik Lilljebjörn ◽  
Marianne Rissler ◽  
Thoas Fioretos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Whole Exome

scholarly journals Whole-Exome Sequencing in Korean Children with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4994-4994
Author(s):  
Ye Jee Shim ◽  
Jung-Sook Ha ◽  
Young-Rok Do ◽  
Heung Sik Kim
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Diagnostic Information ◽  
Cancer Gene ◽  
Korean Children ◽  
Functional Variants ◽  
Hla Dr ◽  
Whole Exome

Abstract Purpose: Next-generation sequencing methods recently have been applied for leukemia patients to discover genetic variants. In this study, we conducted whole-exome sequencing (WES) in Korean acute lymphoblastic leukemia (ALL) children to identify putative genetic drivers of leukemia. Methods: Four Korean ALL children were included for WES. For two of them, we also conducted WES after remission, considered as germline control. The characteristics of subjects and the diagnostic information are described in Table 1. Genomic DNA was extracted from the subject¡¯s bone marrow aspirates at diagnosis of leukemia and/or after remission. Whole-exome was captured by SureSelect Human All Exon V4 (Agilent Technologies, California, USA). Sequencing was performed using HiSeq2000 (Illumina, California, USA). Variants in dbSNP135 and TIARA database were excluded. Variants with minor allele frequencies > 0.5% of 1000g were filtered out. Functional variants (gain of stop codon, frameshifts and nonsynonymous SNVs) were selected as pathogenic mutations and were scanned for the 571 cancer gene set using ¡°Cancer gene Census¡± in COSMIC website. The finally selected variants were verified by PROVEAN, SIFT and PolyPhen-2. This research was approved by The Institutional Review Board in Keimyung University Dongsan Medical Center (Approval No., 2015-05-029-002). Results: After comparison between WES at diagnosis and WES after remission, p.W112C in PAX5 in patient 1 andp.G315C in KMT2C, p.T311P in NOTCH1, p.G11A in HOXD13 in patient 2 were considered as pathogenic, respectively. In patient 3 and 4, p.R293C in FNBP1, p.R254H in PCSK7, p.E11Q in TP53, p.R806Q in MYO5A, p.R108G in PPFIBP1, p.C1785R in RNF213, and p.A963P in WRN were suspected as putative drivers of leukemia. The respective variants are shown in Table 2. Conclusions: This is the first attempt of WES in Korean children with leukemia. WES is a valuable method to identify genomics of childhood ALL. Table 1. Characteristics and diagnostic information of four Korean acute lymphoblastic leukemia children. No. Diagnosis BMblast Karyotype Hemavision FISH Immunophenotype WESAt diagnosis WESAfter remission 1 B-ALL 88.4% 44,XX,der(2)t(2;?),-4,-9,der(9)t(2;9),der(16)t(9;16)(q13;q12) Negative . CD10, D19, CD20, CD22, cCD22,cCD79a, CD34, CD45 Yes Yes 2 Pre B-ALL 95.0% No mitosis t(1;19)(q23;p13) . CD38, CD138, CD10, CD19, CD22,cCD79a, HLA-DR, CD45 Yes Yes 3 B-ALL 88.6% 46,XX Negative . CD10, CD19, CD22, cCD79a, CD34,TdT, HLA-DR, CD45, CD38 Yes No 4 B-ALL 94.3% Hypotriploidywith structural abnormality/46,XY Negative Trisomy 5, 11, 12Tetrasomy 21 CD10, CD19, CD22, cCD79a, CD34,TdT, HLA-DR Yes No Table 2. Identified putative genetic drivers in four Korean acute lymphoblastic leukemia children by whole-exome sequencing. No. Gene Chr:Position Variant PROVEAN (score) SIFT (score) Polyphen-2 (score) Germline or somatic 1 PAX5 9:37015068 exon3:c.G336T:p.W112C Deleterious (-11.12) Damaging (0.000) Probably damaging (0.998) Somatic 2 KMT2C 7:151970859 exon7:c.G943T:p.G315C Deleterious (-7.05) Damaging (0.001) Probably damaging (1.000) Somatic NOTCH1 9:139413211 exon6:c.A931C:p.T311P Deleterious (-4.82) Damaging (0.012) Benign (0.033) Somatic HOXD13 2:176957650 exon1:c.G32C:p.G11A Neutral (-0.88) Tolerated (0.118) Possibly damaging (0.953) Somatic 3 FNBP1 9:132687349 exon9:c.C877T:p.R293C Deleterious (-6.03) Damaging (0.001) Probably damaging (1.000) Somatic PCSK7 11:117097881 exon5:c.G761A:p.R254H Deleterious (-3.30) Damaging (0.007) Probably damaging (0.991) Somatic 4 TP53 17:7579882 exon2:c.G31C:p.E11Q Neutral (0.42) Damaging (0.000) Probably damaging (0.996) Germline/somatic MYO5A 15:52668547 exon19:c.G2417A:p.R806Q Deleterious (-3.12) Damaging (0.003) Possibly damaging (0.575) Somatic PPFIBP1 12:27799046 exon5:c.C322G:p.R108G Deleterious (-5.76) Damaging (0.000) Probably damaging (1.000) Somatic RNF213 17:78313373 exon27:c.T5353C:p.C1785R Deleterious (-10.45) Damaging (0.000) Probably damaging (1.000) Somatic WRN 8:30989942 exon24:c.G2887C:p.A963P Deleterious (-3.90) Damaging (0.003) Probably damaging (0.988) Germline Disclosures No relevant conflicts of interest to declare.

scholarly journals Whole-exome sequencing of pediatric acute lymphoblastic leukemia

Leukemia ◽  
2011 ◽  
Vol 26 (7) ◽  
pp. 1602-1607 ◽  
Author(s):  
H Lilljebjörn ◽  
M Rissler ◽  
C Lassen ◽  
J Heldrup ◽  
M Behrendtz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Whole Exome

Genetic Landscapes Of Childhood T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3786-3786
Author(s):  
Masafumi Seki ◽  
Kenichi Yoshida ◽  
Yusuke Sato ◽  
Yuichi Shiraishi ◽  
Kenichi Chiba ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Suppressor Gene ◽  
Genome Wide ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Generally, childhood T-ALL patients have a worse prognosis than B cell precursor ALL patients. Recent studies have identified a subtype of T-ALL termed “early T-cell precursor” (ETP) ALL, which is associated with a high risk of treatment failure. In spite of recent improvements of risk stratified multiagent chemotherapy, relapsed patients have a poor prognosis even if they were non-ETP ALL. Recent genome-wide approach revealed frequent NOTCH1 and FBXW7 oncogenic mutations mutations in T-ALL. In addition, previous whole-exome sequencing disclosed novel CNOT3 mutations in approximately 10% of adult T-ALL cases, and thus, CNOT3 was thought to be one of the novel tumor suppressor gene for adult T-ALL. CNOT3 is part of the CCR4-NOT complex that is the major deadenylase of mRNA. NT5C2, encoding a 5ʹ-nucleotidase was identified as relapse specific mutation, of which mutation is associated with the outgrowth of drug-resistant clones in ALL. However, these mutations have been found in a fraction of childhood T-ALL suggests that the existence of other genetic pathogenesis. To discover new oncogenic gene mutations which involved in the pathogenesis of relapsed T-ALL and to identify novel prognostic markers of childhood T-ALL, we performed genome-wide analysis using whole-exome sequencing and 250K SNP array analyses in 8 cases with relapsed T-ALL and 16 cases with non-relapsed T-ALL. The mean coverage in the whole-exome sequencing of tumor and germline samples was 108× and 100× for the 50-Mb target regions, respectively, by which more than 90% of the coding sequences were represented by more than 20 independent reads on average. A mean of nonsilent mutations per sample at presentation was 18, and sample at 1st relapsed was 19. There were only 16 recurrent mutations in 24 cases; however no shared mutation in 8 relapsed cases other than NOTCH1 and FBXW7. NOTCH1 mutations were found in 50% (12/24), and were frequently identified in relapsed cases (6/8). FBXW7 mutations were also frequently found in 6/24 cases, and 60 % (3/6) were compound heterozygous mutations. In those 6 cases, only one case with FBWX7 mutation had a NOTCH1 mutation. CNOT3 mutations were reported to be frequent in adult T-ALL, however we found only two cases with CNOT3 mutations (8.3%). In addition, PHF6 mutation, which is known as X-linked tumor suppressor gene in T-ALL, was recurrent in 3 cases. Other recurrent mutations were shared between 2 cases, respectively. NT5C2 mutation has been reported to a relapse-specific mutation, and we also found NT5C2 mutations in 2 relapsed cases, which detected in only relapsed samples. RPL5 and RPL10 mutations were reported to be found in 10 % of pediatric T-ALL; however there was one mutation in RPL related genes in our study. Furthermore, we found common mutations of acute myeloid leukemia such as TCF7, STAT5A, KIT, RUNX1, and EP300 mutations in a single case. On the other hand, although pediatric T-ALL showed largely normal genomic copy number profiles, homozygous deletions at chromosome 9p21 harboring CDKN2A were frequently detected in our study (17/24 71%). Especially, 9p21 deletions were found in all relapsed cases, suggesting that loss of CDKN2A locus was a critical genetic mechanism of relapsed T-ALL. In conclusion, our results revealed mutations in several known genes, but overall frequency of recurrent somatic mutations in childhood T-ALL is low, even in relapsed samples. Although loss of CDKN2A locus was detected in all relapsed cases, recurrent relapse-specific mutations could not be identified other than NT5C2. These findings suggest that the majority of relapsed T-ALL may be driven by aberrations of CDKN2A and minor clone variants and/or epigenetic modifications during tumor evolution. Disclosures: No relevant conflicts of interest to declare.

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