scholarly journals Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2667-2667
Author(s):  
Sarah Bannon ◽  
Mark Routbort ◽  
Guillermo Garcia-Manero ◽  
Naval G. Daver ◽  
Betul Oran ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Germline Mutations ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
History Of ◽  
Related Donor ◽  
Generation Sequencing

Abstract Introduction: Germline predispositions to hematologic malignancies were historically thought to be rare; however growing awareness has raised clinical challenges regarding how to identify, test, and manage these patients. Germline mutations in the gene DDX41 predispose to moderately increased lifetime risks of MDS and AML with a later age of onset. Optimal clinical care of these patients relies on identifying germline mutations and innovative strategies are needed to improve clinical detection. Methods: 1,262 individuals with myeloid malignancies underwent next-generation sequencing (NGS)-based molecular sequencing of DDX41. Individuals identified to have ≥1 DDX41 alterations present at >40% variant allele frequency (VAF) in the bone marrow were flagged for potential referral to genetic counseling (GC). All individuals referred for GC underwent standard genetic counseling evaluation and were offered DDX41 germline analysis on cultured skin fibroblasts. Results: Of 1,262 individuals, 32 (2.5%) were identified to have ≥1 somatic DDX41 mutation(s). Fourteen (44%) were referred for GC and germline confirmation testing. Eleven patients were male (78.5%) and 13/14 (93%) were Caucasian. Average age at diagnosis of myeloid neoplasm was 65 years (range 53-77 years). Fifty-seven percent (8/14) individuals were diagnosed with AML, 6/14 presented with MDS, including therapy-related MDS. 12/14 patients had diploid cytogenetics at presentation. A second somatic DDX41 mutation (biallelic) was identified in 10/14 (71%). There were no other significantly recurrent concomitant somatic mutations. Thirteen patients underwent germline evaluation and 12/13 (92%) were confirmed to have a germline DDX41 mutation. Six individuals underwent hematopoietic stem cell transplantation (SCT); five from a matched related donor, and in four cases, the related donor was negative for the familial DDX41 mutation. Six patients (43%) reported antecedent cytopenias: five with leukopenia and one with anemia. Five patients had a prior history of malignancy: three with prostate cancer, one with Non-Hodgkin's lymphoma and melanoma, and one with MGUS. 13/14 (93%) patients reported a family history of cancer, six (43%) of which included hematologic malignancies and/or cytopenias. From the 12 DDX41 germline-positive patients, 11 unaffected relatives underwent genetic testing. Four (36%) tested positive for the familial DDX41 mutation and seven (64%) tested negative. Conclusions: The detection of somatic DDX41 mutations at near-heterozygous frequencies on NGS panel testing is highly suggestive of a germline mutation and germline testing is strongly recommended. Our data validates existing reports in DDX41 germline patients including primarily high grade myeloid neoplasms, diploid cytogenetics, and later age at diagnosis. Interestingly nearly half of our patients had antecedent cytopenias, most often leukopenia. NGS screening for DDX41 mutations through multi-disciplinary collaboration is a useful and feasible tool to screen unselected myeloid neoplasm patients for high likelihood of germline DDX41 mutations enabling timely and appropriate care of these patients. Disclosures Daver: Novartis: Consultancy; Incyte: Research Funding; Pfizer: Consultancy; ImmunoGen: Consultancy; Pfizer: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Sunesis: Research Funding; Kiromic: Research Funding; Karyopharm: Research Funding; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Incyte: Consultancy; Otsuka: Consultancy; Karyopharm: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; ASTEX: Research Funding. Kadia:Abbvie: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. DiNardo:Karyopharm: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Agios: Consultancy.

scholarly journals Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations

2021 ◽  
Vol 10 ◽  
Author(s):  
Sarah A. Bannon ◽  
Mark J. Routbort ◽  
Guillermo Montalban-Bravo ◽  
Rohtesh S. Mehta ◽  
Fatima Zahra Jelloul ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Family Members ◽  
Hematologic Malignancies ◽  
Prior History ◽  
Cell Transplant ◽  
Next Generation ◽  
Myeloid Neoplasms ◽  
History Of ◽  
Generation Sequencing

Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.

scholarly journals Molecular Features in the Diagnosis of Myeloid Neoplasms in Down Syndrome Patients Less Than Four Years of Age: Experience from a Single Institution

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5180-5180
Author(s):  
Chris Ours ◽  
Fiorella Iglesias ◽  
Erin Morales ◽  
Luke Maese ◽  
Archana M Agarwal ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Next Generation Sequencing ◽  
Refractory Anemia ◽  
Refractory Disease ◽  
Next Generation ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
History Of ◽  
Generation Sequencing

Abstract Introduction: Patients with Down syndrome (DS) have an increased risk of hematological disorders, including transient abnormal myelopoiesis (TAM), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Twenty percent of patients with TAM subsequently develop myeloid neoplasm in the first 4 years of life. MDS represents a clonal aberration thought to be a pre-leukemic condition characterized clinically by cytopenias and erythroid, myeloid and/or megakaryocytic dysplasia in the bone marrow with or without increase in blasts and harbors a concordant, clone-specific mutation of GATA1. WHO 2016 classification of hematopoietic neoplasms does not distinguish between MDS and AML, as their overall prognosis appears to be similar. However, due to the rarity of this disorder, limited clinical and laboratory data is available, contributing to difficulties in establishing the diagnosis. Here we describe our center's recent experience with the diagnosis and molecular findings of myeloid neoplasm associated with Down syndrome (MN-DS). Design/Method: Retrospective review of the patient's electronic medical record and review of the literature was conducted. Routine karyotype, fluorescent in-situ hybridization (FISH) and next generation sequencing (NGS) studies were reviewed where available. Results: Six patients with DS diagnosed with AML or MDS were identified over a 3-year period. Mean age of the cohort was 18.5 (range 12-24) months with a slight female predominance. Three patients had a history of TAM, all of which resolved without intervention. Three patients had asymptomatic thrombocytopenia after birth without blasts or GATA1 mutation confirmation. One of the three patients with a history of TAM presented with overt AML, while in the others diagnosis was challenging. By WHO 2008 classification of myeloid neoplasms, four patients had refractory anemia with excess blasts, one had refractory cytopenia with multilineage dysplasia, and one had AML. For two patients, in whom myeloid directed next generation sequencing was obtained, mutations were found in GATA1, EZH2, and NRAS. One of the patients in our series presented with AML with gain of MECOM, RPN1 loss and D5S23 deletion by FISH and succumbed to relapsed disease. All patients were treated per Children's Oncology Group AAML1531 arm A protocol that included 3 induction cycles and 2 intensification cycles, except for a single patient that received one cycle per AAML0431 and completed therapy per AAML1531 arm B high risk due to persistent disease following initial induction cycle. Two patients are currently receiving treatment, three have no evidence of disease recurrence on follow up ranging from 2 to 18 months, and one of the patients has died due to relapsed/refractory disease. Conclusions: We present six cases of MN-DS in patients less than four years of age. Our cohort is representative of the diversity encountered in this rare disease including patients with 1) isolated cytopenia in the absence of overt morphological findings, 2) myelodysplasia, and 3) AML. In our patient with overt AML there were karyotypic features such as gain of MECOM, which with specific translocation partners has previously been described to portend a poor prognosis. This and other cytogenetic features perhaps warrant further investigation given our patient's refractory disease. In the patient with refractory cytopenia without blasts, there was a subpopulation of cells identified by NGS panel showing mutations in GATA1, EZH2, and NRAS that led to a diagnosis of MDS/MN-DS. Four of the patients had aberrant myeloid populations and dysplasia fitting diagnostic criteria for MDS. Establishing the clonal nature of the disease either by karyotype/FISH or NGS may help with the identification, treatment and prognostication of this unique patient population, and may aid in the diagnosis of MN-DS, which may be challenging in patients with DS once they have recovered from TAM. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Comprehensive Clinical Next Generation Sequencing-Based Assay Can Impact Hematopathologic Diagnosis in a Significant Subset of Patients with Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2984-2984
Author(s):  
Janine D. Pichardo ◽  
Julie T Feldstein ◽  
Maria Arcila ◽  
Connie Batlevi ◽  
Andrew D. Zelenetz ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Genomic Testing ◽  
Genomic Profiling ◽  
Pathologic Assessment ◽  
Somatic Alterations ◽  
The Impact ◽  
Generation Sequencing

Abstract High throughput genomic studies have identified novel recurrent somatic alterations with prognostic or therapeutic relevance in hematological malignancies. By contrast, few studies have investigated the impact on pathologic assessment, and clinicopathologic diagnosis. We therefore assessed the impact of a CLIA-certified CAP-accredited comprehensive clinical grade next-generation sequencing-based assay, FoundationOne Heme (FOH), on hematopathologic assessment of patients at our institution. The FOH assay targets 405 cancer-related genes and 31 frequently rearranged genes by DNA-capture and sequencing, and 265 frequently-rearranged genes by RNA-capture and sequencing. We prospectively tested 92 cases as part of routine clinical practice, including malignant lymphoid neoplasms (n=51) and suspected myeloid malignancies (n=41). (Table 1) The samples submitted included 30 blood, 38 bone marrow and 24 FFPE specimens. We were able to obtain genomic profiling data in90 of the 92 submitted cases (98%) including all FFPE specimens. A total of 282 genomic abnormalities (range 0-11, average 3.2 abnormalities/case) including substitutions, insertions/deletions and gene fusions were detected. There was excellent concordance between conventional cytogenetic or molecular genetic assays and FOH assay. Only 10 cases lacked any genomic abnormality. Six of these were morphologically normal bone marrows submitted to rule out myeloid neoplasia. Of the 4 remaining cases without recurrent somatic alterations, 2 cases were derived from myeloma patients where the sample analyzed had less than 20% plasma cells and 2 cases were from patients with myelodysplasia with likely low tumor content. In 84 cases with a diagnosis of hematologic malignancy, we identified genomic abnormalities with diagnostic relevance in 42 cases (50%). Most importantly, in 12 cases (14% of cohort), the presence of specific genomic alterations led to a change or refinement of the diagnosis. (Table 2) This included two cases in which a diagnosis of T-LGL was confirmed based on the presence of STAT3 mutations, three cases of lymphoma/myeloma in which a specific diagnosis was reached based on identification of pathogenic fusions/rearrangements, and 4 cases of MPN/MDS which could be confirmed based on the presence of known MPN/MDS disease alleles. In addition, we identified genomic alterations with prognostic relevance in 54 cases (64%), and with potential therapeutic impact in 64 cases (76%). Our data demonstrate that the FOH assay can be performed with a very high success rate (98%) in a routine clinical setting and that comprehensive genomic profiling can substantively impact pathologic assessment and diagnosis of a wide spectrum of hematologic malignancies. Genomic testing provided critical diagnostic information in half of the cases, in some instances refining or changing the conventional pathological diagnosis. These findings suggest that comprehensive targeted genomic testing has an important role to play not only in identifying prognostic and therapeutic targets but also in hematopathology diagnosis, and should be considered as a first line testing platform in hematologic malignancies. Table 1:Clinical characteristicsTotal number of casesN=92 Median age58 (18-82) SexMale58 (63%)Female34 (37%) Myeloid neoplasms33 (36%)AML14MDS11MPN6CMML1CML1 Lymphoid neoplasms51 (55%)DLBCL17B-ALL6TLPD6MCL5Myeloma5CLL3MZL3FL3BCL-NOS2CHL1 Normal marrow6 (7%) Sample failed2 (2%) Genomic abnormalities in hematologic malignancies80/84 (93%)Diagnostic42/84 (50%)Prognostic54/84 (64%)Potential therapeutic64/84 (76%) Table 2: Genomic changes which led to improved diagnosis and classification of the hematologic malignancy Case Diagnosis/Problem Genomic alteration Final/refined diagnosis 1 Neutropenia, T-LGL? STAT3 (N647I) T-LGL 2 Neutropenia, T-LGL? STAT3 (D661Y) T-LGL 3 T-LPD? JAK3 (M511I) T-PLL 4 T-LPD? TET2 (Q1523*), TP53 (R175G) PTCL, NOS 5 Transformed FL CIITA-DSCAML1 (Fusion) PMBL 6 CHL vs ALCL IGH-BCL2 (Rearrang.) DLBCL 7 BCL-NOS IGL-MYC (Rearrang.) BCL between DLBCL/BL 8 Myeloma IGH-MAF8 (Rearrang.) High risk myeloma 9 MDS? STK11 (F354L) RUNX1-MECOM (Fusion) MDS 10 MDS? MLL (ITD) MDS 11 MDS? KDM6A MDS 12 MPN MPL (R514_W515>KK) ET Disclosures Moskowitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum•Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Stein:Janssen Pharmaceuticals: Consultancy. He:Foundation Medicine: Employment. Stephens:Foundation Medicine, Inc. : Employment, Equity Ownership. Miller:Foundation Medicine: Employment. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Dogan:Foundation Medicine: Consultancy.

scholarly journals Recipients of Myelotoxic Chemotherapy Have Increased Prevalence of Clonal Hematopoiesis of Indeterminate Potential (CHIP) with a Typical Distribution of Chip-Associated Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3841-3841
Author(s):  
Adam J Olszewski ◽  
Anna Dorota Chorzalska ◽  
Annette S. Kim ◽  
Peter J. Quesenberry ◽  
Mary L Lopresti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Next Generation Sequencing ◽  
Cancer Survivors ◽  
Null Hypothesis ◽  
Research Funding ◽  
Next Generation ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasm ◽  
Typical Distribution ◽  
Generation Sequencing

Abstract Background: Recent studies (Coombs et al., Cell Stem Cell 2017) have identified presence of clonal hematopoiesis of indeterminate potential (CHIP) in samples of solid tumors. CHIP is more prevalent among cancer survivors who subsequently develop therapy-related myeloid neoplasm (Gillis et al., Lancet Oncol 2017; Takahashi et al., Lancet Oncol 2017; Gibson et al., J Clin Oncol 2017). However, the relationship between CHIP and exposure to myelotoxic chemotherapy delivered as part of treatment for solid tumor is uncertain. We hypothesized that CHIP is more prevalent among recipients of myelotoxic chemotherapy compared with age-matched population. Methods: In this prospective, cross-sectional study, we collected peripheral blood samples from survivors of breast cancer or lymphoma who had received anthracycline- and/or alkylator-containing chemotherapy as part of their curative cancer therapy. All subjects had to be clinically free of cancer, and not have any hematologic disorders or unexplained cytopenias. We recruited patients age 50 to 70, because according to published population datasets (Jaiswal et al. and Genovese et al., NEJM 2014) in a cohort with mean age of 60 the expected CHIP prevalence would be about 5%. To minimize any potential contamination by circulating tumor cells, we isolated genomic DNA from purified CD45+ cells. We determined presence of CHIP by next-generation sequencing using an Illumina TruSeq Custom Amplicon kit (MiSeq V2.2). The assay targeted 757 coding exons of 96 genes commonly mutated in hematologic malignancies, including 20 CHIP-defining genes. To establish presence of CHIP, we required a known pathogenic variant with variant allele fraction (VAF) ≥ 2%. According to a pre-specified statistical plan, assuming one-sided alpha of 0.05, the study had 80% power to reject the null hypothesis of baseline CHIP prevalence of 5% in a cohort with sample size of 80. Results: Among 80 enrolled subjects, median age was 62 years (interquartile range, 56-67). There were 78% women, and 88% of subjects were white non-Hispanic. Patients had received doxorubicin- and/or cyclophosphamide-containing adjuvant or curative chemotherapy for breast cancer (56%) or lymphoma (44%). Median time from completion of chemotherapy to enrollment was 27 months (interquartile range, 11-59). We have completed sequencing of 72 samples (updated analysis will be provided at the meeting). Mean coverage depth was 1418x (±224), and ≥200x coverage was achieved in a mean 91.4% (±1.8%) of target amplicons. We detected CHIP in 12 subjects (17%; binomial 95% confidence interval: 10-27%; P=.0002 for the null hypothesis test of 5% prevalence). Mean VAF for the CHIP mutations was 5.3% (range, 1.4% to 29.9%), and patients had up to 4 CHIP-associated mutations (Fig. A). The CHIP-associated mutations had a typical distribution with most common mutations in DNMT3A, ASXL1, SRSF2, and TET2 (Fig. B). There was only 1 TP53 mutation, previously suggested to associate with exposure to chemotherapy (Coombs et al., 2017). Potentially germline variants of unknown significance (VUS) were found in 78% of patients, at mean VAF 49% (Fig. C), most commonly in ATM (12%), NOTCH2 (7%), BCORL1, and DNMT3B (6% each). Additionally, 2 patients had low-VAF variants suspicious for CHIP: ATM c.6059G>A (3.0%); PRPF8 c.790T>C (VAF 2.3%). Presence of CHIP was not significantly associated with age (within the narrow age range in the study cohort), sex, race, type of cancer (breast or lymphoma), count of white cells, red cells, platelets, or time elapsed from completion of chemotherapy. Conclusions: We have detected a significantly increased, more than 3 times the expected value, prevalence of CHIP among cancer survivors who had received myelotoxic chemotherapy. However, the distribution of mutations was typical for CHIP, without previously suggested over-representation of TP53. Further research is ongoing to determine whether presence of CHIP is related to a direct mutagenic effect of chemotherapy or competitive advantage of pre-existing CHIP clones after the hematopoietic stress of chemotherapy. Our data indicate that an affordable next-generation sequencing screen may be useful for detection of CHIP in cancer patients who are planning adjuvant chemotherapy, or as a surveillance tool after such therapy, to predict the risk of a therapy-related myeloid neoplasm and optimize personalized treatment strategies. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Kim:Aushon Biosciences: Consultancy; LabCorp, Inc.: Consultancy; Papgene, Inc: Consultancy. Fenton:Astellas Pharma US: Other: Spouse employment. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding.

Genetic counseling referrals after next generation sequencing testing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1515-1515
Author(s):  
Rafael Gonzalez ◽  
Emma Ryan ◽  
Catherine Watson ◽  
Gloria Broadwater ◽  
Noah D. Kauff ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Hereditary Cancer ◽  
Germline Mutations ◽  
Tumor Board ◽  
Hereditary Cancer Syndrome ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Generation Sequencing ◽  
Germline Testing

1515 Background: Next generation sequencing (NGS) testing of tumor tissue or blood is performed to identify ‘actionable’ mutations that might guide patient care. NGS testing might incidentally identify germline mutations associated with cancer syndromes. No distinction is made between germline and somatic alterations on NGS reports, thus confirmatory germline testing is required. In this quality improvement (QI) initiative, we evaluated the frequency of referrals to genetic counseling (GC) for patients with potentially heritable germline mutations identified through NGS testing. Methods: We generated a list of high-risk mutations (HRMs) which merit GC referral based on NCCN guidelines. NGS test results for 3,400 consecutive patients with solid tumor malignancies were reviewed by the molecular tumor board from 1/2014-9/2019 and were screened for pathogenic HRMs. Basic demographic, oncologic, and GC data were retrospectively abstracted for each patient. The outcomes of interest were the frequency of HRMs identified through NGS testing, the proportion of patients subsequently referred to GC, and the proportion of patients ultimately diagnosed with a hereditary cancer syndrome. Results: 472 individual patients (14%) had NGS testing with one or more HRM identified; 465 patients were evaluable which corresponded to 519 HRMs that were included in the analysis (Table). Malignancies included were gastrointestinal 199 (42.8%), lung 83 (17.8%), genitourinary/renal 56 (12.0%), breast 49 (10.5%), gynecologic 35 (7.5%), and other 43 (9.2%). 75 (16.1%) patients had germline testing prior to NGS testing. Of those patients without prior germline genetic testing, 62 (15.9%) were referred to GC, and 19 (4.9%) patients were diagnosed with a hereditary cancer syndrome. Conclusions: Tumor NGS testing identifies HRMs that may represent an undiagnosed heritable germline mutation. Providers ordering NGS tests should review results for HRMs, refer to GC when appropriate, and offer confirmatory germline testing for patients and their families. [Table: see text]

scholarly journals Targeted Next Generation Sequencing for Myeloid Neoplasm in Pakistani Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5137-5137
Author(s):  
Saba Shahid ◽  
Shariq Ahmed ◽  
Saima Siddiqui ◽  
Misha Sohail ◽  
Tahir S. Shamsi
Keyword(s):  
Next Generation Sequencing ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Next Generation ◽  
Myeloid Malignancies ◽  
Targeted Next Generation Sequencing ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
Recurrent Mutations ◽  
Generation Sequencing

Abstract Introduction: Myeloid malignancies are heterogenous diseases caused by excessive accumulation of apparently myeloid clone of cells. Genomic studies on myeloid malignancies in recent years have identified new genetic alterations with biological and clinical significance. In addition to cytogenetics and morphological examination these genetic mutation play an important role in diagnosis, prognosis and treatment of the patient. We assessed the frequency and clinicopathologic significance of 54 genes in myeloid neoplasm patients by using targeted next-generation sequencing. Methods: About 50 samples were collected from OPD at National Institute of Blood Diseases (NIBD), that consisting of 17 MDS, 18 AML and other myeloid neoplasms. They comprises of 33 males and 17 females with median age of 33 years (range: 5-69 years). The myeloid sequencing panel of 54 genes (complete coding exons of 15 genes and exonic hotspots of 39 genes) was sequenced. The panel total coverage was 141 kb in genomic sequence. TruSight myeloid sequencing (Illumina, CA) libraries were prepared and runs were performed on a MiSeq (Illumina) genome sequencer. The generated data were analyzed by on-instrument software or TruSeq Amplicon® and BaseSpace Apps®. Results: Overall 3092 variants were identified, after excluding intronic and synonymous variants, 380 missense variants were found in 50 patients. Around 38 mutations in 22 genes were identified in 23 out of 50 samples (46 %). The recurrent mutations found in RUNX1, ASXL1, GATA2 and CEPBA genes in our cohort. Conclusion: Most of the myeloid neoplasms are not easily manageable with limited treatment options. Therefore, targeted gene panel by next generation sequencing was an appropriate method for precise identification of mutations in myeloid neoplasms at our institution. Based on the obtained findings we will be able to design patient management plan with respect to individualize genetic mutations in the clinical setting. Disclosures No relevant conflicts of interest to declare.

scholarly journals A case of hypereosinophilic syndrome with STAT5b N642H mutation

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Feihong Ding ◽  
Chaoping Wu ◽  
Yun Li ◽  
Sudipto Mukherjee ◽  
Subha Ghosh ◽  
...  
Keyword(s):  
Complete Blood Count ◽  
Hypereosinophilic Syndrome ◽  
Organ Damage ◽  
Myeloid Neoplasm ◽  
Acute Eosinophilic Pneumonia ◽  
Myeloid Neoplasms ◽  
Somatic Signal ◽  
Generation Sequencing

ABSTRACT Hypereosinophilia is defined as persistent eosinophilia (>1.5 × 109/L). Hypereosinophilic syndrome (HES) is a term used to describe a group of disorders characterized by sustained hypereosinophilia associated with end-organ damage. Based on underlying molecular mechanism of eosinophilia, there are different subtypes of HES. Diagnosis of HES subtype can be challenging, especially in the absence of overt lymphoid/myeloid neoplasms or discernable secondary causes. Long-term outpatient follow-up with periodic complete blood count and repeated bone marrow biopsy may be needed to monitor disease activity. Somatic signal transducer and activation transcription 5b (STAT5b) N642H mutation was recently found to be associated with myeloid neoplasms with eosinophilia. We report a case of HES who presented with pulmonary embolism and acute eosinophilic pneumonia, found to have recurrent STAT5b N642H mutation by next-generation sequencing, suggesting possible underlying myeloid neoplasm.

Myeloid neoplasms in the setting of chronic lymphocytic leukaemia/chronic lymphocytic leukaemia-like disease: a clinicopathological study of 66 cases comparing cases with prior history of treatment to those without

2021 ◽  
pp. jclinpath-2020-207334
Author(s):  
Catherine Luedke ◽  
Yue Zhao ◽  
Jenna McCracken ◽  
Jake Maule ◽  
Lian-He Yang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
The Other ◽  
Prior History ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
History Of ◽  
Cytogenetic Profile ◽  
Group 2 ◽  
Group 1

AimsMyeloid neoplasms occur in the setting of chronic lymphocytic leukaemia (CLL)/CLL-like disease. The underlying pathogenesis has not been elucidated.MethodsRetrospectively analysed 66 cases of myeloid neoplasms in patients with CLL/CLL-like disease.ResultsOf these, 33 patients (group 1) had received treatment for CLL/CLL-like disease, while the other 33 patients (group 2) had either concurrent diagnoses or untreated CLL/CLL-like disease before identifying myeloid neoplasms. The two categories had distinct features in clinical presentation, spectrum of myeloid neoplasm, morphology, cytogenetic profile and clinical outcome. Compared with group 2, group 1 demonstrated a younger age at the diagnosis of myeloid neoplasm (median, 65 vs 71 years), a higher fraction of myelodysplastic syndrome (64% vs 36%; OR: 3.1; p<0.05), a higher rate of adverse unbalanced cytogenetic abnormalities, including complex changes, −5/5q- and/or −7/7q- (83% vs 28%; OR: 13.1; p<0.001) and a shorter overall survival (median, 12 vs 44 months; p<0.05).ConclusionsMyeloid neoplasm in the setting of CLL/CLL-like disease can be divided into two categories, one with prior treatment for CLL/CLL-like disease and the other without. CLL-type treatment may accelerate myeloid leukaemogenesis. The risk is estimated to be 13-fold higher in patients with treatment than those without. The causative agent could be attributed to fludarabine in combination with alkylators, based on the latency of myeloid leukaemogenesis and the cytogenetic profile.

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