Kooperativer Bibliotheksverbund

In: G3 Genes|Genomes|Genetics, Oxford University Press (OUP), Vol. 5, No. 5 ( 2015-05-01), p. 719-740

Abstract: The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Type of Medium: Online Resource

ISSN: 2160-1836

URL: Article

DOI: 10.1534/g3.114.015966

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2015

detail.hit.zdb_id: 2629978-1

In: Blood Advances, American Society of Hematology, Vol. 4, No. 20 ( 2020-10-27), p. 5246-5256

Abstract: Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2020002119

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3

In: The Astrophysical Journal, American Astronomical Society, Vol. 873, No. 2 ( 2019-03-11), p. 111-

Type of Medium: Online Resource

ISSN: 1538-4357

URL: Article

DOI: 10.3847/1538-4357/ab042c

Language: Unknown

Publisher: American Astronomical Society

Publication Date: 2019

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detail.hit.zdb_id: 1473835-1

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 8 ( 2022-04-14), p. 1614-1627

Abstract: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. Experimental Design: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor. Results: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3–32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes. Conclusions: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-21-2451

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2022

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 291-291

Abstract: Background Therapy-related myelodysplastic syndrome (MDS) and acute leukemias represent a major cause of non-relapse morbidity and mortality in childhood cancer survivors, and have been associated with exposure to cytotoxic therapies (e.g. radiation, alkylators, topoisomerase inhibitors). Neuroblastoma (NB) patients receive multimodality therapy with intensive chemotherapy, radiation, and immunotherapy, and have had high rates of treatment-related leukemias (Kushner, Cheung et al. 1998). Whilst specific therapeutic modalities have been associated with distinct cytogenetic and molecular abnormalities, our understanding of the relationships between timing of mutation acquisition, dynamics of clonal selection in relation to specific therapeutic modalities, and how these in unison result in overt leukemia, remains limited. Motivated to study these relationships and inform future screening guidelines, we characterized serial bone marrow (BM) samples obtained during surveillance for NB recurrence and therapy-related leukemias. Methods We studied a total of 219 serial samples from 55 NB patients treated at MSKCC over a 21-year period. These included 19 patients with MDS or leukemic transformation (median time following NB diagnosis 4.4 years), 15 with transient cytogenetic abnormalities (median time to abnormality 3.1 years), and 21 matched controls (median disease-free follow-up 8.1 years). On average, we analyzed 4 samples per transformation patient, representative of pre-treatment timepoints at NB diagnosis, during NB treatment, and throughout follow-up, with a lead time of 18 years - 1 month prior to transformation, and at time of leukemic transformation. Comprehensive genomic profiling with targeted gene sequencing (MSK-IMPACT Heme), RNA-seq, and Archer FusionPlex was performed to capture acquired gene mutations, chromosome-level copy number alterations (CNA), and fusion genes at the time of diagnosis. Backtracking studies were performed in longitudinal samples with complete molecular and clonal characterization. Results We detected at least one disease-defining alteration in all cases with MDS or leukemic transformation at time of diagnosis, with a total of 61 putative oncogenic events across all patients (median 3 alterations per patient, range 1-12). As expected, the most frequent events were MLL fusions (n=6 patients), and mutations in TP53 (n=5 patients). The remaining cases harbored chromosomal aneuploidies or acquired gene mutations in NPM1, IDH1, PTPN11, NRAS, BCOR, CUX1, STAG2, WT1, amongst other genes, at a median variant allele frequency 24% (range 4-68%). Backtracking studies identified at least one of these mutations in 81% of patients at a sampling time point prior to diagnosis. In contrast, only two patients (2/15) from the cohort with transient cytogenetic abnormalities had acquired somatic mutations detected at a median VAF of 3%, with resolution of the molecular alterations in subsequent samples. One of the control cases also had an identified mutation, though this patient died of NB with limited hematologic follow-up. The median time of detection of a putative driver alteration was 6 months prior to leukemic transformation, with the earliest identified at 2.8 years prior to disease transformation. At least 3 cases of MLL fusions were detected 2.2, 14.5, and 20.9 months prior to diagnosis. Mutations in TP53 co-occurred with CNAs in all patients in our cohort, and has been shown to be predictive of chemoresistant disease. Mutations in TP53 were also identified in at least 2 pre-leukemic samples per patient in 4 of 5 cases, at a median VAF 5% (range 5-20%). In all of these cases, TP53 mutations preceded clinically detectable CNA. Genetic evolution led clonal dominance, which, intriguingly, often preceded disease presentation in the context of normal hematopoeisis. We also found evidence of clonal drifts, possibly as a consequence of treatment effects. Conclusions Our preliminary data demonstrate that NB patients at risk of developing secondary leukemia can be identified by molecular profiling of BM aspirates obtained during routine disease surveillance for NB. These findings present an opportunity for the development of early detection studies for patients with pediatric malignancies undergoing intensive therapy and importantly inform studies into mechanisms of leukemic transformation and specific gene-treatment effects. Disclosures Cheung: Ymabs: Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-120005

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 29-30

Abstract: Background Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. The relationship between acquired gene mutations and mCAs in CH and their joint roles in leukemia development have not been systematically investigated. Methods We developed a method to reliably map mCAs at low cell fractions from deep targeted sequencing data. We applied this method in a cohort of 32,442 solid tumor patients who have undergone prospective clinical sequencing (MSK-IMPACT). We characterized gene mutations in our patient cohort using an established variant calling procedure from our previous studies. Results We jointly characterized 383 mCA events (median aberrant cell fraction 32%, range 10%-90%) and 14,789 mutations across 457 genes. mCA was significantly associated with age (OR=1.8, P & lt;0.001), male gender (OR=1.4, P=0.012), white race (OR=1.5, P=0.033) and prior receipt of external beam radiation therapy (OR=1.7, P=0.022). 217 (63%) mCAs co-occurred with at least one gene mutation, while 129 (37%) did not (OR=3.9, P & lt;0.001). mCA was especially enriched in CH cases with high mutation number and VAF, detectable in 5.8% of subjects with ≥3 gene mutations and 4.8% of those with mutations at & gt;20% VAF, compared to 1% of the general cohort. We identify co-mutational patterns characteristic of diverse mechanisms of clonal selection. We observe that mutations in DNMT3A, TET2, JAK2, MPL, EZH2, TP53 and ATM form recurrent double-hits with deletions or CNLOHs, resulting in either oncogene mutant dosage adjustment or inactivation of tumor suppressors. Notably, certain mCA events were highly directed events acting on previously acquired gene mutations in the corresponding loci. Of six events of 7qCNLOH, all six co-localized with an EZH2 (7q36.1) mutation (q & lt;0.001). Of 12 cases with 9pCNLOH, 11 (92%, q & lt;0.001) co-localized with a JAK2 V617F mutation. 4 out of 9 (44%, q & lt;0.001) 1pCNLOH events co-localized with a MPL (1p34.2) mutation. In addition, we observe recurrent composite genotypes (4q24-/SRSF2, 7qCNLOH/ASXL1, 20q-/U2AF1) indicative of co-operating or epistatic interactions as well as loss of gatekeeper function (i.e. TP53) presenting with multiple chromosomal aneuploidies (5-, 7-, 3+). In total, these recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal mCAs. During patient follow-up, the 3-year cumulative incidence of leukemias was significantly higher in patients with composite CH genotypes (14.6%, CI: 7-22%) as compared to patients with either mCA, gene mutation alone or no CH, of which all had a 3-year cumulative incidence of & lt;1% (Figure 1). We performed a multivariable cause-specific Cox regression model and showed that mCA was independently predictive of subsequent leukemia diagnosis (HR=14, 95% CI: 6-33, P=1.2e-09) after adjusting for number of gene mutations and VAF in putative drivers. Conclusions Our joint characterization of gene mutations and mCAs in a large prospective sequencing cohort reveals a previously unrecognized layer of complexity in the evolutionary dynamics of clonal hematopoiesis that converges towards characteristic genotypes associated with distinct leukemia subtypes. This puts mCAs in the context of the continuous evolutionary process of oncogenesis that can often span years and sheds new lights on its patterns of acquisition and progression. We demonstrate that the integration of chromosomal aberrations provides additional resolution to risk stratification as well as interpretation of clinical phenotypes and that mCAs should be screened in conjunction with gene mutations to improve existing CH surveillance programs in cancer patients. Disclosures Bolton: GRAIL: Research Funding. Medina:Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Mantha:MJH Associates: Honoraria; Physicians Education Resource: Honoraria. Solit:Pfizer: Honoraria; Loxo Oncology: Honoraria; Lilly Oncology: Honoraria; Illumina: Honoraria; Vivideon Therapeutics: Honoraria. Diaz:Neophore: Consultancy, Current equity holder in private company; Merck: Consultancy; Johns Hopkins University: Patents & Royalties; Jounce Therapeutics: Current equity holder in private company; Thrive Earlier Detection: Current equity holder in private company; Personal Genome Diagnostics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Berger:Illumina: Research Funding; Roche: Consultancy; Grail: Research Funding. Levine:Lilly: Consultancy, Honoraria; Janssen: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Prelude Therapeutics: Research Funding; Gilead: Honoraria; Amgen: Honoraria; Morphosys: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Zehir:Memorial Sloan Kettering Cancer Center: Current Employment; Illumina: Honoraria. Papaemmanuil:Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; MSKCC: Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-141882

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5105-5105

Abstract: Genome profiling represents a critical pillar for clinical, translational, and basic research studies. Hospitals, core facilities, and research enterprises invest significant resources to generate genomic data sets. Yet, data management and analysis is frequently manual, which demands significant operator time and often results in siloed resources rendering them as single-use assets. Centralization of the genomic capital in a framework that enables automated processing, metadata integration and continuous interrogation maximizes return for investment and serves as the critical catalyst for research innovation, clinical translation and reproducible research. We developed Isabl, a plug-and-play infrastructure for scalable bioinformatics operations. Isabl provides solutions for databasing, assets management, tracking, automated and reproducible data processing. Dynamic reporting and meta-analysis across data assets is enabled. Isabl is built on four main components. First, an individual-centric and extensible relational database with tracking support for samples (temporal, spatial, aliquot), experimental data (assays, platforms, sequencing runs), cohorts (clinical trials, research projects) and versioned bioinformatics applications (assembly aware, tools, results). Second, the database is exposed through a fully featured RESTful API that enables horizontal integration with information systems such as sequencing cores LIMS, variant visualization platforms like cBioPortal, and where applicable, clinical and biospecimen institutional databases. Third, a Software Development Kit (SDK) built for Next Generation Sequencing assets management. The SDK enables automated execution of data import and language-agnostic bioinformatics applications (alignment, variant calling, post-processing) with support for cohort and individual level reporting features. Furthermore, the SDK facilitates dynamic retrieval of results using vertical and horizontal queries (individual and cohort level, respectively). Lastly, Isabl comes with a Single Page Web Application that fosters user interaction with multidisciplinary teams (i.e. researchers, project coordinators, engineers, clinicians) facilitating tracking of analyses, results visualization, and dynamic query processing. Isabl is currently supporting the Memorial Sloan Kettering Genome Pediatrics Precision Medicine Initiative, a prototype platform that delivers integrated, real-time automated reporting of clinical targeted gene re-sequencing, research whole genome and transcriptome profiling data; as well as linked data from pre-clinical models (i.e. PDX) and single cells studies. As an open-source tool, Isabl democratizes access to a purpose built, automated, scalable and fully integrable bioinformatics architecture. Isabl will be available at https://github.com/isabl-io. Citation Format: Juan S. Medina-Martínez, Juan E. Arango-Ossa, Gunes Gundem, Max F. Levine, Minal Patel, Noushin R. Farnoud, Venkata D. Yellapantula, Gao Teng, Joseph G. Mccarter, Elsa Bernard, Franck Rapaport, Dominik Glodzik, Ross L. Levine, Andrew Kung, Elli Papaemmanuil. A plug-and-play infrastructure for scalable bioinformatics operations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5105.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2019-5105

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2019

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Nature Genetics, Springer Science and Business Media LLC, Vol. 52, No. 11 ( 2020-11), p. 1219-1226

Type of Medium: Online Resource

ISSN: 1061-4036 , 1546-1718

URL: Article

DOI: 10.1038/s41588-020-00710-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 1494946-5

SSG: 12

In: Blood Advances, American Society of Hematology, Vol. 2, No. 23 ( 2018-12-11), p. 3526-3539

Abstract: The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring BCR-ABL1 and MLL translocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified PHF6 and DNMT3A mutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and BCR-ABL1/MLL translocations. PHF6- and DNMT3A-mutated MPAL showed marked predilection for T-lineage differentiation (5/6 PHF6 mutated, 6/6 DNMT3A mutated). PHF6-mutated MPAL occurred in a younger patient cohort compared with DNMT3A-mutated cases (median age, 27 years vs 61 years, P & lt; .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored PHF6 mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, P = .001) and a higher relapse incidence (78% vs 22%, P = .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry–sorted populations demonstrated that PHF6 mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating PHF6 as an early mutation in MPAL pathogenesis. In conclusion, PHF6 and DNMT3A mutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2018023531

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 2876449-3

In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-01-12)

Abstract: Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations ( n  = 14,789) and mCAs ( n  = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P   〈  0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-020-20565-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2553671-0