Abstract 5417: Genomic analysis of infantKMT2A-r acute lymphoblastic leukemia reveals weak association with underlying germline cancer predisposition

Mapping Intimacies â—½  
2020 â—½  
Author(s):  
Azhar Saeed â—½  
Midhat Farooqi â—½  
Byunggil Yoo â—½  
Rumen Kostadinov â—½  
Emily Farrow â—½  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia â—½  
Lymphoblastic Leukemia â—½  
Genomic Analysis â—½  
Cancer Predisposition â—½  
Weak Association

scholarly journals Next-Generation Sequencing in Acute Lymphoblastic Leukemia

2019 â—½  
Vol 20 (12) â—½  
pp. 2929 â—½  
Author(s):  
Nicoletta Coccaro â—½  
Luisa Anelli â—½  
Antonella Zagaria â—½  
Giorgina Specchia â—½  
Francesco Albano
Keyword(s):  
Next Generation Sequencing â—½  
Acute Lymphoblastic Leukemia â—½  
Residual Disease â—½  
Age Of Onset â—½  
Lymphoblastic Leukemia â—½  
Genomic Analysis â—½  
Next Generation â—½  
Acute Leukemias â—½  
Next Generation Sequencing Ngs â—½  
Generation Sequencing

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for about a quarter of adult acute leukemias, and features different outcomes depending on the age of onset. Improvements in ALL genomic analysis achieved thanks to the implementation of next-generation sequencing (NGS) have led to the recent discovery of several novel molecular entities and to a deeper understanding of the existing ones. The purpose of our review is to report the most recent discoveries obtained by NGS studies for ALL diagnosis, risk stratification, and treatment planning. We also report the first efforts at NGS use for minimal residual disease (MRD) assessment, and early studies on the application of third generation sequencing in cancer research. Lastly, we consider the need for the integration of NGS analyses in clinical practice for genomic patients profiling from the personalized medicine perspective.

Genomic Characterization Of Histiocytic Lesions Following Pediatric T-Cell Acute Lymphoblastic Leukemia

Blood â—½  
2013 â—½  
Vol 122 (21) â—½  
pp. 4940-4940
Author(s):  
Richard McMasters â—½  
Brian K. Turpin â—½  
Michael J. Absalon â—½  
Christine L. Phillips â—½  
Karen Burns â—½  
...  
Keyword(s):  
Bone Marrow â—½  
Acute Lymphoblastic Leukemia â—½  
Lymphoblastic Leukemia â—½  
Previous History â—½  
Genomic Analysis â—½  
High Dose â—½  
Pet Ct â—½  
History Of â—½  
Genomic Characterization â—½  
Notch1 Mutations

Abstract Introduction The development of histiocytic lesions after acute lymphoblastic leukemia (ALL) is rare, occurring in 6 of 971 patients enrolled on BFM treatment regimens for T-ALL (Trebo 2005).  Few cases of histiocytosis arising after a history of T-ALL have been characterized at the molecular level for genomic alterations. One case of fatal Langerhans cell histiocytosis (LCH) following treatment of T-ALL revealed activating mutations in NOTCH1; in contrast, no NOTCH1 mutations were identified in 24 other cases of LCH or Rosai-Dorfman disease without a previous history of T-ALL (Rodig 2008). In patients without prior leukemia, BRAF V600 mutations have been identified in a significant proportion of patients with LCH or Erdheim-Chester Disease but not in other histiocytoses (Haroche 2012). Methodology and Principal Findings Next generation focused exomic sequencing of 236 genes and 47 Introns was conducted on samples of histiocytic lesions from two patients with a previous history of T-ALL. Case 1 A 2 year-old male presented with marked adenopathy, mediastinal mass and white blood cell count 67,000 cells/uL with 30% blasts. The blasts expressed CD45, CD2, CD3 (surface/cyto), CD5, CD7, CD38, CD45 (bright), TCR gamma-delta, but were negative for CD4, CD8, and TdT.  Karyotype was 46,XY,t(8;14)(q24;q11.2),der(12)t(12;20)(q11;q13.3),der(20)t(12;20)(q21;q13.3) with rearrangement of MYC (8q24) confirmed by FISH. He was treated for T-ALL per Children’s Oncology Group (COG) protocol AALL0434 and had 5% residual bone marrow blasts at day 29 of induction. MRD-negative remission was ultimately achieved with high-dose cytarabine and methotrexate followed by consolidation with nelarabine.  He underwent matched unrelated cord blood transplant following conditioning with cyclophosphamide and total body irradiation with cranial boost, and engrafted at day +14. Surveillance bone marrow at day +110 revealed systemic juvenile xanthogranuloma (JXG) without T-ALL. PET/CT revealed FDG-uptake in the diffusely enlarged spleen and throughout the skeleton. Due to progressive cytopenias, therapy was initiated with vinblastine and prednisone as per LCHIII. However, refractory cytopenias exacerbated by splenic sequestration developed following induction, and he was then treated with thalidomide and splenectomy. The spleen weighed 404 grams (expected 40 grams) and was diffusely infiltrated with JXG. The cytopenias dramatically improved and he continued thalidomide for 2 months until PET scan demonstrated progression. Genomic analysis of the JXG lesion revealed NRAS G13D mutation, and FISH demonstrated MYC rearrangement identical to the initial T-ALL sample. Case 2 A 12-year-old male presented with WBC 142,700 cells/uL and CNS leukemia. Flow cytometry showed T-ALL with CD2, surface CD3, CD4, CD5, CD7, CD8, CD24 (subset), CD71, HLA-DR (subset) and TdT (partial). There was a clonal TCR gamma gene rearrangement and a biallelic CDKN2A (p16) deletion by FISH. He was enrolled on COG AALL0434 and had a rapid response with remission in both CNS and marrow at induction day 29.  Following completion of high-dose methotrexate interim maintenance he developed hepatosplenomegaly, pancytopenia and elevated serum bilirubin, ferritin, and triglycerides.  Bone marrow aspirate showed rare hemophagocytosis but no evidence of T-ALL.  He was treated with dexamethasone and etoposide with no response. Follow-up bone marrow revealed brisk hemophagocytosis and a diffuse histiocytic neoplasm. Karyotype was 48,XY,+7,+11[2] /49,idem,+18[3] /46,XY[14]. PET/CT showed hepatosplenomegaly with FDG uptake in anterior mediastinum, hepatic nodules, spleen, and bone marrow. He was treated with Campath and then with intensive chemotherapy with fludarabine, cytarabine, and liposomal daunorubicin with no response and ultimately succumbed to disease. Genomic analysis of the clonal histiocytic infiltrate revealed KRAS G12C, BRAF G469V, NOTCH1 Q2440, and CCND2 G268R mutations, and FISH positive for biallelic CDKN2A (p16) deletion similar to original T-ALL. Conclusions Our extensive genomic characterization suggests a unique molecular pathogenesis for histiocytic disorders arising after T-cell ALL and identified RAS signaling pathway and NOTCH1 mutations. Furthermore, these findings strongly indicate a potential derivation or trans differentiation from the malignant leukemic stem cell clone. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies

Blood â—½  
2011 â—½  
Vol 118 (19) â—½  
pp. 5218-5226 â—½  
Author(s):  
Laura E. Hogan â—½  
Julia A. Meyer â—½  
Jun Yang â—½  
Jinhua Wang â—½  
Nicholas Wong â—½  
...  
Keyword(s):  
Gene Expression â—½  
Dna Methylation â—½  
Acute Lymphoblastic Leukemia â—½  
Lymphoblastic Leukemia â—½  
Genomic Analysis â—½  
Genetic Alterations â—½  
Mitogen Activated Protein Kinase â—½  
Genetic Changes â—½  
Mitogen Activated Protein â—½  
Dna Methylation Analysis

Abstract Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (≥ 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all 3 platforms identified genes of potential interest, including CDKN2A, COL6A2, PTPRO, and CSMD1. Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways.

scholarly journals Genetic Heterogeneity and Evolution in Lymphoid Malignancies

Blood â—½  
2018 â—½  
Vol 132 (Supplement 1) â—½  
pp. SCI-34-SCI-34
Author(s):  
Charles G. Mullighan
Keyword(s):  
Acute Lymphoblastic Leukemia â—½  
Research Funding â—½  
Drug Exposure â—½  
Lymphoblastic Leukemia â—½  
Clonal Evolution â—½  
Genomic Analysis â—½  
Disease Recurrence â—½  
Relationship Of â—½  
The Relationship â—½  
Limiting Dilution

Abstract Patterns of mutation and clonal evolution in relapsed acute lymphoblastic leukemia Relapsed acute lymphoblastic leukemia remains a major cause of childhood cancer death, and this remains true despite the advent of new targeted and immunotherapeutic approaches. Recent years have witnessed the use of broad and deep serial genomic profiling approaches to dissect the relationship of genetic variegation to clonal evolution and relapse. Studies of over 90 children treated on St Jude Total Therapy protocols, incorporating genome, exome and transcriptome sequencing, coupled with limiting dilution xenografting to formally elucidate clonal structure have provided multiple key insights. In the majority of cases, the relapse-fated clone is a minor clone at diagnosis, that harbors resistance-enriched (and thus relapse-promoting) mutations at diagnosis, and/or acquires additional mutations the confer resistance after initial therapy. Approximately one third of cases relapse from a major clone, or show polyclonal evolution, and such cases typically have a shorter time to disease recurrence and relapse. A subset of cases exhibit complete discordance for somatic non-silent mutations, DNA copy number alterations and antigen receptor rearrangements between diagnosis and relapse, suggesting relapse represents a second leukemia; however such cases typically preserve the founding chromosomal rearrangement and a subset of non-coding mutations, indicating that relapse arises from an ancestral clone that has undergone divergent evolution early in leukemogenesis. Conversely, a subset of cases relapse with myeloid or lineage ambiguous leukemia but preserve genomic alterations indicating a common clonal origin but lineage plasticity: thus, careful genomic analysis is required to interpret the nature of disease recurrence/relapse. Approximately 15% of cases exhibit hypermutation, particularly in aneuploid leukemia and second or later relapse, associated with distinct mutational signatures and kinetics of hypermutation, thus identifying this process as a driver of treatment failure in a subset of ALL cases. Integrated analysis has identified over 80 recurrent targets of alteration at relapse that show variable patterns of enrichment in rising and falling clones. Importantly, several targets (e.g. NT5C2) are never identified at diagnosis despite deep sequencing approaches, suggesting adverse effects on leukemic fitness, and/or an absolute requirement of prior drug exposure to initiate mutagenesis. Integration of limiting dilution xenografting, coupled with genomic analysis of xenografts and drug exposure has not only formally confirmed and extended inferential clonal structures, but shown that in a subset of cases resistance is present at initial diagnosis, rather than being acquired after drug exposure. Finally, several groups have shown that the relationship of relapse-enriched mutations and relapse by be drug agnostic (e.g. IKZF1) or drug specific (e.g. NT5C2 and thiopurine resistance, and CREBBP and glucocorticoid resistance). As such mutations may now be detected at levels suitable for tracking of minimal residual disease, these insights offer the opportunity to identify the relapse-fated clone early in disease evolution, and modulate therapy accordingly to circumvent relapse. Disclosures Mullighan: Pfizer: Honoraria, Research Funding, Speakers Bureau; Cancer Prevention and Research Institute of Texas: Consultancy; Loxo Oncology: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Speakers Bureau.

Abstract 4870: Integrated genomic analysis of hypodiploid acute lymphoblastic leukemia

2012 â—½  
Author(s):  
Linda Holmfeldt â—½  
Ernesto Diaz-Flores â—½  
Jinghui Zhang â—½  
Debbie Payne-Turner â—½  
Anna Andersson â—½  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia â—½  
Lymphoblastic Leukemia â—½  
Genomic Analysis

scholarly journals Genomic analysis of different clonal evolution in a twin pair with t(12;21) positive acute lymphoblastic leukemia sharing the same prenatal clone

Leukemia â—½  
2007 â—½  
Vol 22 (1) â—½  
pp. 208-211 â—½  
Author(s):  
S Bungaro â—½  
J Irving â—½  
R Tussiwand â—½  
R Mura â—½  
L Minto â—½  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia â—½  
Twin Pair â—½  
Lymphoblastic Leukemia â—½  
Clonal Evolution â—½  
Genomic Analysis

scholarly journals Germline Variants Associated with Cancer Predisposition and Bone Marrow Failure Are Common in KMT2A-r Infant Acute Lymphoblastic Leukemia Patients

Blood â—½  
2020 â—½  
Vol 136 (Supplement 1) â—½  
pp. 41-41
Author(s):  
Sarah Mc Dermott â—½  
Midhat S. Farooqi â—½  
Azhar Saeed â—½  
Byunggil Yoo â—½  
Emily Farrow â—½  
...  
Keyword(s):  
Bone Marrow â—½  
Acute Lymphoblastic Leukemia â—½  
Board Of Directors â—½  
Bone Marrow Failure â—½  
Lymphoblastic Leukemia â—½  
Cancer Predisposition â—½  
Advisory Committees â—½  
Germline Variants â—½  
Predisposition Genes â—½  
Infant Acute Lymphoblastic Leukemia

Introduction: Infant acute lymphoblastic leukemia (ALL), is a particularly aggressive subtype of leukemia with an early onset and unfavorable clinical outcome. Most (~70%) cases of infant ALL involve chromosomal rearrangement of KMT2A (KMT2A-r) on chromosome 11q23, the strongest independent predictor of a poor prognosis. To date, genomics studies have consistently demonstrated KMT2A-r infant ALL to have a strikingly silent landscape of DNA mutations, aside from the KMT2A-r itself. Germline mutations in cancer predisposition genes are found in 8.6% of pediatric malignancies and 4.4% of pediatric leukemias, compared to 1.1% in persons in the 1000 Genomes Project (Zhang J et al., N Engl J Med 2015). We hypothesized that germline variants may contribute to the development of KMT2A-r ALL in infants. We examined the germline variants in remission blood samples from a large cohort of infants with KMT2A-r ALL who were enrolled in Children's Oncology Group (COG) trial AALL15P1. Methods: We performed whole genome sequencing (WGS) and whole exome sequencing (WES) on DNA isolated from peripheral blood from 36 KMT2A-r cases at time of remission. Sequencing was performed using an Illumina Hiseq 4000 or 2500 to a minimum depth of 90Gb (WGS) and 15Gb (WES). Alignment and variant calling were performed using the Dragon Bio-IT platform (v 3.2.8, Illumina). Blueprint Genetics clinical panels and the medical literature (Xa M et al., Nature 2018) were used to comprise a list of 346 genes associated with cancer predisposition and bone marrow failure syndromes. From this gene pool, variants were selected for analysis based on a variant allele frequency of ~50% and minor allele frequency &lt;0.1% in control population databases (gnomAD). Variants were analyzed for pathogenicity per the 2015 ACMG/AMP interpretation guidelines for sequence variants. Results: Of 351 variants initially identified, we found 3 likely pathogenic (LP) and 6 pathogenic(P) non-synonymous germline variants (for a total of 9 LP/P variants) and 144 variants of unknown significance (VUS). In total, 19.4% (n=7) of patient samples displayed at least one LP/P variant. Two patient samples contained 2 variants each. Variants classified as VUS, LP, or P were further characterized by possible causative pathway: 37.9% (n=58) of variants were in genes associated with bone marrow failure (BMF), 17.6% (n=27) in driver genes, 13.1% (n=20) in genes associated with inherited leukemias, 11.1% (n=17) in tumor suppressor genes, 7.8% (n=12) in tyrosine kinase genes, and 29.4% (n=45) in other predisposition genes . Many variants were present in more than one pathway and are represented as such. Table 1 demonstrates the genetic characteristics of the 9 P/LP variants found in our cohort. ERCC2 was the only gene with multiple LP/P variants across samples, accounting for 2 (1 LP, 1 P) of the 9 deleterious variants identified (22%). Conclusion: We identified germline variants in cancer predisposition genes in 19.4% of this cohort of infant ALL patients, a higher mutation rate than has previously been reported. Among pathways evaluated, variants in genes associated with bone marrow failure predisposition were the most frequent. Interestingly, variants in ERCC2, which encodes a protein involved with repair of damaged DNA, were recurrent among infants with KMT2A-r ALL. Future directions include comparison to germline variants in cancer predisposition genes in other infant and non-infant ALL cohorts. Disclosures Brown: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Guest:Syndax Pharmaceuticals: Consultancy.

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