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| 8. |
- Ng, M Y M, et al.
(författare)
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Meta-analysis of 32 genome-wide linkage studies of schizophrenia
- 2009
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 14:8, s. 774-785
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Tidskriftsartikel (refereegranskat)abstract
- A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
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| 10. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 11. |
- Nachman, James B, et al.
(författare)
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Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia.
- 2007
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Ingår i: Blood. - 0006-4971. ; 110:4, s. 1112-5
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Tidskriftsartikel (refereegranskat)abstract
- One-hundred thirty-nine patients with acute lymphoblastic leukemia (ALL) and hypodiploidy (fewer than 45 chromosomes) were collected from 10 different national ALL study groups and single institutions. Patients were stratified by modal chromosome number into 4 groups: 24 to 29 (N = 46); 33 to 39 (N = 26); 40 to 43 (N = 13); and 44 (N = 54) chromosomes. Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and were not considered further. Event-free survival (EFS) and overall survival (OS) of the remaining 130 patients were 38.5% +/- 4.4% and 49.8% +/- 4.2% at 8 years, respectively. There were no significant differences in outcome between patients with 24 to 29, 33 to 39, or 40 to 43 chromosomes. Compared with patients with fewer than 44 chromosomes, patients with 44 chromosomes had a significantly better EFS (P = .01; 8-year estimate, 52.2% vs 30.1%) and OS (P = .017; 69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS. Doubling of the hypodiploid clone occurred in 32 patients (24-29 chromosomes [n = 25] and 33-39 chromosomes [n = 7]) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy.
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| 12. |
- Armstrong, Scott A, et al.
(författare)
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FLT3 mutations in childhood acute lymphoblastic leukemia.
- 2004
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 103:9, s. 3544-3546
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of the FLT3 receptor tyrosine kinase are common in acute myelogenous leukemia (AML) but are rare in adult acute lymphoblastic leukemia (ALL). We have recently shown that FLT3 is highly expressed and often mutated in ALLs with rearrangement of the mixed lineage leukemia (MLL) gene on chromosome 11q23. Because hyperdiploid ALL samples also show high-level expression of FLT3, we searched for the presence of FLT3 mutations in leukemic blasts from 71 patients with ALL. The data show that approximately 25% (6 of 25) of hyperdiploid ALL samples possess FLT3 mutations, whereas only 1 of 29 TEL/AML1-rearranged samples harbored mutations (P =.04, Fisher exact test). Three mutations are novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. Finally, 3 samples from patients whose disease would relapse harbored FLT3 mutations. These data suggest that patients with hyperdiploid or relapsed ALL might be considered candidates for therapy with newly described small-molecule FLT3 inhibitors.
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- Buitenkamp, Trudy D., et al.
(författare)
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Acute lymphoblastic leukemia in children with Down syndrome : a retrospective analysis from the Ponte di Legno study group
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 123:1, s. 70-77
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Tidskriftsartikel (refereegranskat)abstract
- Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.
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| 15. |
- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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| 16. |
- Li, Aihong, et al.
(författare)
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Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias.
- 2005
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 131:2, s. 185-92
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Tidskriftsartikel (refereegranskat)abstract
- Infant acute lymphoblastic leukaemia (ALL) represents a rare but unique subset with poor prognosis. We analysed mixed-lineage leukaemia (MLL) gene rearrangements and the sequences of complete and incomplete immunoglobulin heavy chain gene rearrangements (IGH) in 14 infants (age < or = 12 months at diagnosis) enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. The dynamics of the leukaemic clone were followed during the course of the disease by quantitative real-time polymerase chain reaction of IGH rearrangements. Sixteen sequences were obtained from 13 (93%) of these infants. There was marked over usage of the V(H)6.1 gene segment (64%) in infants compared with older children with ALL (8%), (P < 0.001) and overusage of D(H)6 (P = 0.004) and J(H)1 (P = 0.004). Poor outcome was associated with MLL gene rearrangements rather than any specific V(H)D(H)J(H) gene usage patterns. Levels of minimal residual disease (MRD) at the end of induction appeared to be high in infants with ALL compared with older children, and although the number of infant cases studied was small, there were no differences in MRD levels after induction therapy in infant ALL with or without MLL gene rearrangements (P = 0.41) and quantitative MRD assessment at the early time points may not be predictive of outcome. Novel treatment strategies are required to improve the outcome in this poor prognosis subset of children with ALL.
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| 17. |
- Li, Aihong, et al.
(författare)
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Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse : implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection.
- 2003
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 102:13, s. 4520-4526
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements provide clonal markers useful for diagnosis and measurement of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We analyzed the sequences of Ig and TCR gene rearrangements obtained at presentation and relapse in 41 children with ALL to study clonal stability, which has important implications for monitoring MRD, during the course of the disease. In 42%, all original Ig and/or TCR sequences were conserved. In 24%, one original sequence was preserved but the other lost, and in 14% the original sequences were conserved with new sequences identified at relapse. In 20% only new sequences were found at relapse. Using primers designed from the novel relapse sequences, the relapse clone could be identified as subdominant clones in the diagnostic sample in 8 of 14 patients. Alteration of these clonal gene rearrangements is a common feature in childhood ALL. MRD detection should include multiple gene targets to minimize false-negative samples or include also multicolor flow cytometry. In some cases the leukemic progenitor cell might arise earlier in lineage before DHJH recombination but retain the capacity to further differentiate into cells capable of altering the pattern of Ig and/or TCR rearrangements.
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| 18. |
- Li, Aihong, et al.
(författare)
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Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia : implications for the mechanisms of VDJ recombination and for pathogenesis.
- 2004
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 103:12, s. 4602-9
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Tidskriftsartikel (refereegranskat)abstract
- Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the V(H)D(H)J(H) gene utilization profiles. The D(H)J(H)-proximal V(H) segments and the D(H)2 gene family were significantly overrepresented. Only 21% of V(H)-J(H) joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the V(H) locus is involved in preferential usage of D(H)J(H)-proximal V(H) segments whereas D(H) and J(H) segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL.
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| 19. |
- Pui, Ching-Hon, et al.
(författare)
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Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia : A Retrospective Multinational Study
- 2019
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 37:10, s. 770-779
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials.PATIENTS AND METHODS: This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome.RESULTS: With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction.CONCLUSION: MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.
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| 20. |
- Zhou, Jianbiao, et al.
(författare)
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Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01.
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:5, s. 1607-11
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Tidskriftsartikel (refereegranskat)abstract
- In a prospective trial in 284 children with B-lineage acute lymphoblastic leukemia (ALL), we assessed the clinical utility of real-time quantitative polymerase chain reaction analysis of antigen receptor gene rearrangements for detection of minimal residual disease (MRD) to identify children at high risk of relapse. At the end of induction therapy, the 5-year risk of relapse was 5% in 176 children with no detectable MRD and 44% in 108 children with detectable MRD (P < .001), with a linear association of the level of MRD and subsequent relapse. Recursive partitioning and clinical characteristics identified that the optimal cutoff level of MRD to predict outcome was 10(-3). The 5-year risk of relapse was 12% for children with MRD less than one leukemia cell per 10(3) normal cells (low MRD) but 72% for children with MRD levels greater than this level (high MRD) (P < .001) and children with high MRD had a 10.5-fold greater risk of relapse. Based upon these results we have altered our treatment regimen for children with B-lineage ALL and children with MRD levels greater than or equal to 10(-3) at the end of 4 weeks of multiagent induction chemotherapy now receive intensified treatment to attempt to decrease their risk of subsequent relapse.
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