P–381 Deciphering the genetic cause of recurrent and sporadic pregnancy loss

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
R Essers ◽  
G Acharya ◽  
S Al-Nasiry ◽  
H Brunner ◽  
S P Deligiannis ◽  
...  
Keyword(s):  
Copy Number ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
De Novo ◽  
Snp Array ◽  
Paternal Age ◽  
Chromosome 5 ◽  
Chorionic Villi ◽  
Genome Wide ◽  
Extraembryonic Mesoderm

Abstract Study question To investigate the prevalence and effect of (mosaic) de novo genomic aberrations in recurrent pregnancy loss (RPL) and sporadic abortion (SA). Summary answer Prevalence of maternal uniparental disomies (UPDs) was high in both cohorts. While chromosomal UPDs were found in both cohorts, genome wide UPDs were RPL specific. What is known already Spontaneous abortion occurs in 10–15% of clinically recognized pregnancies and recurrent pregnancy loss in 1–3%. SA and RPL are associated with reduced quality of life. Multiple factors contribute to SA and RPL, such as uterine malformations and parental/fetal chromosomal abnormalities. However, in ∼60% of SA and RPL the cause remains unknown. UPD is defined as the presence of two homologues chromosomes originating from a single parent. This phenomenon can lead to imprinting disorders that are characterised by clinical features affecting growth, development and metabolism in liveborn offspring. However, it could also be responsible for pregnancy loss. Study design, size, duration We recruited 32 families with pregnancy loss (n = 16 RPL cohort, n = 16 SA cohort) with no known genetic predispositions and normal karyotyping results in both parents and the fetus. Average maternal age was 28.68 years (SD = 5.43), paternal age 30.3 years (SD = 5.53), and the gestational age at pregnancy loss was 8.65 weeks (SD = 2.47). The average number of miscarriages in the RPL group was 3.57 (SD = 0.84). We profiled the genomic landscape of both cohorts using SNP typing. Participants/materials, setting, methods We isolated DNA from blood of both parents and the placental tissues from the miscarried products of conception. The placenta tissues were sampled from two distinct extraembryonic and embryonic germ layers, the extraembryonic mesoderm and the chorionic villi cytotrophoblast. Subsequently, we performed SNP-genotyping using Illumina’s Global-Screening Array–24 v2.0 BeadChips and applied haplarithmisis to delineate allelic architecture of fetal tissues of both cohorts. This allowed us to detect large de novo copy-number and -neutral (>10kb) changes. Main results and the role of chance In this pilot study, we have analyzed 132 DNA samples (n = 32 families), of which 16 families were in the RPL cohort and 16 in the SA cohort. Within the RPL cohort, we found: one family with mosaic genome wide hexaploidy both in the extraembryonic mesoderm and chorionic villi, one family with a non-mosaic genome wide hetero UPD of the chorionic villi tissue, one family with a mosaic UPD of chromosome 14 in both tissues and tetraploidy exclusively in the chorionic villi, one family with a mosaic UPD of chromosome 16 in both tissues, one family with a mosaic UPD of chromosome 6 in both tissues, and another family with a mosaic UPD of chromosome 5 in the extraembryonic mesoderm. Within the SA group, one family showed a UPD of chromosome 7 and another family showed a segmental UPD of chromosome 5 in both tissues. Strikingly, all the UPDs found in this study were maternal in origin. Limitations, reasons for caution The main limitation of this study is the resolution of detecting copy-neutral and copy-number variations, which is an inherent limiting factor of SNP-array technology. In addition, in the sample in which we observed non-mosaic genome wide UPD, maternal contamination is likely that can be investigated by other technologies. Wider implications of the findings: Multiple genome wide UPDs are found in the RPL group but none in the SA group, indicating an association between genome wide mosaic UPD and RPL. These findings could lead to a better understanding of causative factors for SA and RPL and the need for a SNP-based non-invasive prenatal testing. Trial registration number Not applicable

scholarly journals Potential genetic causes of miscarriage in euploid pregnancies: a systematic review

2019 ◽  
Vol 25 (4) ◽  
pp. 452-472 ◽  
Author(s):  
Emily Colley ◽  
Susan Hamilton ◽  
Paul Smith ◽  
Neil V Morgan ◽  
Arri Coomarasamy ◽  
...  
Keyword(s):  
Systematic Review ◽  
Copy Number Variation ◽  
Exome Sequencing ◽  
Copy Number ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Current Evidence ◽  
Genetic Causes ◽  
Search Terms ◽  
Number Variation

Abstract BACKGROUND Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized. OBJECTIVE AND RATIONALE The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss. SEARCH METHODS A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms ‘spontaneous abortion’, ‘miscarriage’, ‘pregnancy loss’, or ‘lethal’ were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including ‘exome’, ‘human genome’, ‘sequencing analysis’, ‘sequencing’, ‘copy number variation’, ‘single-nucleotide polymorphism’, ‘microarray analysis’, and ‘comparative genomic hybridization’. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle–Ottawa scale. OUTCOMES A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage. WIDER IMPLICATIONS Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.

Genome-Wide DNA Copy Number Analysis by SNP Arrays of B-Cell Chronic Lymphocytic Leukemia: Correlation with Known Biological and Molecular Prognostic Markers.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1061-1061
Author(s):  
Laura Mosca ◽  
Sonia Fabris ◽  
Giovanna Cutrona ◽  
Luca Agnelli ◽  
Serena Matis ◽  
...  
Keyword(s):  
High Resolution ◽  
Copy Number ◽  
Prognostic Markers ◽  
Snp Array ◽  
Lymphocytic Leukemia ◽  
Array Analysis ◽  
Genome Wide ◽  
Trisomy 12 ◽  
Snp Array Analysis ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is a genetically heterogeneous disease with a variable clinical course. Chromosomal changes have been identified by FISH in approximately 80% of patients, and the presence of specific lesions, such as trisomy 12 and 13q14, 11q23, 17p13.1 and 6q23 deletions represent prognostic markers for disease progression and survival. In order to characterize further the complexity of B-CLL genomic lesions, we performed high density, single nucleotide polymorphism (SNP) array analysis in highly purified neoplastic cells (>92%) from a panel of 100 untreated, newly diagnosed patients (57 males and 43 females; age, median 63 years, range 30–87) in Binet stage A. All patients were investigated by FISH for the presence of trisomy 12 (21 cases); 13q14 deletion (44 cases, 34 as the sole abnormality); 11q22.3, 17p13.1 and 6q23 (15, 7 and 2 patients, respectively). In addition, ZAP-70 and CD38 expression resulted positive in 42 and 46 patients, whereas IgVH genes were mutated in 45 patients. Genome-wide DNA profiling data were generated on GeneChip® Human Mapping 250K NspI arrays (Affymetrix); copy number alterations (CNA) were calculated using the DNA copy Bioconductor package, which looks for optimal breakpoints using circular binary segmentation (CBS) (Olshen et al, 2004). A total of 782 CNAs (ranging from 1 to 31 per sample, mean and median values 7.82 and 7, respectively) were detected; DNA losses (365/782=46.67% loss; 194/782=24.81% biallelic deletion) were found to be more frequent than gains (148/782=18.93% gain; 75/782=9.59% amplification). The most recurrent alterations detected by FISH were all confirmed by SNP array analysis, strengthening further the good reliability of such high-resolution technology. We identified 12 minimally altered regions (MARs) larger than 100 kb with a frequency higher than 5%. Among well known alterations, the largest was represented by chromosome 12 trisomy, followed by 6q, 17p and 11q23 deletions (32.87, 19.09 and 10.43 Mb, respectively) and 13q14 deletion (635 kb). Gain of 2p25.3 involves a common region of 4.39 Mb region in 7 patients, although it was extended to the whole short arm of chromosome 2 in 3 cases. Among those alterations previously described in B-CLL, we found losses at 14q32.33 (12 pts) and 22q11.2 (5 pts) involving the IGH and IGLλ loci, respectively. With regard to novel regions, we identified losses at 4q35.2 (5 pts) and 11q25 (6 pts). In addition we found a high frequency of losses/gains at 14q11.2 (42 pts) and 15q11.2 (33 pts), two genomic regions reported to be affected by DNA copy number variations in normal individuals. As regards correlations between CNAs and biological markers, we found that the number of CNAs is significantly higher in cases with unmutated IgVH (9.4; range 2–31) as compared with mutated IgVH (6; range 1–13) (p=0.002), while neither CD38 nor ZAP-70 expression showed significant correlation. In addition, a significant higher number of either CNAs (p=0.001), total MARs (p<0.0001) or even only novel MARs (p=0.009) was significantly associated with cases with 17p deletion or multiple cytogenetic aberrations as evaluated by FISH analysis. Our data indicate that genetic abnormalities involving chromosomal gains and losses are very common in early-stage B-CLL and further support the application of high resolution SNP array platforms in the characterization of genetic changes in the disease. In addition, we detected novel altered chromosomal regions that warrant further investigations to better define their pathogenetic and prognostic role in B-CLL.

scholarly journals Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss

2010 ◽  
Vol 25 (11) ◽  
pp. 2913-2922 ◽  
Author(s):  
E. Rajcan-Separovic ◽  
D. Diego-Alvarez ◽  
W.P. Robinson ◽  
C. Tyson ◽  
Y. Qiao ◽  
...  
Keyword(s):  
Copy Number ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Copy Number Variants

scholarly journals Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xingyu Zhang ◽  
Bo Wang ◽  
Guoling You ◽  
Ying Xiang ◽  
Qihua Fu ◽  
...  
Keyword(s):  
Copy Number ◽  
Trisomy 21 ◽  
Single Ventricle ◽  
Snp Array ◽  
Copy Number Variations ◽  
Chinese Children ◽  
Atrioventricular Canal ◽  
Genome Wide ◽  
Number Variation ◽  
Complete Atrioventricular

Abstract Background Congenital heart disease (CHD) is one of the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here we screened genome-wide CNVs in Chinese children with complete atrioventricular canal (CAVC) and single ventricle (SV), since there were scarce researches dedicated to these two types of CHD. Methods We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases. Results Among 262 CAVC patients, we identified 6 potentially-causative CNVs in 43 individuals (16.41%, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 90.70% CAVC patients with detected CNVs (39/43) were found to carry duplications of 21q11.2–21q22.3, which were recognized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1.0 (24:15), and the rate of pulmonary hypertension (PH) was 41.03% (16/39). Additionally, 6 potentially-causative CNVs were identified in the SV patients (2.32%, 6/259), and none of them was trisomy 21. Most CNVs identified in our cohort were classified as rare (< 1%), occurring just once among CAVC or SV individuals except the 21q11.2–21q22.3 duplication (14.89%) in CAVC cohort. Conclusions Our study identified 12 potentially-causative CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and high incidence of PH. The presence of potentially-causative CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

Infant ALL Patients Carrying t(4;11) Have a Different Genotypic Profile Than Older ALL Children.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1436-1436
Author(s):  
Michela Bardini ◽  
Lilia Corral ◽  
Eleonora Mangano ◽  
Roberta Spinelli ◽  
Grazia Fazio ◽  
...  
Keyword(s):  
Copy Number ◽  
Critical Role ◽  
Snp Array ◽  
Point Mutations ◽  
Latency Period ◽  
Older Children ◽  
Available N ◽  
Childhood All ◽  
Genome Wide ◽  
The Individual

Abstract Mice models and prenatal studies indicate that in childhood ALL the individual genetic lesions alone are insufficient to generate a full leukemic phenotype, and cooperating oncogenic lesions are required. Recently, multiple genome-wide studies on childhood ALL (1–18 years) identified deletions at several loci, mainly affecting genes that play a critical role in regulating B cell development and differentiation. By contrast, the prenatal and postnatal steps in the pathogenesis of Infant ALL (less than 1 year at diagnosis) are not defined. Infant ALL is a very aggressive disease, with t(4;11)/MLL-AF4 fusion representing the major subgroup. Although the very short latency period suggests that leukemogenic events occur prenatally, mice models indicates that MLL-AF4 alone is not sufficient to induce leukemia, and additional mutations may occur. Also unclear is whether the molecular pathways needed for lymphoid cell differentiation are altered in cases with an MLL rearrangement and, if so, whether these alterations differ between the leukemia of infants and older children. Aim of this study was to detect MLL-cooperating aberrations, undetectable by conventional techniques, by using genome-wide single nucleotide polymorphism (SNP) genome wide analysis (100K SNP human mapping, Affymetrix). More specifically, we searched for Loss of Heterozygosity (LOH) associated or not to copy number alteration. The identification of these lesions could help identifying leukemia pathogenesis, as well as providing the basis for targeted therapy. We have analyzed 28 cases of Infant ALL with t(4;11) at diagnosis and their corresponding samples at remission, when available (n=18). SNP data were analyzed by using dChip software, and confirmed by CNAG 2.0. A more dense SNP array analysis (250K) has been applied in selected cases to confirm LOH and precisely dissect the affected chromosomal regions. Compared to older childhood ALL patients, a far limited number of deletions/amplifications has been found; only 2/28 patients showed deletions, namely 1p36.33-p36.31 in 1 patient and 3p11.1-p12.2 plus 7q22.1-q22.2 in another patient, while 26/28 Infant ALL did not present any visible structural variation. Different from older children, several segmental copy-number neutral (CNN) LOH have been detected by dChip. The extension and prevalence of the affected regions was variable; among them 6p21.32 (4/28 cases), 7q31.33-q32.1 (3/28), 8q21.12-q21.3 (2/28), 8q24.11 (2/28) and 14q21.2 (2/28). Overall, these results confirm that Infant ALL with t(4;11)/MLL-AF4 fusion represents a biologically unique disease, different from other type of leukemia occurring in older children. While in older children a multistep mechanism (with the involvement of several genes) is required for the full leukemic phenotype, MLL rearrangements per se might play a major role on the leukemogenesis. By this approach it could not be excluded that different mechanisms could cooperate with MLL in transforming cells, including point mutations. The functional role of CNN-LOH still needs to be understood: they could either reflect the duplication of oncogenic mutations, or be related to epigenetic mechanisms.

SNP-A Based Karyotyping Facilitates Improved Mapping of Deletions and Uniparental Disomy within the Long Arm of Chromosome 5 in Myeloid Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2435-2435 ◽  
Author(s):  
Lukasz P. Gondek ◽  
Andrew Dunbar ◽  
Christine O’Keefe ◽  
Michael A. McDevitt ◽  
Denise Batista ◽  
...  
Keyword(s):  
Copy Number ◽  
Chromosomal Rearrangement ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 5 ◽  
Chromosome 5Q ◽  
Complex Chromosomal Rearrangement ◽  
Pathogenic Genes ◽  
Definition Of ◽  
Copy Number Changes

Abstract In MDS, cytogenetics has a major prognostic influence on the phenotype of the malignant clone and specific defects may point towards potential therapeutic targets. However, traditional metaphase cytogenetics (MC) has limited resolution and does not allow for detection of uniparental disomy (UPD). Defects on chromosome 5q have been studied using various methods to identify a minimal commonly deleted region (CDR). SNP-array karyoptyping (SNP-A) allows for precise detection of copy number changes as well as UPD. We hypothesized that SNP-A may reveal new lesions on chromosome 5 and allow for better definition of CDRs and pathogenic genes. Of 512 patients, 15% showed a 5q abnormality as a sole or associated aberration by MC. DNA was available in 189 patients and was subjected to 250K SNP-A. In 7 patients with normal/non-informative MC, a deletion on 5q was clearly detectable by SNP-A; in total, SNP-A identified 5q abnormalities in 14% patients in this group (vs. 11% by MC). UPD 5q was found in one patient with CMML. By SNP-A, 6/27 patients showed an isolated 5q deletion. SNP-A can also be used to construct precise cytogenetic maps. The commonly deleted region (CDR1,5q31.2, 137,472,900–139,451,900) was present in 24/27 patients. Significant overlap occurs with the CDR previously defined by Fairman, Zhao, Horrigan et al. This region includes important genes such as Cdc25C and EGR1. Of 24 patients with a deletion in CDR1, 21 had multilineage dysplasia predominantly in the megakaryocytic line (92%). While elevated platelet counts occurred in 3 patients, increased levels of megakaryocytes were common (83%). Previous studies by Bouldwood/Jaju suggested that the minimal CDR among patients with 5q- syndrome (CDR2, 5q33.1-33.2) differs slightly from that associated with secondary AML/MDS (CDR1). However, when patients (5/27) with classical 5q- syndrome were analyzed, all displayed single deletions spanning both CDR1 and CDR2. Other areas of partial overlaps were also identified (5q12.1; 5q13.3) more centromeric to CDR1 and present in 7/27 patients. 2 cases were particularly interesting: 1 with segmental UPD involving the CDR, the other showing a small deletion defining the CDR itself. In the latter patient, marked thrombocytosis was present and SNP-A demonstrated a complex chromosomal rearrangement. While MC revealed a segmental deletion of 5q and a concomitant duplication of this abnormal homolog, SNP-A showed that while the p arm portion had been duplicated, the q arm, with the exception of two small deletions (1.35 and 1.98Mb in length, confirmed by FISH), had a normal diploid set. SKY clarified that chr. 5 material had indeed been displaced to both chr. 3 and 7 with a reciprocal translocation of chr. 3 material occurring on the abnormal chr. 5. In sum, our studies demonstrate the utility of SNP-A as a karyotyping tool that can detect previously cryptic areas of LOH on chr. 5 and facilitate definition of shared 5q defects. We also show that our patients with 5q- syndrome had lesions spanning both 5q33 and the more proximal 5q31.2 area, making pathogenic distinction based on cytogenetics difficult.

Genome-Wide Analysis of Genetic Alterations in Chronic Myelogenous Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1089-1089 ◽  
Author(s):  
Charles G Mullighan ◽  
Ina Radtke ◽  
Jinghui Zhang ◽  
Letha A. Phillips ◽  
Xiaoping Su ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Copy Number ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Disease Stage ◽  
Genome Wide Analysis ◽  
Genome Wide

Abstract Expression of BCR-ABL1 is the hallmark of chronic myelogenous leukemia (CML) and a subset of de novo acute lymphoblastic leukemia (ALL), but the factors determining disease lineage, and progression of CML to myeloid or lymphoid blast crisis, are incompletely understood. We recently reported deletion of IKZF1 (encoding the lymphoid transcription factor Ikaros) in 85% of de novo pediatric and adult BCR-ABL1 ALL, and in lymphoid blast crisis in a small cohort of CML cases (Nature2008;453:110), suggesting that IKZF1 deletion is important in the pathogenesis of BCR-ABL1 lymphoid leukemia. To identify genetic determinants of disease stage and blast crisis lineage in CML, we have now performed high-resolution, genome wide analysis of DNA copy number abnormalities (CNA) and loss-of heterozygosity (LOH) and candidate gene resequencing in a cohort of 90 CML patients that included 64 samples obtained at chronic phase (CP), 15 samples at accelerated phase (AP), 9 lymphoid blast crisis (LBC) and 22 myeloid blast crisis (MBC) samples. Importantly, 25 patients had sequential samples (CP and/or AP, as well as blast crisis samples) enabling analysis of lesions acquired at progression to blast crisis. All blast crisis samples were flow sorted to at least 90% purity prior to DNA extraction. Germline samples for 28 cases obtained at remission or by flow sorting of blast crisis samples were also examined. Affymetrix SNP 6.0 arrays, interrogating over 1.87 million genomic loci, were used for 85 samples, and 500K arrays for the remainder. Identification of tumor-specific (somatic) copy number analysis was performed by directly comparing CML samples to matched germline samples were available, or by filtering results against databases of inherited copy number variants for samples lacking germline material. Genomic resequencing of IKZF1, PAX5 and TP53 was performed for all AP, LBC and MBC samples. There were few CNAs in CP-CML (mean 0.27 deletions and 0.07 gains per case), with no recurring lesions identified apart from deletions or gains at the chromosomal breakpoints of BCR and ABL1 (3 cases each). Notably, the size of these translocation associated deletions was highly variable, ranging from 6kb (one ABL1 deletion) and 15 kb (one BCR deletion) to deletions extending to the telomeres of chromosomes 9 and 22. No significant increase in lesion frequency was identified in AP cases (0.14 deletions and 0.9 gains per case), however the number and cumulative extent of genomic aberrations was significantly higher in both lymphoid and myeloid blast crisis samples. LBC cases had a mean of 8.1 deletions/case (P&lt;0.0001v CP) and 2.8 gains/case (P=0.0024), where as MBC had fewer alterations with only an average of 2.8 deletions/ case (P=0.028 v CP) and 2.2 gains/case (P=0.0018). Similarly, the cumulative extent of DNA altered by CNAs was higher in both LBC (200 Mb/case) and MBC (257 Mb/case) than CP-CML (4.1 Mb/case). There were striking differences in the type of CNAs in MBC and LBC samples. Seven of 9 LBC cases had focal CNAs targeting genes regulating normal B-lymphoid development, including IKZF1 (6 cases, 2 homozygous), PAX5 (4 cases), and EBF1 (1 case with focal homozygous deletion restricted to the EBF1 locus). Thus, of these 7 cases, two had a single CNA in this pathway, three had two lesions, and two cases had three lesions. In contrast, only 4 of 22 MBC cases had lesions in this pathway, most commonly from whole or sub chromosomal deletions involving chromosomes 7 and 9. Deletion of the CDKN2A/B locus (encoding the tumor suppressors and cell cycle regulators INK4A, ARF and INK4B) was seen in 6 (67%) LBC samples, but only 2 (9%) MBC cases, and never in CP or AP CML. Other lesions commonly seen in de novo BCR-ABL1 ALL were also observed in LBC samples, including deletions of MEF2C, C20orf94, and the HBS1L gene immediately upstream of the oncogene MYB. Apart from acquisition of new or more complex abnormalities involving BCR and ABL1, the only recurring mutation observed in MBC was deletion (4 cases) or splice-site point mutations (2 cases) of TP53. These data demonstrate a lack of genomic instability with few genetic alterations in CP or AP CML. Lymphoid blast crisis samples have similar genetic alterations to those seen in de novo BCR-ABL1 ALL, whereas myeloid blast crisis displays completely distinct patterns of mutation, most commonly targeting P53. These results indicate that genomic abnormalities are important determinants of lineage and disease progression in BCR-ABL1 leukemia.

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