Papers by Andrea Biloglav
Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia all insta... more Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases,
British Journal of Haematology
Leukemia, 2022
TO THE EDITOR Single base substitutions (SBSs) and insertions/deletions (indels; IDs) arise throu... more TO THE EDITOR Single base substitutions (SBSs) and insertions/deletions (indels; IDs) arise through several mechanisms such as errors during DNA replication/repair and exposures to mutagens, with the different mutational processes occasionally generating specific mutational signatures. SBS signatures (SBSsigns) result from recurring trinucleotide patterns of the transition/transversion types of somatic single nucleotide variants (SNVs) and their flanking nucleotides, whereas ID signatures (IDsigns) are defined according to size, nucleotides affected, and the presence of repetitive/ microhomology regions (https://cancer.sanger.ac.uk/signatures/). Some signatures are associated with underlying etiologic factors, e.g. SBS7 and ID13 in UV-associated melanoma and SBS4 and ID3 in smoking-induced lung cancer [1, 2], whereas others are linked to inherent defects of DNA recombination, replication, and repair (SBS6 and ID1) or caused by spontaneous or enzymatic deamination of 5-methylcytosine to thymine (SBS1) (https://cancer.sanger. ac.uk/signatures/). Based on whole genome sequencing (WGS) of pediatric acute myeloid leukemia (AML), we recently reported that SBS18a signature characterized by frequent C > A transversionsis enriched in t(8;21)(q22;q22)/RUNX1::RUNX1T1-positive cases [3] (gene fusion designation according to recent guidelines [4]). Brandsma et al. [5] subsequently also showed that SBS18 is common in childhood AML, including cases with RUNX1::RUNX1T1. Considering that SBS18 has been associated with DNA damage caused by reactive oxygen species (ROS) (https://cancer.sanger.ac. uk/signatures/sbs/sbs18/) and that the RUNX1::RUNX1T1 chimeric protein is known to downregulate the expression of the OGG1 gene encoding a DNA glycosylase that excises oxidized guanines [6], we hypothesized that ROS could be involved in the genesis of childhood AML with RUNX1::RUNX1T1 [3]. Whether SBS18 is overrepresented also in adult RUNX1:: RUNX1T1-positive AML is unknown. In fact, our knowledge of SBSsigns is rudimentary-and non-existing as regards IDsigns-in adult core binding factor (CBF) AML, which consists of cases positive for either RUNX1::RUNX1T1 or CBFB::MYH11 [inv(16) (p13q22)/t(16;16)(p13;q22)] [7]. The only publication to date addressing SBSsigns in adult CBF AML reported a high frequency
British Journal of Haematology, 2021
the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol. 2011;153:92–104. 2. U.S. Food & ... more the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol. 2011;153:92–104. 2. U.S. Food & Drug Administration (FDA).FDA approves voxelotor for sickle cell disease, 2019. Available at: https://www.FDA.gov/drugs/resources-inf ormation-approved-drugs/fda-approves-voxelotor-sickle-cell-disease. Accessed January 2021. 3. Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. New Eng J Med. 2019;381:509–19.
Blood, 2021
Introduction. Pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) is the most commo... more Introduction. Pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) is the most common pediatric hematological malignancy and it remains an important cause of morbidity and mortality in children. In this study, we performed an allele-specific expression (ASE) analysis of pediatric BCP ALL with the aim to investigate the relationship between cis-regulatory mutations and gene expression patterns. Materials and methods. Twenty-two high hyperdiploid ALL, twenty ETV6/RUNX1-positive ALL, seven TCF3/PBX1-positive ALL and twenty-eight genetically unclassified BCP ALL ("B-other") were subjected to whole genome sequencing, SNP array analysis and RNA sequencing. The binomial test was applied to estimate the allelic bias of heterozygous exonic single nucleotide variants (SNVs) in the RNA sequencing data against the genomic data. Allelic ratios >2 or <0.5, and P values <0.05 were used to identify allele-specific expression protein-coding genes. Results. We identifi...
Genes, Chromosomes and Cancer, 2016
Leukemia, 2012
obtained classification may be clinically significant. Figure 1d shows the incidence of negative ... more obtained classification may be clinically significant. Figure 1d shows the incidence of negative prognostic features, such as Binet C stage, unmutated (UM) immunoglobulin variable region genes (IgVH), CD38 positivity (X30%) and short (o6 months) lymphocyte doubling time (LDT), in different clusters. No significant relationship was found with Binet C stage. In contrast, clusters with enhanced telomere and chromosome instability showed higher incidences of classical biological factors of poor prognosis. Of note, the strongest associations with UM IgVH and CD38 positivity were found for clusters obtained by combining telomeric and cytogenetic parameters, whereas the links with telomeric clusters were weaker but still significant and, finally, the associations with cytogenetic clusters were not significant. Only the combined model showed a significant relationship with short LDT. Cytogenetics and telomeres are known to represent valuable prognostic factors in CLL, 2 and perhaps the combinations of both characteristics could provide a more accurate prediction of disease progression. Our study was prospective, and so far we were not able to compare survival of patients from different clusters. This issue can be addressed in a large cohort of CLL patients with adequate follow-up. In conclusion, the identification of groups with distinct telomeric and cytogenetic profiles supports the link between telomere status and genomic instability in CLL. Telomere shortening, changes in shelterin and hTERT gene expression coincided with increasing levels of chromosome aberrations, and this was particularly affected by p53 or ATM gene deletions. Theses CLL groups are associated with established prognostic factors and may be clinically significant.
Genes, Chromosomes and Cancer
Genes, Chromosomes and Cancer
Blood
Pediatric acute lymphoblastic leukemia (ALL) has a very favorable prognosis, effective treatment ... more Pediatric acute lymphoblastic leukemia (ALL) has a very favorable prognosis, effective treatment protocols and display a cure rate of more than 80%. However, adult ALL is associated with a much poorer prognosis; the long-term survival rate for adult cases is only a mere 30-40%, decreasing with higher age. For an improved prognosis and better treatment stratification in adult ALL, it is important to identify acquired genetic aberrations that could be linked to outcome. We present here the largest SNP array analysis to date, covering 5 million markers with a resolution of 10kb to investigate a consecutive series of 215 adult ALL cases, including samples obtained at diagnosis and relapse. We detected characteristic deletions, such as CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. In addition, the investigation uncovered several recurrent cryptic genetic events not previously implicated in adult ALL; the BCAT1, SERP2, RAB30, SRPR, ST3GAL4, ASS1, RASSF3, FUBP3, BCL11A, GAB1, LINGO2, TO...
Blood
A comprehensive genetic characterization comprising conventional chromosome banding, fluorescence... more A comprehensive genetic characterization comprising conventional chromosome banding, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) array analyses as well as large-scale sequencing of 75 genes were performed on a consecutive series of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. An abnormal karyotype was identified in 46% of the cases. Recurrent cytogenetic aberrations comprised T-cell receptor (TCR) translocations and deletions of 6q and 9p. FISH analyses of TCR rearrangements were positive in 26% of the investigated cases. The vast majority (37/39; 95%) of cases analyzed by SNP arrays displayed aberrations, with a median of 3 changes (range 0-11) per case. The genes recurrently deleted were CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. One case displayed chromothripsis involving 6q. No case had a whole chromosome uniparental isodisomy (wUPID); in fact, only one T-ALL of 123 informative cases in the literature has had a wUPID....
Leukemia, Jan 12, 2018
High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and... more High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of...
Leukemia, 2018
Acquired whole chromosome/segmental uniparental disomies (wUPDs/sUPDs) are common in myeloid mali... more Acquired whole chromosome/segmental uniparental disomies (wUPDs/sUPDs) are common in myeloid malignancies [1, 2]. Already in the first publication on acquired UPDs in AML [1], it was reported that a case with UPD19q12-qter harbored a homozygous mutation in the CEBPA gene in 19q13.11 and, soon afterward, AML cases with sUPDs of 11p, 13q, and 21q were shown to carry homozygous mutations of the WT1, FLT3, and RUNX1 genes [3]. There are now several examples of other UPDassociated homozygously mutated genes in myeloid malignancies, where heterozygous somatic mutations precede the mitotic recombination events [2]. UPDs occur with a similar frequency in BCP ALL as in AML (~20%) [4, 5]. However, next to nothing is known about the molecular consequences of UPDs in BCP ALL. UPD9p is the only UPD investigated in any detail in BCP ALL, where it is often associated with homozygous CDKN2A deletions [4], and, to the best of our knowledge, UPD16p is the only UPD in BCP ALL that has been
Endocrine-related cancer, May 1, 2017
Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median survival t... more Anaplastic thyroid cancer (ATC) is a highly malignant disease with a very short median survival time. Few studies have addressed the underlying somatic mutations, and the genomic landscape of ATC thus remains largely unknown. In the present study, we have ascertained copy number aberrations, gene fusions, gene expression patterns, and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA sequencing and whole exome sequencing. The ATC cell line genomes were highly complex and displayed signs of replicative stress and genomic instability, including massive aneuploidy and frequent breakpoints in the centromeric regions and in fragile sites. Loss of heterozygosity involving whole chromosomes was common, but there were no signs of previous near-haploidisation events or chromothripsis. A total of 21 fusion genes were detected, including six predicted in-frame fusions; none were recurrent. Global gene expre...
New England Journal of Medicine, 2010
The in vivo clinical significance of malignant stem cells remains unclear. Patients who have the ... more The in vivo clinical significance of malignant stem cells remains unclear. Patients who have the 5q deletion (del[5q]) myelodysplastic syndrome (interstitial deletions involving the long arm of chromosome 5) have complete clinical and cytogenetic remissions in response to lenalidomide treatment, but they often have relapse. To determine whether the persistence of rare but distinct malignant stem cells accounts for such relapses, we examined bone marrow specimens obtained from seven patients with the del(5q) myelodysplastic syndrome who became transfusion-independent while receiving lenalidomide treatment and entered cytogenetic remission. Virtually all CD34+, CD38+ progenitor cells and stem cells that were positive for CD34 and CD90, with undetectable or low CD38 (CD38−/low), had the 5q deletion before treatment. Although lenalidomide efficiently reduced these progenitors in patients in complete remission, a larger fraction of the minor, quiescent, CD34+,CD38-/low, CD90+ del(5q) stem cells as well as functionally defined del(5q) stem cells remained distinctly resistant to lenalidomide. Over time, lenalidomide resistance developed in most of the patients in partial and complete remission, with recurrence or expansion of the del(5q) clone and clinical and cytogenetic progression. In these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)
Leukemia & Lymphoma, 2007
Genes, Chromosomes and Cancer, 2005
The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q... more The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q23, is one of the most common translocations in acute lymphoblastic leukemia (ALL). It is seen either as a balanced t(1;19) or as an unbalanced der(19)t(1;19); occasional cases with coexisting t(1;19)-and der(19)-positive clones also have been described. Although it generally has been assumed that the unbalanced form arises from the balanced t(1;19) through loss of the derivative chromosome 1 followed by duplication of the normal homologue, this has never been proved. At least two other mechanisms are possible for the formation of the der(19): an initial trisomy 1 followed by translocation and subsequent loss of the der(1) or a rearrangement during the G2 phase of the cell cycle, with the derivative chromosomes 1 and 19 ending up in separate daughter cells. The different alternatives may be distinguished by investigation of markers proximal to the breakpoint in 1q23 because they would be expected to lead to different allelic patterns. Thus, loss of heterozygosity as a result of the presence of uniparental disomy (UPD)-both copies of a chromosome being derived from only one parent-for chromosome 1 would be present in all der(19)-harboring cases arising via the duplication pathway and in one-third of cases arising via the trisomy pathway, but in none of the der(19) formed via the G2 pathway. In this study, we used quantitative fluorescence PCR with polymorphic microsatellite markers to investigate chromosomes 1 and 19 in two t(1;19)-and four der(19)-positive ALLs. None of the der(19) cases displayed UPD for chromosome 1, excluding that this aberration arises through the duplication pathway. Because previous findings of cases with coexisting t(1;19) and der(19) clones are difficult to explain if the translocation originated in G2, the present results suggest that an unbalanced der(19) may arise from an initial trisomy 1 followed by t(1;19) translocation and loss of the derivative chromosome 1.
Genes, Chromosomes and Cancer, 2013
Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC tran... more Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%-80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 1-21) than did the childhood cases (median 1.5; range 0-5) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.
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Papers by Andrea Biloglav