Summary of recurrent CNAs found in the global series.

<p>(<b>A</b>) Proportion of the whole series of patients with normal and abnormal aCGH profiles. Each aCGH category is then divided by the cytogenetic subgroups detected by CC studies: normal, abnormal and non-informative karyotype. Percentages represent the proportion of patients from the total number of patients within each cytogenetic subgroup. (<b>B</b>) Frequency of large recurrent genomic abnormalities and frequency of cryptic recurrent CNAs involving genes of known significance in MDS and MDS/MPN patients only seen by aCGH. All abnormalities are classified by MDS and MDS/MPN subtypes and color-coded as indicated on the right panel of the figure.</p

Main characteristics of the whole series of patients included in the study.

<p>Main characteristics of the whole series of patients included in the study.</p

Combination of aCGH and NGS analysis for regions with frequently mutated genes in MDS and MDS/MPN.

<p>(<b>A</b>, <b>C</b>, <b>D</b>, <b>E</b>, <b>G</b>) Detailed view of the whole chromosomes 2, 4, 17, 21 and X, where recurrent regions of deletion where found by aCGH, indicated by the red-shaded box. A magnified view of the minimal deleted regions with a schematic diagram showing the genes included within the deletion. For all figures, genomic locations are indicated in Mb, and the chromosome position (bp) and size (kb) of the minimal deleted regions are indicated in the upper part of each chromosome view ratio plots. The Y-axis represents the log₂ ratio values and all probes for each chromosome are sorted by genomic position along the X-axis. (<b>A</b>) A 533.4-kb deletion on 2p23.3 affecting the <i>DNMT3A</i> locus. (<b>C</b>) A 298.7-kb deletion on 21q22.12 affecting the <i>RUNX1</i> locus. (<b>D</b>) A 697.1-kb deletion on Xp11.4 affecting the <i>BCOR</i> locus. (<b>E</b>) A 381.2-kb deletion on 4q24 affecting the <i>TET2</i> locus. (<b>G</b>) An 11.14-Mb deletion on 17p13.3-p12 affecting the <i>TP53</i> locus. Genes were represented using the R package “GenomeGraphs”. (<b>B</b>, <b>F</b>, <b>H</b>) Distribution of <i>DNMT3A</i>, <i>TET2</i> and <i>TP53</i> mutations identified by targeted amplicon-based deep sequencing. The variant allele frequencies (VAFs) are represented in brackets. The complete coding regions of <i>DNMT3A</i>, <i>TET2</i> and <i>TP53</i> are illustrated and the respective exons and amino acid (AA) positions are indicated below. Each circle represents a mutation found in a single patient. Green, red and blue circles depict missense, nonsense and frameshift mutations, respectively. (<b>B</b>) One patient carried a <i>DNMT3A</i> missense mutation located in the MTase domain. The following protein domains are shown: PWWP, proline-tryptophan-tryptophan-proline domain; ZNF, zinc finger domain; MTase, methyltransferase domain. (<b>F</b>) Three patients with a <i>TET2</i> deletion harbored one nonsense, one missense and one frameshift mutation each. The two evolutionarily conserved domains, boxes 1 and 2, are shown. (<b>H</b>) Four patients carried one <i>TP53</i> missense mutation each. The following protein domains are shown: TAD1 and TAD2, amino-terminal transactivation domains 1 and 2; DBD, sequence-specific DNA-binding domain; NLS, nuclear localization signalling domain; 4D, carboxy-terminal tetrame-rization domain; Neg, negative regulation domain. Gene variants were represented using the R package “R453PlusToolbox” [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164370#pone.0164370.ref053" target="_blank">53</a>].</p

Recurrent chromothripsis on chromosome 13 in high-risk MDS.

<p>(<b>A</b>) Whole genome view ratio plots derived from aCGH data of MDS patients (#026, #027 and #072) showing chromothripsis on chromosome 13, indicated by the red-shaded box. The three patients had complex karyotypes: patient #026 had 33 aberrations and affecting seven chromosomes; patient #027 had 19 abnormalities affecting five chromosomes; patient #072 had 21 aberrations affecting six chromosomes. The Y-axis represents the log₂ ratio values of MDS:control signal intensities for each probe. The X-axis illustrates all the probes in the array sorted by chromosome and physical mapping position. Chromosome numbers are indicated below the X-axis. (<b>B</b>) Detailed view of the whole chromosome 13 in patients #026, #027 and #072 showing a complex pattern of alternating copy number gains and losses. The grey area represents the thresholds of signal values (log₂ ratio) to call CNAs, red lines indicate segmented copy number profiles, and boxes shaded in pale-red and pale-blue depict copy number losses and gains, respectively. Patient #026 had 18 alternating copy number changes, patient #027 had 11, and patient #072 had 16 changes along the whole chromosome 13. Copy number profiles differed between these patients. The Y-axis represents log₂ ratios and the X-axis shows all probes of chromosome 13 sorted by chromosome position. Genomic location (Mb) is indicated below the X-axis. (<b>C</b>) Distribution of <i>TP53</i> mutations identified by amplicon-based deep sequencing in the three MDS patients with chromothripsis. All <i>TP53</i> mutations were located in the sequence-specific DNA binding domain. One patient had two mutations in heterozygosis, while the other two patients had one mutation each in homozygosis. The variant allele frequencies (VAFs) are represented in brackets. Each circle represents a mutation found in one patient. Green and red circles depict missense and nonsense mutations, respectively. Each patient is illustrated by a different-colour triangle. The complete coding region of <i>TP53</i> is illustrated and the respective exons and amino acid (AA) positions are indicated at the bottom. The following protein domains are shown: TAD1 and TAD2, amino-terminal transactivation domains 1 and 2; DBD, sequence-specific DNA-binding domain; NLS, nuclear localization signalling domain; 4D, carboxy-terminal tetramerization domain; Neg, negative regulation domain. Gene variants were represented using the R package “R453PlusToolbox” [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164370#pone.0164370.ref053" target="_blank">53</a>].</p

Patterns and frequencies of DNA copy alterations in ALL patients.

<p>(A) Log₂-ratio copy number heatmap of array-based comparative genomic hybridization (aCGH) data in childhood (left) and adult (right) ALL. (gains: red; losses: blue). (B) Overall frequency of copy number changes in childhood (left) and adult (right) ALL. (gains: red; losses: blue) (C) Regions of significant recurrent amplification and deletion in childhood (left) and adult (right) ALL (q<0.05).</p

Characteristics of patients with ALL included in the study.

<p>Characteristics of patients with ALL included in the study.</p

Association of DNA/chromosomal aberrations with clinical characteristics in the whole cohort of patients with ALL.

<p>Association of DNA/chromosomal aberrations with clinical characteristics in the whole cohort of patients with ALL.</p

Univariate and multivariate analysis of overall survival in adults with ALL.

<p>Univariate and multivariate analysis of overall survival in adults with ALL.</p

Univariate and multivariate analysis of overall survival in children with ALL.

<p>Univariate and multivariate analysis of overall survival in children with ALL.</p

Kaplan—Meier plots demonstrating the effect of copy number changes on overall survival (OS) in children with ALL.

<p>(A) OS of the whole cohort of children with ALL with respect to the presence of deletions in 14q32.33. (B) OS of the whole cohort of children with ALL with respect to the presence of deletions in 15q13.2. (C) OS of the children with ALL without chromosomal abnormalities associated with good-risk (hyperdiploid and t(12;21)) or poor risk (t(9;22), t(v;11q23) and hypodiploidy) with respect to the presence of gains of 1p36.11.</p