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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic myeloid leukemia &#40;CML&#41; is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome &#40;Ph&#41; which is the derivative chromosome 22 of the translocation t&#40;9&#59;22&#41;&#40;q34&#46;1&#59;q11&#46;2&#41;&#46; Due to this rearrangement&#44; the break-point cluster region &#40;<span class="elsevierStyleItalic">BCR</span>&#41; gene at position 22q11&#46;2 is juxtaposed to the c-Abelson &#40;<span class="elsevierStyleItalic">ABL1</span>&#41; gene at 9q34&#44; resulting in the <span class="elsevierStyleItalic">BCR-ABL1</span> fusion gene&#44; encoding a constitutively active tyrosine kinase protein&#46; The identification of this abnormality is important for the diagnosis of the disease as determined by the WHO Tumor Classification<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and for treatment purposes&#46; The first therapeutic choice&#44; tyrosine kinase inhibitors&#44; has shown great therapeutic efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The Ph is detected by G-band karyotyping in around 90&#37; of CML patients among whom 5&#8211;10&#37; may have variant types&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Variant Ph chromosomes are characterized by the involvement of another chromosome in addition to chromosome 9 or 22&#46; It can be a simple type of variant when only one additional chromosome is involved&#44; or complex&#44; in which two or more chromosomes&#44; besides chromosomes 9 and 22&#44; take part in the translocation&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Variant Ph breakpoints occur in hotspots across the genome&#44; usually in the G-light bands&#44; within the cytosine and guanine &#40;CG&#41; rich parts of the genome&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> CG content correlates with chromatin condensation and transcription activity&#59; that is&#44; open chromatin is transcriptionally active and relatively likely to undergo breakage and repair with a consequent tendency to illegitimate recombination and translocation&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The 3&#8242; portion of the <span class="elsevierStyleItalic">BCR</span> gene recombines preferentially with Alu elements at the breaks&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> However&#44; the mechanism of variant Ph generation and the molecular bases of biological differences between classic Ph and variant Ph chromosomes are not fully understood&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Recently&#44; Albano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> reported a study they performed on gene expression profiling &#40;GEP&#41; using microarrays to identify some of these differences&#46; They found 59 genes showing differential expressions&#46; Some of them &#40;<span class="elsevierStyleItalic">TR1B1</span>&#44; <span class="elsevierStyleItalic">PTK2B</span> and <span class="elsevierStyleItalic">C5AR1</span>&#41; were involved in the MAPK pathway&#44; which is already known to play a role in CML pathogenesis&#46; The prognostic significance of variant Ph chromosomes has already been discussed&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and it has been shown that the variant aberration does not impact on cytogenetic or molecular responses or even on clinical outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Variant Ph chromosomes are distinguished from additional chromosomal abnormalities or clonal evolution that drives disease progression&#46; The clonal evolution is a reflection of a genetic instability that characterizes the transition to advanced phase&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In this situation&#44; i&#40;17q&#41;&#44; a second Ph and &#43;8 are frequently found&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Few studies have reported the incidence of variant Ph chromosomes&#44; or the breakpoints involved&#44; in Brazilian CML patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objective</span><p id="par0030" class="elsevierStylePara elsevierViewall">The aim of this report is to describe the diversity of variant Ph chromosomes found in a group of Brazilian CML patients and to highlight some interesting breakpoint candidates for further studies&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">A search was conducted of variant Ph chromosomes among all the cases of CML in the Cytogenetics Section Database of Fleury Laboratory &#40;S&#227;o Paulo&#44; Brazil&#41;&#44; during a 12-year period &#40;from 1999 to 2010&#41;&#46; The diagnosis of CML was made according to WHO Tumor Classification&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> with analysis of complete blood count&#44; marrow aspiration and&#47;or biopsy and karyotyping&#46; Acute myeloid or lymphoid leukemia cases were excluded&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Karyotype analyses were performed from marrow samples&#44; through non-stimulated short term cultures and classified according to the International System for Human Cytogenetics Nomenclature &#40;ISCN&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> CML cases with positive <span class="elsevierStyleItalic">BCR-ABL1</span> detection by fluorescent <span class="elsevierStyleItalic">in situ</span> hybridization &#40;FISH&#41; or polymerase chain reaction &#40;PCR&#41; at diagnosis&#44; but with cryptic rearrangements by karyotyping&#44; were excluded from the study since they were cytogenetically invisible&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The study was approved by the Institution Ethics Committee&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">Fifty cases &#40;5&#46;17&#37;&#41; of variant t&#40;9&#59;22&#41; were found out of 1071 Ph-positive CML&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the list of the variant Philadelphia translocation cases &#40;some of these cases were previously reported<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#41; and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the rearrangement breakpoints&#46; A total of 33 different regions and almost all chromosomes were involved in rearrangements&#44; except for chromosomes&#58; 8&#44; 9&#44; 18&#44; 21&#44; 22&#44; X and Y&#46; In two cases it was not possible to identify the extra chromosome of the variant translocation&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Discussion</span><p id="par0055" class="elsevierStylePara elsevierViewall">The incidence of variant Ph chromosomes in Brazilian CML patients was similar to published data &#40;5&#46;17&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Forty-four &#40;88&#37;&#41; were simple variants and six &#40;12&#37;&#41; complex &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; also in accordance with previous reports&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The most frequently involved chromosome was 17 &#40;eleven times more common in the present report&#41;&#44; followed by chromosome 1 &#40;six times&#41;&#44; 20 &#40;five times&#41;&#44; 6&#44; 11 &#40;four times each&#41;&#44; and 2&#44; 10&#44; 12 and 15 &#40;three times each&#41;&#46; Marzocchi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> reported four cases of the involvement of chromosome 17 out of 30 variants&#46; The chromosomes not involved in Ph variant translocations in the present study were&#58; 8&#44; 9&#44; 18&#44; 21&#44; 22&#44; X and Y&#44; while other studies have shown rearrangements of these chromosomes&#44; except for Y&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;17&#44;18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Among all breakpoints seen in this survey&#44; six were repeated&#58; 11p15&#44; 14q32&#44; 15q11&#46;2&#44; 16p13&#46;1&#44; 17p13 and 17q21&#44; differing from the report by Marzocchi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> who did not find any recurrent breakpoints&#46; On the other hand&#44; Reid et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> listed nine recurring breakpoints in variant Ph translocations&#44; most of which had been reported by others&#46; In fact&#44; it seems that most breakpoints related to variant Ph chromosomes occur in regions of known oncogenes or typical secondary breakpoints in other types of cancer&#46; Indeed&#44; we endorse this statement&#44; since the current study also identified some breakpoints common to other cancers&#44; such as 12p13&#44; 17p13 and 17q21&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Some of the genes located in these regions are related to hematological malignancies &#40;i&#46;e&#46; <span class="elsevierStyleItalic">ETV6</span>&#44; <span class="elsevierStyleItalic">CD9</span>&#44; <span class="elsevierStyleItalic">RARA</span>&#44; <span class="elsevierStyleItalic">GAS7</span>&#44; <span class="elsevierStyleItalic">IGH-2</span>&#44; <span class="elsevierStyleItalic">MYB</span>&#41;&#46; However&#44; additional genes have already been reported in respect to CML&#44; including <span class="elsevierStyleItalic">TP53</span>&#44; located at 17p13&#44; and involved in up to 30&#37; of CML cases in blast crisis<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and <span class="elsevierStyleItalic">MECOM</span> and <span class="elsevierStyleItalic">VRK1</span> that play a role in blast crises&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Moreover&#44; it is also known that the <span class="elsevierStyleItalic">BCR-ABL1</span> tyrosine kinase activity activates the <span class="elsevierStyleItalic">P13K&#47;AKT</span> signaling pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Thus&#44; more studies regarding the function&#44; expression and regulation of these and other genes may help to explain how variant Ph translocations occur&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Controversies were found in respect to the meaning of variant Ph chromosomes&#46; Some authors have stated that the involvement of additional oncogenes could be associated to poorer prognosis although the European LeukemiaNet recommendations do not provide advice for patients with variant translocations&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a> In the tyrosine kinase inhibitors era&#44; it seems that variant Ph translocations have no implication on the prognosis&#44; evolution of the disease and response to treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;18</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0075" class="elsevierStylePara elsevierViewall">Due to the large variety of Ph variant translocations&#44; it seems that many possible interactions exist with some occurring in regions already reported as hotspots of oncogenes or related to different types of cancer&#46; This suggests that there must be local phenomena favoring the predisposition to the involvement of these breakpoints&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The incidence of Ph variant translocations in Brazilian patients is similar to other reports worldwide however some new variants were found&#46; 17q21 was the most frequent and repeated breakpoint and so this region is the most likely to be involved in Ph variant translocations&#46; Nevertheless&#44; the pathological implication of these variants remains unclear&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "sec0035"
          "titulo" => "Conflicts of interest"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2014-01-31"
    "fechaAceptado" => "2014-06-04"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec843173"
          "palabras" => array:5 [
            0 => "Leukemia&#44; myelogenous&#44; chronic&#44; BCR-ABL positive"
            1 => "Philadelphia chromosome"
            2 => "Chromosome breakpoints"
            3 => "Oncogenes"
            4 => "Brazil"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronic myeloid leukemia is a myeloproliferative disorder characterized by the Philadelphia chromosome or t&#40;9&#59;22&#41;&#40;q34&#46;1&#59;q11&#46;2&#41;&#44; resulting in the break-point cluster region-Abelson tyrosine kinase fusion gene&#44; which encodes a constitutively active tyrosine kinase protein&#46; The Philadelphia chromosome is detected by karyotyping in around 90&#37; of chronic myeloid leukemia patients&#44; but 5&#8211;10&#37; may have variant types&#46; Variant Philadelphia chromosomes are characterized by the involvement of another chromosome in addition to chromosome 9 or 22&#46; It can be a simple type of variant when one other chromosome is involved&#44; or complex&#44; in which two or more chromosomes take part in the translocation&#46; Few studies have reported the incidence of variant Philadelphia chromosomes or the breakpoints involved among Brazilian chronic myeloid leukemia patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The aim of this report is to describe the diversity of the variant Philadelphia chromosomes found and highlight some interesting breakpoint candidates for further studies&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">the Cytogenetics Section Database was searched for all cases with diagnoses of chronic myeloid leukemia during a 12-year period and all the variant Philadelphia chromosomes were listed&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fifty &#40;5&#46;17&#37;&#41; cases out of 1071 Philadelphia-positive chronic myeloid leukemia were variants&#46; The most frequently involved chromosome was 17&#44; followed by chromosomes&#58; 1&#44; 20&#44; 6&#44; 11&#44; 2&#44; 10&#44; 12 and 15&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Among all the breakpoints seen in this survey&#44; six had previously been described&#58; 11p15&#44; 14q32&#44; 15q11&#46;2&#44; 16p13&#46;1&#44; 17p13 and 17q21&#46; The fact that some regions get more frequently involved in such rare rearrangements calls attention to possible predisposition that should be further studied&#46; Nevertheless&#44; the pathological implication of these variants remains unclear&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Objective"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Methods"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
          ]
          4 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusion"
          ]
        ]
      ]
    ]
    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of translocation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;1&#59;9&#59;22&#59;16&#41;&#40;q32&#59;q34&#46;1&#59;q11&#46;2&#59;p13&#41;&#91;2&#93;&#47;46&#44;XY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;1&#59;13&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p12&#59;q34&#41;&#91;17&#93;&#47;46&#44;XX&#91;3&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;1&#59;&#63;3&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q36&#46;3&#59;&#63;q26&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;1&#59;9&#59;22&#59;14&#41;&#40;p21&#59;q34&#46;1&#59;q11&#46;2&#59;q32&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;1&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p34&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;1&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p36&#46;3&#41;&#91;19&#93;&#47;46&#44;XX&#91;1&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;2&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q37&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;2&#59;9&#59;22&#41;&#40;p21&#59;q34&#46;1&#59;q11&#46;2&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;2&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q24&#41;&#91;8&#93;&#47;46&#44;XY&#91;12&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;4&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p16&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#63;&#40;9&#59;22&#59;10&#59;11&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q22&#59;q25&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;5&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;6&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;6&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q27&#41;&#91;7&#93;&#47;46&#44;idem&#44;&#63;del&#40;12&#41;&#40;p11&#46;2p13&#41;&#91;3&#93;&#47;46&#44;XX&#91;10&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;6&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;15&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q11&#46;2&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;7&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p22&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;&#63;9&#59;22&#59;7&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q36&#41;&#44; 9phqh&#91;14&#93;&#47;46&#44;XX&#44; 9phqh&#91;6&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;10&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q21&#41;&#91;17&#93;&#47;46&#44;XY&#91;3&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#63;&#40;9&#59;22&#59;10&#59;11&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q22&#59;q25&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;4&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p16&#41;&#91;1&#93;&#47;45&#44;idem&#44;add&#40;7&#41;&#40;p22&#41;&#44;-8&#91;18&#93;&#47;46&#44;XY&#91;1&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#8764;45&#44;XX&#44;t&#40;7&#59;12&#41;&#40;q11&#46;2&#59;p12&#41;&#44;&#63;t&#40;9&#59;22&#59;11&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p15&#41;&#44;-14&#44;-15&#44;1min&#91;cp18&#93;&#47;46&#44;XX&#91;2&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;11&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p15&#41;&#44;9ph&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;&#63;22&#59;12&#41;&#40;q34&#46;1&#59;&#63;q11&#46;2&#59;q24&#41;&#91;17&#93;&#47;46&#44;XX&#91;3&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;1&#59;7&#41;&#40;p22&#59;q22&#41;&#44;t&#40;9&#59;22&#59;20&#41;&#40;q34&#46;1&#59;q11&#59;q11&#46;2&#41;&#91;4&#93;&#47;46&#44;XY&#44;t&#40;9&#59;22&#59;20&#41;&#40;q34&#46;1&#59;q11&#59;q11&#46;2&#41;&#91;3&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;12&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;14&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q32&#41;&#91;19&#93;&#47;46&#44;XY&#91;1&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;15&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q25&#41;&#44;t&#40;17&#59;19&#41;&#40;q12&#59;q13&#46;4&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;15&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q11&#46;2&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;6&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q27&#41;&#91;7&#93;&#47;46&#44;idem&#44;&#63;del&#40;12&#41;&#40;p11&#46;2p13&#41;&#91;3&#93;&#47;46&#44;XX&#91;14&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#63;&#40;9&#59;22&#59;16&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#46;3&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q21&#63;&#41;&#91;14&#93;&#47;46&#44;XX&#91;6&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q&#63;21&#41;&#91;16&#93;&#47;46&#44;XX&#91;4&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q21&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#41;&#44;t&#40;12&#59;13&#41;&#40;q13&#59;p11&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q24&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q21&#41;&#91;10&#93;&#47;&#47;46&#44;XX&#91;10&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#41;&#91;3&#93;&#47;75&#8764;77&#44;XY&#44;&#43;X&#44;&#43;1&#44;&#43;5&#44;&#43;6&#44;&#43;9&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;p13&#41;x2&#44;&#43;10&#44;&#43;11&#44;&#43;12&#44;&#43;20&#44;&#43;21&#44;&#43;22&#91;cp16&#93;&#47;46&#44;XY&#91;1&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q24&#41;&#91;1&#93;&#47;47&#44;XX&#44;&#43;8&#91;8&#93;&#47;46&#44;XX&#91;11&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;1&#59;7&#41;&#40;p22&#59;q22&#41;&#44;t&#40;9&#59;22&#59;20&#41;&#40;q34&#46;1&#59;q11&#59;q11&#46;2&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;19&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q11&#46;2&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;20&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q11&#46;2&#41;&#91;13&#93;&#47;46&#44;XY&#44;t&#40;1&#59;7&#41;&#40;p22&#59;q22&#41;&#44;idem&#91;7&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;1&#59;7&#41;&#40;p22&#59;q22&#41;&#44;t&#40;9&#59;22&#59;20&#41;&#40;q34&#46;1&#59;q11&#59;q11&#46;2&#41;&#91;2&#93;&#47;46&#44;XY&#91;18&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XX&#44;t&#40;9&#59;22&#59;17&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q24&#41;&#91;1&#93;&#47;47&#44;XX&#44;&#43;8&#91;11&#93;&#47;46&#44;XX&#91;8&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;12&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;q24&#46;3&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;1&#59;7&#41;&#40;p22&#59;q22&#41;&#44;t&#40;9&#59;22&#59;20&#41;&#40;q34&#46;1&#59;q11&#59;q11&#46;2&#41;&#91;1&#93;&#47;46&#44;XY&#91;9&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;&#63;&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;&#63;&#41;&#91;11&#93;&#47;46&#44;XY&#91;9&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#44;XY&#44;t&#40;9&#59;22&#59;&#63;&#41;&#40;q34&#46;1&#59;q11&#46;2&#59;&#63;&#41;&#91;20&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simple&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1431506.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">List of the variant Philadelphia translocations found&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Chromosome region</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1p34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2q37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10q21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15q11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1p36&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3q26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10q22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15q25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1q11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4p16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11p15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16p13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1q12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5p13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11q25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17p13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1q32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6q22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12p13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17q21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1q36&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6q27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12q24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17q24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2p21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7p22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13q34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19q11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2q24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7q36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14q32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20q11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1431505.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">List of regions involved in Ph variant translocations&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:21 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "WHO Classification of tumors of haematopoietic and lymphoid tissues"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;H&#46; Swerdlow"
                            1 => "E&#46; Campo"
                            2 => "N&#46;L&#46; Harris"
                            3 => "E&#46;S&#46; Jaffe"
                            4 => "S&#46;A&#46; Pileri"
                            5 => "H&#46; Stein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:5 [
                        "edicion" => "4th ed&#46;"
                        "fecha" => "2008"
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Vol. 37. Núm. 1.
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Original article
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Diversity of breakpoints of variant Philadelphia chromosomes in chronic myeloid leukemia in Brazilian patients
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Maria de Lourdes Lopes Ferrari Chauffaillea,b, Ana Carolina de Almeida Bandeirab,
Autor para correspondência
anacarolusp@gmail.com

Corresponding author at: Setor de Citogenética, Grupo Fleury, Av. Gal. Valdomiro de Lima, 508, 04344-903 São Paulo, SP, Brazil.
, Aline Schiavoni Guarnieri da Silvab
a Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
b Grupo Fleury, São Paulo, SP, Brazil
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Table 1. List of the variant Philadelphia translocations found.
Table 2. List of regions involved in Ph variant translocations.
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Abstract
Background

Chronic myeloid leukemia is a myeloproliferative disorder characterized by the Philadelphia chromosome or t(9;22)(q34.1;q11.2), resulting in the break-point cluster region-Abelson tyrosine kinase fusion gene, which encodes a constitutively active tyrosine kinase protein. The Philadelphia chromosome is detected by karyotyping in around 90% of chronic myeloid leukemia patients, but 5–10% may have variant types. Variant Philadelphia chromosomes are characterized by the involvement of another chromosome in addition to chromosome 9 or 22. It can be a simple type of variant when one other chromosome is involved, or complex, in which two or more chromosomes take part in the translocation. Few studies have reported the incidence of variant Philadelphia chromosomes or the breakpoints involved among Brazilian chronic myeloid leukemia patients.

Objective

The aim of this report is to describe the diversity of the variant Philadelphia chromosomes found and highlight some interesting breakpoint candidates for further studies.

Methods

the Cytogenetics Section Database was searched for all cases with diagnoses of chronic myeloid leukemia during a 12-year period and all the variant Philadelphia chromosomes were listed.

Results

Fifty (5.17%) cases out of 1071 Philadelphia-positive chronic myeloid leukemia were variants. The most frequently involved chromosome was 17, followed by chromosomes: 1, 20, 6, 11, 2, 10, 12 and 15.

Conclusion

Among all the breakpoints seen in this survey, six had previously been described: 11p15, 14q32, 15q11.2, 16p13.1, 17p13 and 17q21. The fact that some regions get more frequently involved in such rare rearrangements calls attention to possible predisposition that should be further studied. Nevertheless, the pathological implication of these variants remains unclear.

Keywords:
Leukemia, myelogenous, chronic, BCR-ABL positive
Philadelphia chromosome
Chromosome breakpoints
Oncogenes
Brazil
Texto Completo
Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome (Ph) which is the derivative chromosome 22 of the translocation t(9;22)(q34.1;q11.2). Due to this rearrangement, the break-point cluster region (BCR) gene at position 22q11.2 is juxtaposed to the c-Abelson (ABL1) gene at 9q34, resulting in the BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase protein. The identification of this abnormality is important for the diagnosis of the disease as determined by the WHO Tumor Classification1 and for treatment purposes. The first therapeutic choice, tyrosine kinase inhibitors, has shown great therapeutic efficacy.2

The Ph is detected by G-band karyotyping in around 90% of CML patients among whom 5–10% may have variant types.3–5

Variant Ph chromosomes are characterized by the involvement of another chromosome in addition to chromosome 9 or 22. It can be a simple type of variant when only one additional chromosome is involved, or complex, in which two or more chromosomes, besides chromosomes 9 and 22, take part in the translocation.6,7

Variant Ph breakpoints occur in hotspots across the genome, usually in the G-light bands, within the cytosine and guanine (CG) rich parts of the genome.4 CG content correlates with chromatin condensation and transcription activity; that is, open chromatin is transcriptionally active and relatively likely to undergo breakage and repair with a consequent tendency to illegitimate recombination and translocation.4 The 3′ portion of the BCR gene recombines preferentially with Alu elements at the breaks.8 However, the mechanism of variant Ph generation and the molecular bases of biological differences between classic Ph and variant Ph chromosomes are not fully understood.9 Recently, Albano et al.10 reported a study they performed on gene expression profiling (GEP) using microarrays to identify some of these differences. They found 59 genes showing differential expressions. Some of them (TR1B1, PTK2B and C5AR1) were involved in the MAPK pathway, which is already known to play a role in CML pathogenesis. The prognostic significance of variant Ph chromosomes has already been discussed,11 and it has been shown that the variant aberration does not impact on cytogenetic or molecular responses or even on clinical outcome.5

Variant Ph chromosomes are distinguished from additional chromosomal abnormalities or clonal evolution that drives disease progression. The clonal evolution is a reflection of a genetic instability that characterizes the transition to advanced phase.12 In this situation, i(17q), a second Ph and +8 are frequently found.

Few studies have reported the incidence of variant Ph chromosomes, or the breakpoints involved, in Brazilian CML patients.13,14

Objective

The aim of this report is to describe the diversity of variant Ph chromosomes found in a group of Brazilian CML patients and to highlight some interesting breakpoint candidates for further studies.

Methods

A search was conducted of variant Ph chromosomes among all the cases of CML in the Cytogenetics Section Database of Fleury Laboratory (São Paulo, Brazil), during a 12-year period (from 1999 to 2010). The diagnosis of CML was made according to WHO Tumor Classification,1 with analysis of complete blood count, marrow aspiration and/or biopsy and karyotyping. Acute myeloid or lymphoid leukemia cases were excluded.

Karyotype analyses were performed from marrow samples, through non-stimulated short term cultures and classified according to the International System for Human Cytogenetics Nomenclature (ISCN).15 CML cases with positive BCR-ABL1 detection by fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) at diagnosis, but with cryptic rearrangements by karyotyping, were excluded from the study since they were cytogenetically invisible.

The study was approved by the Institution Ethics Committee.

Results

Fifty cases (5.17%) of variant t(9;22) were found out of 1071 Ph-positive CML. Table 1 shows the list of the variant Philadelphia translocation cases (some of these cases were previously reported16) and Table 2 shows the rearrangement breakpoints. A total of 33 different regions and almost all chromosomes were involved in rearrangements, except for chromosomes: 8, 9, 18, 21, 22, X and Y. In two cases it was not possible to identify the extra chromosome of the variant translocation.

Table 1.

List of the variant Philadelphia translocations found.

Case  Karyotype  Type of translocation 
46,XY,t(1;9;22;16)(q32;q34.1;q11.2;p13)[2]/46,XY  Complex 
46,XX,t(9;22;1;13)(q34.1;q11.2;p12;q34)[17]/46,XX[3]  Complex 
46,XY,t(9;22;1;?3)(q34.1;q11.2;q36.3;?q26)[20]  Complex 
46,XX,t(1;9;22;14)(p21;q34.1;q11.2;q32)[20]  Complex 
46,XX,t(9;22;1)(q34.1;q11.2;p34)[20]  Simple 
46,XX,t(9;22;1)(q34.1;q11.2;p36.3)[19]/46,XX[1]  Simple 
46,XX,t(9;22;2)(q34.1;q11.2;q37)[20]  Simple 
46,XY,t(2;9;22)(p21;q34.1;q11.2)[20]  Simple 
46,XY,t(9;22;2)(q34.1;q11.2;q24)[8]/46,XY[12]  Simple 
10  46,XY,t(9;22;4)(q34.1;q11.2;p16)[20]  Simple 
11  46,XY,t?(9;22;10;11)(q34.1;q11.2;q22;q25)[20]  Complex 
12  46,XY,t(9;22;5)(q34.1;q11.2;p13)[20]  Simple 
13  46,XY,t(9;22;6)(q34.1;q11.2;q22)  Simple 
14  46,XX,t(9;22;6)(q34.1;q11.2;q27)[7]/46,idem,?del(12)(p11.2p13)[3]/46,XX[10]  Simple 
15  46,XY,t(9;22;6)(q34.1;q11.2;q22)  Simple 
16  46,XY,t(9;22;15)(q34.1;q11.2;q11.2)[20]  Simple 
17  46,XX,t(9;22;7)(q34.1;q11.2;p22)[20]  Simple 
18  46,XX,t(?9;22;7)(q34.1;q11.2;q36), 9phqh[14]/46,XX, 9phqh[6]  Simple 
19  46,XY,t(9;22;10)(q34.1;q11.2;q21)[17]/46,XY[3]  Simple 
20  46,XY,t?(9;22;10;11)(q34.1;q11.2;q22;q25)[20]  Complex 
21  46,XY,t(9;22;4)(q34.1;q11.2;p16)[1]/45,idem,add(7)(p22),-8[18]/46,XY[1]  Simple 
22  44∼45,XX,t(7;12)(q11.2;p12),?t(9;22;11)(q34.1;q11.2;p15),-14,-15,1min[cp18]/46,XX[2]  Simple 
23  46,XY,t(9;22;11)(q34.1;q11.2;p15),9ph[20]  Simple 
24  46,XX,t(9;?22;12)(q34.1;?q11.2;q24)[17]/46,XX[3]  Simple 
25  46,XY,t(1;7)(p22;q22),t(9;22;20)(q34.1;q11;q11.2)[4]/46,XY,t(9;22;20)(q34.1;q11;q11.2)[3]  Simple 
26  46,XY,t(9;22;12)(q34.1;q11.2;p13)[20]  Simple 
27  46,XY,t(9;22;14)(q34.1;q11.2;q32)[19]/46,XY[1]  Simple 
28  46,XY,t(9;22;15)(q34.1;q11.2;q25),t(17;19)(q12;q13.4)[20]  Simple 
29  46,XY,t(9;22;15)(q34.1;q11.2;q11.2)[20]  Simple 
30  46,XX,t(9;22;6)(q34.1;q11.2;q27)[7]/46,idem,?del(12)(p11.2p13)[3]/46,XX[14]  Simple 
31  46,XX,t?(9;22;16)(q34.1;q11.2;p13.3)[20]  Simple 
32  46,XX,t(9;22;17)(q34.1;q11.2;q21?)[14]/46,XX[6]  Simple 
33  46,XX,t(9;22;17)(q34.1;q11.2;q?21)[16]/46,XX[4]  Simple 
34  46,XY,t(9;22;17)(q34.1;q11.2;q21)[20]  Simple 
35  46,XX,t(9;22;17)(q34.1;q11.2),t(12;13)(q13;p11)[20]  Simple 
36  46,XY,t(9;22;17)(q34.1;q11.2;p13)[20]  Simple 
37  46,XX,t(9;22;17)(q34.1;q11.2;q24)[20]  Simple 
38  46,XY,t(9;22;17)(q34.1;q11.2;p13)[20]  Simple 
39  46,XX,t(9;22;17)(q34.1;q11.2;q21)[10]//46,XX[10]  Simple 
40  46,XY,t(9;22;17)(q34.1;q11.2;p13)[3]/75∼77,XY,+X,+1,+5,+6,+9,t(9;22;17)(q34.1;q11.2;p13)x2,+10,+11,+12,+20,+21,+22[cp16]/46,XY[1]  Simple 
41  46,XX,t(9;22;17)(q34.1;q11.2;q24)[1]/47,XX,+8[8]/46,XX[11]  Simple 
42  46,XY,t(1;7)(p22;q22),t(9;22;20)(q34.1;q11;q11.2)[20]  Simple 
43  46,XY,t(9;22;19)(q34.1;q11.2;q11.2)[20]  Simple 
44  46,XY,t(9;22;20)(q34.1;q11.2;q11.2)[13]/46,XY,t(1;7)(p22;q22),idem[7]  Simple 
45  46,XY,t(1;7)(p22;q22),t(9;22;20)(q34.1;q11;q11.2)[2]/46,XY[18]  Simple 
46  46,XX,t(9;22;17)(q34.1;q11.2;q24)[1]/47,XX,+8[11]/46,XX[8]  Simple 
47  46,XY,t(9;22;12)(q34.1;q11.2;q24.3)[20]  Simple 
48  46,XY,t(1;7)(p22;q22),t(9;22;20)(q34.1;q11;q11.2)[1]/46,XY[9]  Simple 
49  46,XY,t(9;22;?)(q34.1;q11.2;?)[11]/46,XY[9]  Simple 
50  46,XY,t(9;22;?)(q34.1;q11.2;?)[20]  Simple 
Table 2.

List of regions involved in Ph variant translocations.

Chromosome region
1p34  2q37  10q21  15q11.2 
1p36.3  3q26  10q22  15q25 
1q11.2  4p16  11p15  16p13 
1q12  5p13  11q25  17p13 
1q32  6q22  12p13  17q21 
1q36.3  6q27  12q24  17q24 
2p21  7p22  13q34  19q11.2 
2q24  7q36  14q32  20q11.2 
Discussion

The incidence of variant Ph chromosomes in Brazilian CML patients was similar to published data (5.17%).17 Forty-four (88%) were simple variants and six (12%) complex (Table 1), also in accordance with previous reports.4

The most frequently involved chromosome was 17 (eleven times more common in the present report), followed by chromosome 1 (six times), 20 (five times), 6, 11 (four times each), and 2, 10, 12 and 15 (three times each). Marzocchi et al.5 reported four cases of the involvement of chromosome 17 out of 30 variants. The chromosomes not involved in Ph variant translocations in the present study were: 8, 9, 18, 21, 22, X and Y, while other studies have shown rearrangements of these chromosomes, except for Y.14,17,18

Among all breakpoints seen in this survey, six were repeated: 11p15, 14q32, 15q11.2, 16p13.1, 17p13 and 17q21, differing from the report by Marzocchi et al.5 who did not find any recurrent breakpoints. On the other hand, Reid et al.19 listed nine recurring breakpoints in variant Ph translocations, most of which had been reported by others. In fact, it seems that most breakpoints related to variant Ph chromosomes occur in regions of known oncogenes or typical secondary breakpoints in other types of cancer. Indeed, we endorse this statement, since the current study also identified some breakpoints common to other cancers, such as 12p13, 17p13 and 17q21.19 Some of the genes located in these regions are related to hematological malignancies (i.e. ETV6, CD9, RARA, GAS7, IGH-2, MYB). However, additional genes have already been reported in respect to CML, including TP53, located at 17p13, and involved in up to 30% of CML cases in blast crisis20 and MECOM and VRK1 that play a role in blast crises.21 Moreover, it is also known that the BCR-ABL1 tyrosine kinase activity activates the P13K/AKT signaling pathway.21 Thus, more studies regarding the function, expression and regulation of these and other genes may help to explain how variant Ph translocations occur.

Controversies were found in respect to the meaning of variant Ph chromosomes. Some authors have stated that the involvement of additional oncogenes could be associated to poorer prognosis although the European LeukemiaNet recommendations do not provide advice for patients with variant translocations.2,5 In the tyrosine kinase inhibitors era, it seems that variant Ph translocations have no implication on the prognosis, evolution of the disease and response to treatment.5,18

Conclusions

Due to the large variety of Ph variant translocations, it seems that many possible interactions exist with some occurring in regions already reported as hotspots of oncogenes or related to different types of cancer. This suggests that there must be local phenomena favoring the predisposition to the involvement of these breakpoints.

The incidence of Ph variant translocations in Brazilian patients is similar to other reports worldwide however some new variants were found. 17q21 was the most frequent and repeated breakpoint and so this region is the most likely to be involved in Ph variant translocations. Nevertheless, the pathological implication of these variants remains unclear.

Conflicts of interest

The authors declare no conflicts of interest.

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PMID: 23161685. Avaiable from: http://AtlasGeneticsOncology.org
Copyright © 2014. Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular
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