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Raoul C M Hennekam - One of the best experts on this subject based on the ideXlab platform.

  • array comparative genomic hybridization analysis of a familial duplication of Chromosome 13q a recognizable syndrome
    American Journal of Medical Genetics Part A, 2005
    Co-Authors: Inge B Mathijssen, Raoul C M Hennekam, J M N Hoovers
    Abstract:

    We report on a family with six persons in three generations who have mild mental retardation, behavioral problems, seizures, hearing loss, strabismus, dental anomalies, hypermobility, juvenile hallux valgus, and mild dysmorphic features. Classical cytogenetic analysis showed a partial duplication of Chromosome 13q, array comparative genomic hybridization showed the duplication to span approximately 21 Mb, ranging from Chromosome band 13q21.31 to 13q31.1. The relatively mild presentation of this large duplication may be explained by the relative paucity of genes in the Chromosome region involved. Genotype-phenotype correlations in patients with similar partial 13q duplications are inconsistent. Emerging cytogenetic techniques will allow more reliable genotype -phenotype correlations. (c) 2005 Wiley-Liss, Inc

  • Array comparative genomic hybridization analysis of a familial duplication of Chromosome 13q: a recognizable syndrome.
    Am J Med Genet A, 2005
    Co-Authors: Raoul C M Hennekam
    Abstract:

    We report on a family with six persons in three generations who have mild mental retardation, behavioral problems, seizures, hearing loss, strabismus, dental anomalies, hypermobility, juvenile hallux valgus, and mild dysmorphic features. Classical cytogenetic analysis showed a partial duplication of Chromosome 13q, array comparative genomic hybridization showed the duplication to span approximately 21 Mb, ranging from Chromosome band 13q21.31 to 13q31.1. The relatively mild presentation of this large duplication may be explained by the relative paucity of genes in the Chromosome region involved. Genotype-phenotype correlations in patients with similar partial 13q duplications are inconsistent. Emerging cytogenetic techniques will allow more reliable genotype-phenotype correlations.

Hannes Kaufmann - One of the best experts on this subject based on the ideXlab platform.

  • Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation.
    European Journal of Haematology, 2020
    Co-Authors: Werner Rabitsch, Hannes Kaufmann, Jutta Ackermann, Sonja Seidl, Erika Prinz, Stefan Wöhrer, Felix Keil, Peter Kalhs, Hildegard T. Greinix, Heinz Gisslinger
    Abstract:

    : Objectives:  Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem celltransplantation in the context of s2 microglobulin and Chromosome 13q. Methods:  All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. Results:  There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5–128) nine patients (70%) are still allive, and six of them have remained progression free. Among five patients with low s2 microglobulin and normal Chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated s2 microglobulin and/or deletion of Chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. Conclusions:  Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.

  • bortezomib in relapsed multiple myeloma response rates and duration of response are independent of a Chromosome 13q deletion
    Leukemia, 2007
    Co-Authors: Verena Sagaster, Heinz Ludwig, Hannes Kaufmann, Viktoria Odelga, Niklas Zojer, Jutta Ackermann, Elisabeth Kuenburg, Rotraud Wieser, Christoph C Zielinski, Johannes Drach
    Abstract:

    Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a Chromosome 13q-deletion

  • favorable survival of multiple myeloma patients with t 11 14 q13 q32 plus normal Chromosome 13q
    Blood, 2004
    Co-Authors: Hannes Kaufmann, Verena Sagaster, Jutta Ackermann, Heinz Gisslinger, Catrin Baldia, Sonja Seidl, Thomas Noesslinger, Ulrich Jaeger, Andrea Keck, Heinz Ludwig
    Abstract:

    Previous studies have shown that specific chromosomal abnormalities are of major prognostic significance in patients with multiple myeloma (MM). It has been recently suggested that a t(11;14)(q13;q32) may be an indicator of favorable outcome in MM. In this investigation, we analyzed 163 patients with newly diagnosed MM (53% treated by high-dose therapy) to address the question whether or not the simultaneous occurrence of a t(11;14) and a deletion 13q [del(13q)], an established negative prognostic factor in MM, has any impact on prognosis. DNA-specific probes for IgH (14q32) and cyclin-D1 (11q13) were used for interphase FISH analysis of clonal plasma cells (cytoplasmic Ig positive). A t(11;14) by FISH was shown in 27 of the 163 MM patients (16.6%); the abnormality was present in the majority (median, 89%) of clonal plasma cells. Immunohistochemical analysis of CYCLIN-D1 expression was carried out in 72 patients, of whom 11 had a t(11;14) by FISH; all 11 patients had evidence for CYCLIN-D1 protein expression. Presence of a t(11;14) did not show significant correlations with standard laboratory and clinical MM features including type of the paraprotein, hemoglobin, creatinine, LDH, albumine, calcium, CRP, and beta-2-microglobulin (b2M). In contrast to a recent report, there was also no association with CD20 expression by MM cells. With respect to survival, presence of any 14q-translocation (52% of patients) was associated with similar overall survival times (OS) compared to patients lacking a t(14q), whereas patients with a t(11;14) experienced prolonged OS (median, 70+ months vs. 59.8 months among patients without t(11;14); P = .071). This survival advantage was even greater among the 16 patients with t(11;14) who were also normal for 13q (P = .02); however, occurrence of a del(13q) concomitantly with a t(11;14) was indicative for shortened progression-free survial (17.7 months vs. 31.6 months; P = .17) and OS (P = .07). A survival benefit of MM patients with a t(11;14) was particularly evident for the population receiving standard-dose chemotherapy (median OS not yet reached; P = .02). By multivariate Cox regression analysis, low serum b2M at diagnosis (P = .001), absence of a del(13q) (P = .004), high-dose therapy (P = .034), and presence of t(11;14)/no del(13q) (P = .069) emerged as independent favorable parameters for OS. Thus, according to the cytogenetic pattern, three prognostic groups of patients could be discriminated (P

  • both igh translocations and Chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma
    Leukemia, 2004
    Co-Authors: Hannes Kaufmann, Verena Sagaster, Jutta Ackermann, Rotraud Wieser, Ulrich Jäger, Heinz Gisslinger, Catrin Baldia, Thomas Nosslinger, Sonja Seidl, Michael Pfeilstocker
    Abstract:

    Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and Chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

  • both Chromosome 13 abnormalities by metaphase cytogenetics and deletion of 13q by interphase fish only are prognostically relevant in multiple myeloma
    European Journal of Haematology, 2003
    Co-Authors: Hannes Kaufmann, Jutta Ackermann, Thomas Nosslinger, Elisabeth Kromer, Ansgar Weltermann, Regina Reisner, Marianne Bernhart, Johannes Drach
    Abstract:

    : Objectives: Deletion of Chromosome 13q [del(13q)] has emerged as a major adverse prognostic factor in multiple myeloma (MM). Del(13q) is detected two to three times more frequently by interphase fluorescence in situ hybridization (FISH) than by metaphase cytogenetics (CG). However, it has remained unclear whether or not del(13q) detected by FISH only provides the same prognostic information as its detection by CG. Methods: We investigated the outcome of 118 consecutive patients with newly diagnosed MM who were studied by both CG and FISH (RB-1 and/or D13S319 probes). Results: CG revealed informative MM karyotypes in 35 patients (29.7%), with monosomy 13/del(13q) in 16 of them. FISH was indicative for a del(13q) in 43 patients (36.4%). A del(13q) by FISH was present in all 16 patients with monosomy 13/del(13q) by CG and also in four of 19 patients with informative karyotypes and diploid Chromosome 13. Furthermore, del(13q) was present by FISH in 23 of 84 patients with diploid/non-informative metaphases by CG. Overall survival of patients with monosomy 13/del(13q) by CG and of patients with del(13q) by FISH only was not significantly different (median, 35.2 months vs. 33.2 months, P = 0.58). In contrast, patients with diploid Chromosome 13 by either technique experienced prolonged survival (median, 65.6 months). Presence of abnormal karyotypes was significantly associated with an increased Ki67 growth fraction. Conclusion: FISH of Chromosome 13q adds prognostic information to that provided by CG. It is suggested to use FISH analysis in clinical trials if risk stratifications take into consideration the Chromosome 13q status.

Charles W Richard - One of the best experts on this subject based on the ideXlab platform.

  • a radiation hybrid map of 95 stss spanning human Chromosome 13q
    Genomics, 1995
    Co-Authors: Sarah H Shaw, Joan E Farr, Bonnie A Thiel, Tara C Matise, Jean Weissenbach, Aravinda Chakaravarti, Charles W Richard
    Abstract:

    Abstract We have constructed a high-resolution physical map of the long arm of human Chromosome 13 using a panel of 94 radiation hybrids. A comprehensive map of 95 Chromosome 13-specific sequence tagged sites (STSs) spanning 13q from the presumed centromere at D13Z1 to the known telomere was obtained by multipoint maximum likelihood statistical methods. The 95 markers have an average retention frequency of 10%, with markers closer to the centromere having much greater retention frequencies (22-49%) than distal 13q markers (2-12%) The most likely radiation hybrid map localized the 95 STSs into 54 unique map positions, 34 with odds of 1000:1 or greater; the comprehensive map localized all but 17 STSs with odds exceeding 10:1. The total map length of 13q was 1302 cR 9000 (range 6.4-94.4 cR 9000 ) and a physical distance of 98 Mb, so that 1% breakage in the RH panel corresponds to 75 kb. A comparison of the comprehensive RH map to genetic maps of Chromosome 13q shows identical locus orders for the common markers, with two exceptions over 1-cM distances. We discuss the possible relationships between the genetic and the radiation hybrid maps.

Jutta Ackermann - One of the best experts on this subject based on the ideXlab platform.

  • Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation.
    European Journal of Haematology, 2020
    Co-Authors: Werner Rabitsch, Hannes Kaufmann, Jutta Ackermann, Sonja Seidl, Erika Prinz, Stefan Wöhrer, Felix Keil, Peter Kalhs, Hildegard T. Greinix, Heinz Gisslinger
    Abstract:

    : Objectives:  Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem celltransplantation in the context of s2 microglobulin and Chromosome 13q. Methods:  All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. Results:  There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5–128) nine patients (70%) are still allive, and six of them have remained progression free. Among five patients with low s2 microglobulin and normal Chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated s2 microglobulin and/or deletion of Chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. Conclusions:  Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.

  • bortezomib in relapsed multiple myeloma response rates and duration of response are independent of a Chromosome 13q deletion
    Leukemia, 2007
    Co-Authors: Verena Sagaster, Heinz Ludwig, Hannes Kaufmann, Viktoria Odelga, Niklas Zojer, Jutta Ackermann, Elisabeth Kuenburg, Rotraud Wieser, Christoph C Zielinski, Johannes Drach
    Abstract:

    Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a Chromosome 13q-deletion

  • favorable survival of multiple myeloma patients with t 11 14 q13 q32 plus normal Chromosome 13q
    Blood, 2004
    Co-Authors: Hannes Kaufmann, Verena Sagaster, Jutta Ackermann, Heinz Gisslinger, Catrin Baldia, Sonja Seidl, Thomas Noesslinger, Ulrich Jaeger, Andrea Keck, Heinz Ludwig
    Abstract:

    Previous studies have shown that specific chromosomal abnormalities are of major prognostic significance in patients with multiple myeloma (MM). It has been recently suggested that a t(11;14)(q13;q32) may be an indicator of favorable outcome in MM. In this investigation, we analyzed 163 patients with newly diagnosed MM (53% treated by high-dose therapy) to address the question whether or not the simultaneous occurrence of a t(11;14) and a deletion 13q [del(13q)], an established negative prognostic factor in MM, has any impact on prognosis. DNA-specific probes for IgH (14q32) and cyclin-D1 (11q13) were used for interphase FISH analysis of clonal plasma cells (cytoplasmic Ig positive). A t(11;14) by FISH was shown in 27 of the 163 MM patients (16.6%); the abnormality was present in the majority (median, 89%) of clonal plasma cells. Immunohistochemical analysis of CYCLIN-D1 expression was carried out in 72 patients, of whom 11 had a t(11;14) by FISH; all 11 patients had evidence for CYCLIN-D1 protein expression. Presence of a t(11;14) did not show significant correlations with standard laboratory and clinical MM features including type of the paraprotein, hemoglobin, creatinine, LDH, albumine, calcium, CRP, and beta-2-microglobulin (b2M). In contrast to a recent report, there was also no association with CD20 expression by MM cells. With respect to survival, presence of any 14q-translocation (52% of patients) was associated with similar overall survival times (OS) compared to patients lacking a t(14q), whereas patients with a t(11;14) experienced prolonged OS (median, 70+ months vs. 59.8 months among patients without t(11;14); P = .071). This survival advantage was even greater among the 16 patients with t(11;14) who were also normal for 13q (P = .02); however, occurrence of a del(13q) concomitantly with a t(11;14) was indicative for shortened progression-free survial (17.7 months vs. 31.6 months; P = .17) and OS (P = .07). A survival benefit of MM patients with a t(11;14) was particularly evident for the population receiving standard-dose chemotherapy (median OS not yet reached; P = .02). By multivariate Cox regression analysis, low serum b2M at diagnosis (P = .001), absence of a del(13q) (P = .004), high-dose therapy (P = .034), and presence of t(11;14)/no del(13q) (P = .069) emerged as independent favorable parameters for OS. Thus, according to the cytogenetic pattern, three prognostic groups of patients could be discriminated (P

  • both igh translocations and Chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma
    Leukemia, 2004
    Co-Authors: Hannes Kaufmann, Verena Sagaster, Jutta Ackermann, Rotraud Wieser, Ulrich Jäger, Heinz Gisslinger, Catrin Baldia, Thomas Nosslinger, Sonja Seidl, Michael Pfeilstocker
    Abstract:

    Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and Chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

  • both Chromosome 13 abnormalities by metaphase cytogenetics and deletion of 13q by interphase fish only are prognostically relevant in multiple myeloma
    European Journal of Haematology, 2003
    Co-Authors: Hannes Kaufmann, Jutta Ackermann, Thomas Nosslinger, Elisabeth Kromer, Ansgar Weltermann, Regina Reisner, Marianne Bernhart, Johannes Drach
    Abstract:

    : Objectives: Deletion of Chromosome 13q [del(13q)] has emerged as a major adverse prognostic factor in multiple myeloma (MM). Del(13q) is detected two to three times more frequently by interphase fluorescence in situ hybridization (FISH) than by metaphase cytogenetics (CG). However, it has remained unclear whether or not del(13q) detected by FISH only provides the same prognostic information as its detection by CG. Methods: We investigated the outcome of 118 consecutive patients with newly diagnosed MM who were studied by both CG and FISH (RB-1 and/or D13S319 probes). Results: CG revealed informative MM karyotypes in 35 patients (29.7%), with monosomy 13/del(13q) in 16 of them. FISH was indicative for a del(13q) in 43 patients (36.4%). A del(13q) by FISH was present in all 16 patients with monosomy 13/del(13q) by CG and also in four of 19 patients with informative karyotypes and diploid Chromosome 13. Furthermore, del(13q) was present by FISH in 23 of 84 patients with diploid/non-informative metaphases by CG. Overall survival of patients with monosomy 13/del(13q) by CG and of patients with del(13q) by FISH only was not significantly different (median, 35.2 months vs. 33.2 months, P = 0.58). In contrast, patients with diploid Chromosome 13 by either technique experienced prolonged survival (median, 65.6 months). Presence of abnormal karyotypes was significantly associated with an increased Ki67 growth fraction. Conclusion: FISH of Chromosome 13q adds prognostic information to that provided by CG. It is suggested to use FISH analysis in clinical trials if risk stratifications take into consideration the Chromosome 13q status.

Heinz Gisslinger - One of the best experts on this subject based on the ideXlab platform.

  • Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation.
    European Journal of Haematology, 2020
    Co-Authors: Werner Rabitsch, Hannes Kaufmann, Jutta Ackermann, Sonja Seidl, Erika Prinz, Stefan Wöhrer, Felix Keil, Peter Kalhs, Hildegard T. Greinix, Heinz Gisslinger
    Abstract:

    : Objectives:  Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem celltransplantation in the context of s2 microglobulin and Chromosome 13q. Methods:  All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. Results:  There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5–128) nine patients (70%) are still allive, and six of them have remained progression free. Among five patients with low s2 microglobulin and normal Chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated s2 microglobulin and/or deletion of Chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. Conclusions:  Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.

  • deletions of Chromosome 13q in myeloproliferative neoplasms mapping relation to the jak2 v617f mutation and evaluation of potential tumor suppressor candidates
    Blood, 2008
    Co-Authors: Damla Olcaydu, Heinz Gisslinger, Tiina Berg, Bettina Gisslinger, Robert Kralovics
    Abstract:

    Chronic myeloproliferative neoplasms (MPN) are a heterogeneous group of disorders characterized by clonal hematopoiesis, excessive production of myeloid cells and an inherent tendency for thrombosis, bleeding, secondary fibrosis and leukemic transformation. Chromosomal aberrations are present at diagnosis in 34% of patients with polycythemia vera (PV), 40% of primary myelofibrosis (PMF) and 5% of essential thrombocythemia (ET) patients. Deletions of the long arm of Chromosome 13 (del13q) are among the recurrent cytogenetic abnormalities found not only in MPN but also in other hematological malignancies. The frequency of del13q is highest in PMF and post-polycythemic myelofibrosis (13–20% of all aberrations). A common deleted region of 16 mega base pairs (Mb) has been previously defined for del13q in MPN and the tumor suppressor RB1 was proposed to be the likely target of the deletion. In this study, we aimed to investigate the role of del13q in the clonal evolution and pathogenesis of MPN. We determined the frequency of del13q in a cohort of 367 MPN patients using microsatellite PCR with a series of markers covering a 10 Mb chromosomal region. We identified 8 patients with loss of heterozygosity (LOH) in at least one microsatellite marker (8/367, 2.18%). Three of 8 del13q patients were diagnosed with PMF, 4 with PV and one with ET. To map the minimal deleted region of del13q we performed microarray-based karyotype analysis and defined a common deleted region (CDR) of 9.8 Mb. As this newly defined del13q CDR included the RB1 tumor suppressor gene, we investigated whether haploinsufficiency or complete loss of RB1 function could be involved in MPN pathogenesis. Gene expression analysis of RB1 in del13q-positive MPN patient granulocytes did not show any significant difference in mRNA level compared to del13q-negative patients (P=0.6857) and healthy controls. No point mutations were found by sequence analysis of the remaining RB1 allele in del13q patients. We did not observe any effect of RB1 shRNA knock-down on cytokine-dependent proliferation of UT7/TPO cells. Our data suggest that complete loss or haploinsufficiency of RB1 is an unlikely pathogenetic mechanism associated with del13q in MPN. In addition to complete loss of Chromosome 13q, we observed partial allelic loss (partial LOH) in 27 additional patients (7.36%), consistent with the presence of del13q in only a proportion of myeloid cells. To confirm that del13q represents a minor clone in these patients we genotyped BFU-E and CFU-GM progenitor colonies for del13q. In concordance with the microsatellite PCR data patients with partial LOH exhibited del13q only in a proportion of progenitor colonies. Therefore, the overall frequency of del13q in our MPN cohort was 9.54% (35/367). Of these 35 del13q-positive patients, 24 were positive for the JAK2-V617F mutation whereas 11 patients tested negative. Thus, del13q is not acquired preferentially in patients positive for JAK2-V617F (P=0.3642). Furthermore, when progenitor colonies of del13q positive patients were genotyped for both del13q and JAK2-V617F we observed that del13q can occur before or after the acquisition of JAK2-V617F or as a sole chromosomal lesion. In conclusion, del13q is one of the most frequent chromosomal aberrations in MPN and is acquired independently from the JAK2-V617F mutation. Since recent studies of PMF and post-PV myelofibrosis patients with or without del13q did not reveal any significant differences in clinical phenotype, del13q provides only clonal advantage to hematopoietic cells without effecting the disease phenotype. The molecular pathway involved in del13q-dependent clonal expansion remains to be identified.

  • favorable survival of multiple myeloma patients with t 11 14 q13 q32 plus normal Chromosome 13q
    Blood, 2004
    Co-Authors: Hannes Kaufmann, Verena Sagaster, Jutta Ackermann, Heinz Gisslinger, Catrin Baldia, Sonja Seidl, Thomas Noesslinger, Ulrich Jaeger, Andrea Keck, Heinz Ludwig
    Abstract:

    Previous studies have shown that specific chromosomal abnormalities are of major prognostic significance in patients with multiple myeloma (MM). It has been recently suggested that a t(11;14)(q13;q32) may be an indicator of favorable outcome in MM. In this investigation, we analyzed 163 patients with newly diagnosed MM (53% treated by high-dose therapy) to address the question whether or not the simultaneous occurrence of a t(11;14) and a deletion 13q [del(13q)], an established negative prognostic factor in MM, has any impact on prognosis. DNA-specific probes for IgH (14q32) and cyclin-D1 (11q13) were used for interphase FISH analysis of clonal plasma cells (cytoplasmic Ig positive). A t(11;14) by FISH was shown in 27 of the 163 MM patients (16.6%); the abnormality was present in the majority (median, 89%) of clonal plasma cells. Immunohistochemical analysis of CYCLIN-D1 expression was carried out in 72 patients, of whom 11 had a t(11;14) by FISH; all 11 patients had evidence for CYCLIN-D1 protein expression. Presence of a t(11;14) did not show significant correlations with standard laboratory and clinical MM features including type of the paraprotein, hemoglobin, creatinine, LDH, albumine, calcium, CRP, and beta-2-microglobulin (b2M). In contrast to a recent report, there was also no association with CD20 expression by MM cells. With respect to survival, presence of any 14q-translocation (52% of patients) was associated with similar overall survival times (OS) compared to patients lacking a t(14q), whereas patients with a t(11;14) experienced prolonged OS (median, 70+ months vs. 59.8 months among patients without t(11;14); P = .071). This survival advantage was even greater among the 16 patients with t(11;14) who were also normal for 13q (P = .02); however, occurrence of a del(13q) concomitantly with a t(11;14) was indicative for shortened progression-free survial (17.7 months vs. 31.6 months; P = .17) and OS (P = .07). A survival benefit of MM patients with a t(11;14) was particularly evident for the population receiving standard-dose chemotherapy (median OS not yet reached; P = .02). By multivariate Cox regression analysis, low serum b2M at diagnosis (P = .001), absence of a del(13q) (P = .004), high-dose therapy (P = .034), and presence of t(11;14)/no del(13q) (P = .069) emerged as independent favorable parameters for OS. Thus, according to the cytogenetic pattern, three prognostic groups of patients could be discriminated (P

  • both igh translocations and Chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma
    Leukemia, 2004
    Co-Authors: Hannes Kaufmann, Verena Sagaster, Jutta Ackermann, Rotraud Wieser, Ulrich Jäger, Heinz Gisslinger, Catrin Baldia, Thomas Nosslinger, Sonja Seidl, Michael Pfeilstocker
    Abstract:

    Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and Chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

  • Deletions of Chromosome 13q in monoclonal gammopathy of undetermined significance
    Leukemia, 2000
    Co-Authors: Robert Königsberg, Hannes Kaufmann, Niklas Zojer, Jutta Ackermann, E. Urbauer, E. Krömer, Ulrich Jäger, Heinz Gisslinger, S. Schreiber, R. Heinz
    Abstract:

    Since deletion of Chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the Chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion