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H. Döhner - One of the best experts on this subject based on the ideXlab platform.
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Clonal Evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival
Haematologica, 2007Co-Authors: Stephan Stilgenbauer, Lars Bullinger, Sandrine Sander, Axel Benner, Elke Leupolt, Dirk Winkler, Alexander Kröber, Dirk Kienle, Peter Lichter, H. DöhnerAbstract:In chronic lymphocytic leukemia (CLL), the acquisition of new genomic aberrations during the disease course (Clonal Evolution) is thought to be an infrequent phenomenon but comprehensive analyses are limited. Genomic aberrations were analyzed by fluorescence in situ hybridization (FISH) at various time points during the disease course of 64 CLL patients. Results were correlated with the mutation status of the immunoglobulin heavy-chain variableregion genes (VH) and clinical characteristics. Following a median observation time of 42.3 months (range 23.2-73) after first genetic study, 11 out of the 64 (17%) patients showed Clonal Evolution with the following newly acquired aberrations: del(17p13) (n=4), del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and Evolution from monoallelic to biallelic del(13q14) (n=3). Interestingly, Clonal Evolution only occurred among cases with unmutated VH status. The group with Clonal Evolution showed a higher rate of progression in Binet stage (82% vs. 28%), a possibly greater need for treatment (91% vs. 62% previously untreated patients received their first therapy), and a higher hazard risk of death (HR = 2.97, 95% CI 1.40-6.27, p=0.004) in multivariable analysis. The estimated median survival time after the occurrence of Clonal Evolution was 21.7 months. Expansion of the clone with del(17p13) was observed in all patients during treatment, indicating in vivo resistance to therapy. In multivariable Andersen-Gill regression analysis, Clonal Evolution was identified as an independent prognostic factor for overall survival. Clonal Evolution only occurred in CLL with unmutated VH indicating to karyotypic instability as a pathomechanism. Acquisition of genomic aberrations was associated with poor outcome based on multivariable analysis. In vivo resistance to chemotherapy of CLL clones with del(17p13) emphasizes the need for alternative treatment approaches in these patients.
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Clonal Evolution in Chronic Lymphocytic Leukemia: Acquisition of High-Risk Genomic Aberrations Associated with Unmutated VH, Resistance to Therapy, and Short Survival.
Blood, 2006Co-Authors: Stephan Stilgenbauer, Lars Bullinger, Sandrine Sander, Axel Benner, Elke Leupolt, Dirk Winkler, Alexander Kröber, Dirk Kienle, Peter Lichter, H. DöhnerAbstract:Genomic aberrations were analyzed by fluorescence in situ hybridization (FISH) at various time points during the disease course of 64 patients with chronic lymphocytic leukemia (CLL) from a single institution. After a median time of 42 (23–73) months, 11 of the 64 (17%) patients acquired the following additional aberrations: del(17p13) (n=4), del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and Evolution from monoallelic to biallelic del(13q14) (n=3). The baseline clinical characteristics of the patients with and without Clonal Evolution were not significantly different. Remarkably, Clonal Evolution occurred exclusively among cases with unmutated VH status (Figure 1). The group with Clonal Evolution showed a higher rate of progression in stage (82% vs. 28%), a greater need for treatment (100% vs. 62%), and a higher death rate (67% vs. 28%). The median survival time after the occurrence of Clonal Evolution was 22 months. Expansion of the clone with del(17p13) was observed in all patients during chemotherapy (chlorambucil n=4, fludarabine n=3, FC n=2, rituximab n=1) indicating in-vivo resistance to treatment (Figure 2). In multivariate analysis, Clonal Evolution was identified as independent adverse factor with regard to overall survival.
Gudrun Göhring - One of the best experts on this subject based on the ideXlab platform.
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Routes of Clonal Evolution into Complex Karyotypes in Myelodysplastic Syndrome Patients with 5q Deletion
International journal of molecular sciences, 2018Co-Authors: Simone Feurstein, Winfried Hofmann, Arnold Ganser, Hans Kreipe, Brigitte Schlegelberger, Kathrin Thomay, Guntram Buesche, Felicitas Thol, Michael Heuser, Gudrun GöhringAbstract:Myelodysplastic syndrome (MDS) can easily transform into acute myeloid leukemia (AML), a process which is often associated with Clonal Evolution and development of complex karyotypes. Deletion of 5q (del(5q)) is the most frequent aberration in complex karyotypes. This prompted us to analyze Clonal Evolution in MDS patients with del(5q). There were 1684 patients with low and intermediate-risk MDS and del(5q) with or without one additional cytogenetic abnormality, who were investigated cytogenetically in our department, involving standard karyotyping, fluorescence in situ hybridization (FISH) and multicolor FISH. We identified 134 patients (8%) with aspects of Clonal Evolution. There are two main routes of cytogenetic Clonal Evolution: a stepwise accumulation of cytogenetic events over time and a catastrophic event, which we defined as the occurrence of two or more aberrations present at the same time, leading to a sudden development of highly complex clones. Of the 134 patients, 61% underwent a stepwise accumulation of events whereas 39% displayed a catastrophic event. Patients with isolated del(5q) showed significantly more often a stepwise accumulation of events rather than a catastrophic event. The most frequent aberrations in the group of stepwise accumulation were trisomy 8 and trisomy 21 which were significantly more frequent in this group compared to the catastrophic event group. In the group with catastrophic events, del(7q)/-7 and del(17p)/-17 were the most common aberrations. A loss of 17p, containing the tumor suppressor gene TP53, was found significantly more frequent in this group compared to the group of stepwise accumulation. This leads to the assumption that the loss of TP53 is the driving force in patients with del(5q) who undergo a sudden catastrophic event and evolve into complex karyotypes.
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Routes of Clonal Evolution Into Complex Karyotypes in Myelodysplastic Syndrome Patients with Del(5q)
Blood, 2012Co-Authors: Gudrun Göhring, Simone Feurstein, Winfried Hofmann, Arnold Ganser, Hans Kreipe, Brigitte SchlegelbergerAbstract:Abstract 522 Introduction: A complex karyotype, detected in approximately 10%-15% of patients with myelodysplastic syndromes (MDS), is associated with a very short median survival and a high risk of transformation into AML. The most frequent chromosome aberration in complex karyotypes is a deletion of 5q (del(5q)). It is still unclear, how complex karyotypes develop. One possibility is via stepwise accumulation of chromosome aberrations according to the so-called Vogelstein model (Fearon ER, Vogelstein B, Cell 1990; 61:759–67). Another possibility is a one-step catastrophic event called chromothripsis that seems to be associated with TP53 inactivation (Rausch T et al., Cell 2012;148:59–71). We recently described that leukemic progression in low-grade MDS with isolated del(5q) is associated with Clonal Evolution (Tehranchi R et al., N Engl J Med 2010;363:1025–37, Gohring G et al., Ann Hematol 2010; 89:365–74) and identified TP53 mutations and excessive telomere shortening as driving forces for Clonal Evolution and leukemic progression in MDS with del(5q) (Jadersten M et al., J Clin Oncol 2011; 29:1971–9, Gohring G et al., Leukemia 2012; 26:356–8). Yet, the modes of Clonal Evolution and the mechanisms responsible for the induction of chromosomal instability in MDS with isolated del(5q) remain largely unclear. Patients and Methods: Among 1645 patients with MDS and del(5q) investigated cytogenetically in our institution, 157 patients (9.5%) acquired additional aberrations and thus underwent Clonal Evolution. We reviewed the cytogenetic follow-up data of the 157 patients and carefully evaluated all additional aberrations, particularly those of complex karyotypes, which are defined as at least 3 aberrations, i.e. del(5q) and two additional chromosome abnormalities. Moreover, we investigated the Clonal heterogeneity and the presence of independent clones, defined as clones that do not contain a del(5q). Results: During follow-up, 76 of 157 patients (48%) acquired two or more aberrations, thus evolving into a complex karyotype. Eighty-nine of 157 patients (57%) underwent a stepwise accumulation of additional aberrations (range 1–8, median: 1), while 38 patients (24%) developed highly complex clones (no of aberrations: 3–35, median: 7.5) at one time point during follow-up. This “catastrophic” route led to the development of a complex karyotype significantly more frequently than the stepwise accumulation of chromosome aberrations (38 of 38 cases compared to 38 of 89 patients; p Conclusions: Although MDS with del(5q) is assumed to be a genetically stable hematologic neoplasm, Clonal Evolution, even into complex karyotypes, occurs in a significant proportion of patients. There are two routes of Clonal Evolution. One route of stepwise acquisition of additional aberrations resulted in Clonal selection of clones that had accumulated mostly only one or two additional aberrations. In contrast, the other route led to an immediate development of highly complex clones. In some of these cases, this catastrophic event was preceded by the acquisition of one aberration, repeatedly by loss of 12p or loss of 17p harboring the ETV6/TEL and TP53 genes, respectively. These data provide further evidence that the inactivation of TP53 seems to play an important role in Clonal Evolution and leukemic progression. Disclosures: No relevant conflicts of interest to declare.
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Telomere shortening, Clonal Evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide.
Leukemia, 2011Co-Authors: Gudrun Göhring, Winfried Hofmann, Kathrin Lange, K V Nielsen, Eva Hellström-lindberg, Lydia Roy, Michael A. Morgan, Hans-heinrich Kreipe, Guntram Büsche, A.a.n. GiagounidisAbstract:Telomere shortening, Clonal Evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide
Li Ding - One of the best experts on this subject based on the ideXlab platform.
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Abnormal clones and Clonal Evolution of bcr-abl-negative myeloproliferative neoplasms
Journal of Leukemia and Lymphoma, 2015Co-Authors: Li DingAbstract:In recent years,studies committed to the myeloproliferative neoplasms (MPN) pathogenesis suggest that potential somatic genetic alterations, and epigenetic events might contribute to MPN development, influence the MPN disease phenotype, progression, and promote transformation. The most relevant mutations identified so far can be broadly classified into two main groups. Mutations associated with dysregulated JAK-STAT signal transduction pathway, including mutations in JAK2, CALR, MPL, CBL, LNK, SOCS. Mutations in several epigenetic modifiers, including mutations in TET2, ASXL1, IDH1/2, DNMT3A, EZH2 and so on. In this paper, the abnormal clones and Clonal Evolution of MPN were reviewed. Key words: Myeloproliferative neoplasms; Abnormal clones; Clonal Evolution
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Advances for studying Clonal Evolution in cancer
Cancer letters, 2013Co-Authors: Li Ding, Benjamin J. Raphael, Feng Chen, Michael C. WendlAbstract:The “Clonal Evolution” model of cancer emerged and “evolved” amid ongoing advances in technology, especially in recent years during which next generation sequencing instruments have provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors. It has become increasingly clear that Clonal Evolution is not a single sequential process, but instead frequently involves simultaneous Evolution of multiple subclones that co-exist because they are of similar fitness or are spatially separated. Co-Evolution of subclones also occurs when they complement each other’s survival advantages. Recent studies have also shown that Clonal Evolution is highly heterogeneous: different individual tumors of the same type may undergo very different paths of Clonal Evolution. New methodological advancements, including deep digital sequencing of a mixed tumor population, single cell sequencing, and the development of more sophisticated computational tools, will continue to shape and reshape the models of Clonal Evolution. In turn, these will provide both an improved framework for the understanding of cancer progression and a guide for treatment strategies aimed at the elimination of all, rather than just some, of the cancer cells within a patient.
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Clonal Evolution in relapsed acute myeloid leukaemia revealed by whole genome sequencing
Nature, 2012Co-Authors: Li Ding, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. Mclellan, Joshua F McmichaelAbstract:The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of Clonal Evolution, with chemotherapy appearing to have a role in both patterns. Many patients with acute myeloid leukaemia (AML) achieve remission, but it is often short-lived and the returned disease is usually refractory to therapy. Genome sequencing of eight patients with AML before and after relapse reveals two major patterns of tumour cell Evolution. The founding clone survives chemotherapy in all patients, and, in one Clonal pattern, it acquires new mutations and expands at relapse. In the other, a subclone surviving from the original tumour expands and then acquires new mutations. Comparisons of relapse-specific and primary tumour mutations point to an increase in transversions, implying DNA damage caused by cytotoxic chemotherapy. This work demonstrates that the AML genome in an individual patient presents a moving target, and highlights the importance of striving to eradicate both the founding clone and all of its subclones. Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with Clonal Evolution at the cytogenetic level1,2 . To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define Clonality and Clonal Evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major Clonal Evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and Clonal Evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
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Clonal Evolution in relapsed acute myeloid leukaemia revealed by whole genome sequencing
Nature, 2012Co-Authors: Li Ding, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. Mclellan, Joshua F McmichaelAbstract:The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of Clonal Evolution, with chemotherapy appearing to have a role in both patterns.
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Clonal Evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
Nature, 2012Co-Authors: Li Ding, Timothy J. Ley, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. MclellanAbstract:Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with Clonal Evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define Clonality and Clonal Evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major Clonal Evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and Clonal Evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
Stephan Stilgenbauer - One of the best experts on this subject based on the ideXlab platform.
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Clonal Evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival
Haematologica, 2007Co-Authors: Stephan Stilgenbauer, Lars Bullinger, Sandrine Sander, Axel Benner, Elke Leupolt, Dirk Winkler, Alexander Kröber, Dirk Kienle, Peter Lichter, H. DöhnerAbstract:In chronic lymphocytic leukemia (CLL), the acquisition of new genomic aberrations during the disease course (Clonal Evolution) is thought to be an infrequent phenomenon but comprehensive analyses are limited. Genomic aberrations were analyzed by fluorescence in situ hybridization (FISH) at various time points during the disease course of 64 CLL patients. Results were correlated with the mutation status of the immunoglobulin heavy-chain variableregion genes (VH) and clinical characteristics. Following a median observation time of 42.3 months (range 23.2-73) after first genetic study, 11 out of the 64 (17%) patients showed Clonal Evolution with the following newly acquired aberrations: del(17p13) (n=4), del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and Evolution from monoallelic to biallelic del(13q14) (n=3). Interestingly, Clonal Evolution only occurred among cases with unmutated VH status. The group with Clonal Evolution showed a higher rate of progression in Binet stage (82% vs. 28%), a possibly greater need for treatment (91% vs. 62% previously untreated patients received their first therapy), and a higher hazard risk of death (HR = 2.97, 95% CI 1.40-6.27, p=0.004) in multivariable analysis. The estimated median survival time after the occurrence of Clonal Evolution was 21.7 months. Expansion of the clone with del(17p13) was observed in all patients during treatment, indicating in vivo resistance to therapy. In multivariable Andersen-Gill regression analysis, Clonal Evolution was identified as an independent prognostic factor for overall survival. Clonal Evolution only occurred in CLL with unmutated VH indicating to karyotypic instability as a pathomechanism. Acquisition of genomic aberrations was associated with poor outcome based on multivariable analysis. In vivo resistance to chemotherapy of CLL clones with del(17p13) emphasizes the need for alternative treatment approaches in these patients.
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Clonal Evolution in Chronic Lymphocytic Leukemia: Acquisition of High-Risk Genomic Aberrations Associated with Unmutated VH, Resistance to Therapy, and Short Survival.
Blood, 2006Co-Authors: Stephan Stilgenbauer, Lars Bullinger, Sandrine Sander, Axel Benner, Elke Leupolt, Dirk Winkler, Alexander Kröber, Dirk Kienle, Peter Lichter, H. DöhnerAbstract:Genomic aberrations were analyzed by fluorescence in situ hybridization (FISH) at various time points during the disease course of 64 patients with chronic lymphocytic leukemia (CLL) from a single institution. After a median time of 42 (23–73) months, 11 of the 64 (17%) patients acquired the following additional aberrations: del(17p13) (n=4), del(6q21) (n=3), del(11q23) (n=2), +(8q24) (n=1), and Evolution from monoallelic to biallelic del(13q14) (n=3). The baseline clinical characteristics of the patients with and without Clonal Evolution were not significantly different. Remarkably, Clonal Evolution occurred exclusively among cases with unmutated VH status (Figure 1). The group with Clonal Evolution showed a higher rate of progression in stage (82% vs. 28%), a greater need for treatment (100% vs. 62%), and a higher death rate (67% vs. 28%). The median survival time after the occurrence of Clonal Evolution was 22 months. Expansion of the clone with del(17p13) was observed in all patients during chemotherapy (chlorambucil n=4, fludarabine n=3, FC n=2, rituximab n=1) indicating in-vivo resistance to treatment (Figure 2). In multivariate analysis, Clonal Evolution was identified as independent adverse factor with regard to overall survival.
Joshua F Mcmichael - One of the best experts on this subject based on the ideXlab platform.
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Clonal Evolution in relapsed acute myeloid leukaemia revealed by whole genome sequencing
Nature, 2012Co-Authors: Li Ding, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. Mclellan, Joshua F McmichaelAbstract:The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of Clonal Evolution, with chemotherapy appearing to have a role in both patterns. Many patients with acute myeloid leukaemia (AML) achieve remission, but it is often short-lived and the returned disease is usually refractory to therapy. Genome sequencing of eight patients with AML before and after relapse reveals two major patterns of tumour cell Evolution. The founding clone survives chemotherapy in all patients, and, in one Clonal pattern, it acquires new mutations and expands at relapse. In the other, a subclone surviving from the original tumour expands and then acquires new mutations. Comparisons of relapse-specific and primary tumour mutations point to an increase in transversions, implying DNA damage caused by cytotoxic chemotherapy. This work demonstrates that the AML genome in an individual patient presents a moving target, and highlights the importance of striving to eradicate both the founding clone and all of its subclones. Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with Clonal Evolution at the cytogenetic level1,2 . To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define Clonality and Clonal Evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major Clonal Evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and Clonal Evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
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Clonal Evolution in relapsed acute myeloid leukaemia revealed by whole genome sequencing
Nature, 2012Co-Authors: Li Ding, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. Mclellan, Joshua F McmichaelAbstract:The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of Clonal Evolution, with chemotherapy appearing to have a role in both patterns.