The level of deletion 17p and bi-allelic inactivation of
            <i>TP53</i>
            has a significant impact on clinical outcome in multiple myeloma

Thanendrarajan, Sharmilan; Tian, Erming; Qu, Pingping; Mathur, Pankaj; Schinke, Carolina; Rhee, Frits van; Zangari, Maurizio; Rasche, Leo; Weinhold, Niels; Alapat, Daisy; Bellamy, William; Ashby, Cody; Mattox, Sandra G.; Epstein, Joshua; Yaccoby, Shmuel; Barlogie, Bart; Hoering, Antje; Bauer, Michael; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.

doi:10.3324/haematol.2017.168872

Cited by 66 publications

(65 citation statements)

References 15 publications

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“…[3][4][5] Currently, the minimum percentage of del17p cancer clonal fraction (CCF) indicative of poor prognosis is not known, with most studies reporting arbitrary threshold levels ranging from a single FISH 1 cell to exceeding 60% FISH 1 MM cells. [6][7][8][9] The lack of uniform analytical methods for cytogenetic assessment of del17p by FISH adds to discordant claims about CCF threshold for poor prognosis. 4,6,8,9 Genetic defects in 17p are complex and include either a deletion only or a mutation only in 1 allele of the TP53 gene or both (biallelic inactivation).…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9] The lack of uniform analytical methods for cytogenetic assessment of del17p by FISH adds to discordant claims about CCF threshold for poor prognosis. 4,6,8,9 Genetic defects in 17p are complex and include either a deletion only or a mutation only in 1 allele of the TP53 gene or both (biallelic inactivation). Biallelic inactivation in the TP53 gene (ie, double hit) is associated with very poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Thakurta¹,

Ortiz²,

Blecua³

et al. 2019

Blood

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K E Y P O I N T S l Association of del17p CCF threshold and poor prognosis in NDMM is established via fluorescence in situ hybridization and sequencing methods. l TP53 mutations are enriched in a high-risk patient segment characterized by high del17p CCF.Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization-and sequencingbased methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis. (Blood. 2019; 133(11):1217-1221

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Thakurta¹,

Ortiz²,

Blecua³

et al. 2019

Blood

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“…This is particularly important, because patients with biallelic TP53 inactivation exhibit significantly inferior outcomes. 35 Nevertheless, it should be noted that cytokinesis failure could also promote tumorigenesis, as was observed in tetraploid cells devoid of p53. 21 It has long been known that tumorigenesis can happen as a result of DNA-damaging therapy; however, melphalan, a DNAdamaging alkylator, is still among the most potent cytoreductors, with a well-established role in MM treatment.…”

Section: Discussionmentioning

confidence: 99%

Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma

Şahin

Kawano

Sklavenitis-Pistofidis

et al. 2019

Blood Advances

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Key Points• CIT is upregulated in multiple myeloma.• CIT inhibition leads to cytokinesis failure and reduction in tumor burden in vitro and in vivo.Citron Rho-interacting serine/threonine kinase (CIT) is a serine/threonine kinase that acts as a key component of the midbody and is essential for cytokinesis. CIT has been reported to be highly expressed in some tumor tissues and to play a role in cancer proliferation; however, the significance of CIT has not been investigated in multiple myeloma (MM). Here, we identified, by protein microarray and immunohistochemistry, that CIT is 1 of the upregulated proteins in the plasma cells of MM patients compared with healthy controls. Analysis of a gene expression profile data set showed that MM patients with high CIT gene expression had significantly worse overall survival compared with MM patients with low CIT gene expression. CIT silencing in MM cell lines induced cytokinesis failure and resulted in decreased MM cell proliferation in vitro and in vivo. TP53 expression was found to be an independent predictor of CIT dependency, with low-TP53 cell lines exhibiting a strong dependency on CIT. This study provides the rationale for CIT being a potential therapeutic target in MM in future trials.

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“…We currently have used TarPan for the visualization and analysis of 100 multiple myeloma samples which are available under European Genome Archive (EGA) accession number EGAS00001002859. In addition, there have been several peer reviewed publications [10][11][12][13] where TarPan was used for screening, validation, or analysis. Examples showing important multiple myeloma events in TarPan are shown such as bi-allelic inactivation of TP53 (Fig.…”

Section: Visualization Of Multiple Myeloma Data Using Tarpanmentioning

confidence: 99%

TarPan: an easily adaptable targeted sequencing panel viewer for research and clinical use

et al. 2020

Self Cite

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Background: The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data. Results: TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications. Conclusions:We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.

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The level of deletion 17p and bi-allelic inactivation of TP53 has a significant impact on clinical outcome in multiple myeloma

Cited by 66 publications

References 15 publications

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma

TarPan: an easily adaptable targeted sequencing panel viewer for research and clinical use

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