Journal articles: 'Clonal heterogeneity'

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Schuringa, Jan Jacob, and Constanze Bonifer. "Dissecting Clonal Heterogeneity in AML." Cancer Cell 38, no. 6 (December 2020): 782–84. http://dx.doi.org/10.1016/j.ccell.2020.11.011.

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Campos, Paulo R. A., Pedro S. C. A. Neto, Viviane M. de Oliveira, and Isabel Gordo. "ENVIRONMENTAL HETEROGENEITY ENHANCES CLONAL INTERFERENCE." Evolution 62, no. 6 (June 2008): 1390–99. http://dx.doi.org/10.1111/j.1558-5646.2008.00380.x.

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Rousselot, Philippe. "Clonal heterogeneity in acute lymphoblastic leukemias." Hématologie 17, no. 2 (March 2011): 120–22. http://dx.doi.org/10.1684/hma.2011.0601.

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Shlush, Liran I., and Dov Hershkovitz. "Clonal Evolution Models of Tumor Heterogeneity." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): e662-e665. http://dx.doi.org/10.14694/edbook_am.2015.35.e662.

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Somatic/clonal evolution is the process of sequential acquisition of vertically transmittable genetic/epigenetic elements in multicellular organisms. Cancer is the result of somatic evolution. Understanding the processes that shape the evolution of individual tumors might help us to treat cancer more efficiently. The initiating genetic/epigenetic events occur in functional cells and provide the cell of origin a selective advantage under a changing environment. The initiating genetic events tend to be enriched in specific tissues (and are sometimes specific for those tissues), as different tissues undergo different changes in the environment that will activate selective forces on different cells of origin. For the initial clonal expansion to occur premalignant clones need to have a relative fitness advantage over their competitors. It is estimated that the premalignant phase can take several years. Once the premalignant clonal expansion is established, the premalignant cells will contribute to the changing environment and will start competing among themselves. In late stages of cancer evolution the environmental changes might be similar across different tissues, including a lack of physical space, a shortage of energy, and activation of the immune system, and more and more of the hallmarks of cancer will evolve. In this review we will explore the possible clinical relevance of the heterogeneity that evolves during this long somatic evolution. Above all, it should be stressed that the earlier the clonal expansion is recognized, the less diverse and less fit for survival the cells in the population are.

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Quinn, Jason George, and Irene Sadek. "Clonal heterogeneity in plasma cell myeloma." Lancet 387, no. 10022 (March 2016): e22. http://dx.doi.org/10.1016/s0140-6736(15)00384-0.

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Takhaveev, Vakil, and Matthias Heinemann. "Metabolic heterogeneity in clonal microbial populations." Current Opinion in Microbiology 45 (October 2018): 30–38. http://dx.doi.org/10.1016/j.mib.2018.02.004.

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García-Marqués, Jorge, and Laura López-Mascaraque. "Clonal Identity Determines Astrocyte Cortical Heterogeneity." Cerebral Cortex 23, no. 6 (May 22, 2012): 1463–72. http://dx.doi.org/10.1093/cercor/bhs134.

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Alonso-Alvarez, Sara, Alba Redondo-Guijo, Óscar Blanco, Miguel Alcoceba, Ana Balanzategui, Juan C. Caballero, Julio Dávila, et al. "Lymphoma Heterogeneity: Three Different Histological Pictures and One Unique Clone." Case Reports in Hematology 2016 (2016): 1–4. http://dx.doi.org/10.1155/2016/3947510.

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We report a patient who developed up to three different lymphomas with the same clonal IGH rearrangement. She was first diagnosed of splenic zone marginal lymphoma and relapsed for the first time with Hodgkin lymphoma histology and later with diffuse large B-cell lymphoma histology. Subsequent biopsies and analysis of clonally rearranged IGH genes helped to elucidate the clonal relationship between the three histologies and to confirm a common origin from the three tissue histologies. An integrated diagnosis should always be performed in order to achieve the most accurate diagnosis and be able to choose the best therapeutic options for our patients.

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Nepstad, Ina, Kimberley Joanne Hatfield, Tor Henrik Anderson Tvedt, Håkon Reikvam, and Øystein Bruserud. "Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis." Cancers 10, no. 9 (September 14, 2018): 332. http://dx.doi.org/10.3390/cancers10090332.

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Clonal heterogeneity detected by karyotyping is a biomarker associated with adverse prognosis in acute myeloid leukemia (AML). Constitutive activation of the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in AML cells, and this pathway integrates signaling from several upstream receptors/mediators. We suggest that this pathway reflects biologically important clonal heterogeneity. We investigated constitutive PI3K-Akt-mTOR pathway activation in primary human AML cells derived from 114 patients, together with 18 pathway mediators. The cohort included patients with normal karyotype or single karyotype abnormalities and with an expected heterogeneity of molecular genetic abnormalities. Clonal heterogeneity reflected as pathway mediator heterogeneity was detected for 49 patients. Global gene expression profiles of AML cell populations with and without clonal heterogeneity differed with regard to expression of ectopic olfactory receptors (a subset of G-protein coupled receptors) and proteins involved in G-protein coupled receptor signaling. Finally, the presence of clonal heterogeneity was associated with adverse prognosis for patients receiving intensive antileukemic treatment. The clonal heterogeneity as reflected in the activation status of selected mediators in the PI3K-Akt-mTOR pathway was associated with a different gene expression profile and had an independent prognostic impact. Biological heterogeneity reflected in the intracellular signaling status should be further investigated as a prognostic biomarker in human AML.

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de Mel, Sanjay, Su Hong Lim, Moon Ley Tung, and Wee-Joo Chng. "Implications of Heterogeneity in Multiple Myeloma." BioMed Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/232546.

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Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.

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Fedyanin, M. Yu, H. H. M. Elsnukaeva, and S. A. Tjulandin. "Heterogeneity and clonal evolution of colorectal cancer." Advances in molecular oncology 4, no. 1 (January 1, 2017): 24–34. http://dx.doi.org/10.17650/2313-805x-2017-4-1-24-34.

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Mora, J., N.-K. V. Cheung, and W. L. Gerald. "Genetic heterogeneity and clonal evolution in neuroblastoma." British Journal of Cancer 85, no. 2 (July 2001): 182–89. http://dx.doi.org/10.1054/bjoc.2001.1849.

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Buth, D. G., M. S. Gordon, I. Plaut, S. L. Drill, and L. G. Adams. "Genetic heterogeneity in isogenic homozygous clonal zebrafish." Proceedings of the National Academy of Sciences 92, no. 26 (December 19, 1995): 12367–69. http://dx.doi.org/10.1073/pnas.92.26.12367.

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Weaver, Casey T., Arman Saparov, Lisa A. Kraus, William O. Rogers, Richard D. Hockett, and R. Pat Bucy. "Heterogeneity in the clonal T cell response." Immunologic Research 17, no. 3 (June 1998): 279–302. http://dx.doi.org/10.1007/bf02786452.

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Roederer, Mario. "D-107 Antigenic Heterogeneity of Clonal Envelopes." JAIDS Journal of Acquired Immune Deficiency Syndromes 67 (November 2014): 57. http://dx.doi.org/10.1097/01.qai.0000456122.97923.a7.

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16

Dang, Ha X., Bradley A. Krasnick, Brian S. White, Julie G. Grossman, Matthew S. Strand, Jin Zhang, Christopher R. Cabanski, et al. "The clonal evolution of metastatic colorectal cancer." Science Advances 6, no. 24 (June 2020): eaay9691. http://dx.doi.org/10.1126/sciadv.aay9691.

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Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.

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Benot, Marie-Lise, Anne Bonis, Nicolas Rossignol, and Cendrine Mony. "Spatial patterns in defoliation and the expression of clonal traits in grazed meadows." Botany 89, no. 1 (January 2011): 43–54. http://dx.doi.org/10.1139/b10-082.

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Clonal plant species dominate meadow vegetation where grazing can generate spatial heterogeneity at different scales and can select for species that express particular sets of clonal traits. This in situ study aimed to characterize fine-grained spatial patterns of defoliation (<1 m) induced by contrasting cattle grazing intensities and to link these spatial patterns with the abundance of species-specific clonal traits. Using correlogams and synthetic spatio-temporal indices, the heterogeneity of vegetation height and leaf damage was monitored along a cattle grazing gradient. Species were identified and their clonal traits retrieved from the database CLO-PLA3. Under moderate grazing, fine-grained spatial patterns of defoliation were not stable over time. Defoliation was heterogeneous during the first months of the grazing season and then became homogeneous. Intensive grazing generated homogeneous defoliation, regardless of the date. In the study meadow, grazing gave rise to communities containing a greater abundance of annual species. However, clonal traits assumed to enable clonal fragments to benefit from heterogeneity do not seem advantageous. Increasing grazing intensity promoted species with clonal traits expected to minimize costs associated with clonality (aboveground clonal growth forms, short-distance lateral spread, and (or) short-lived connections). Ungrazed conditions favoured species with clonal traits associated with a high competitive ability.

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Bianchi, Giada, and Irene Ghobrial. "Biological and Clinical Implications of Clonal Heterogeneity and Clonal Evolution in Multiple Myeloma." Current Cancer Therapy Reviews 10, no. 2 (November 24, 2014): 70–79. http://dx.doi.org/10.2174/157339471002141124121404.

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Brock, Amy. "Abstract IA004: Tracking population heterogeneity and chemoresistance with functionalized cell barcodes." Cancer Research 82, no. 10_Supplement (May 15, 2022): IA004. http://dx.doi.org/10.1158/1538-7445.evodyn22-ia004.

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Abstract Heterogeneity across individual cancer cells and clonal populations impacts growth rate, tumor composition, and response to therapy. To improve treatment, new tools are required to measure and control the contributions of diverse cell subpopulations. Our team has developed a high-complexity expressed barcode system, ClonMapper, that integrates expressed cell barcoding with single-cell RNA-sequencing and clonal isolation to characterize and track subpopulation trajectories. Using this approach, we uncovered subsets of cells from cell models with distinct transcriptional signatures and chemotherapy survivorship trajectories. To gain a deeper understanding of the process of clonal diversification, we profiled clones and retrieved sub-clones over the course of expansion and treatment. Supervised learning indicated that clonal subpopulations have characteristic transcriptomic signatures that are well-conserved under a variety of therapeutic perturbations. By providing the capability for systematic dissection of complex clonal dynamics, ClonMapper enables the delineation of an underlying engine of clonal diversification in cancer cell populations and refines our understanding of clonal identity. Citation Format: Amy Brock. Tracking population heterogeneity and chemoresistance with functionalized cell barcodes [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA004.

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Roeder, Ingo, Katrin Horn, Hans-Bernd Sieburg, Rebecca Cho, Christa Muller-Sieburg, and Markus Loeffler. "Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: a model-based approach." Blood 112, no. 13 (December 15, 2008): 4874–83. http://dx.doi.org/10.1182/blood-2008-05-155374.

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Abstract Hematopoietic stem cells (HSCs) show pronounced heterogeneity in self-renewal and differentiation behavior, which is reflected in their repopulation kinetics. Here, a single-cell–based mathematical model of HSC organization is used to examine the basis of HSC heterogeneity. Our modeling results, which are based on the analysis of limiting dilution competitive repopulation experiments in mice, demonstrate that small quantitative but clonally fixed differences of cellular properties are necessary and sufficient to account for the observed functional heterogeneity. The model predicts, and experimental data validate, that competitive pressures will amplify small clonal differences into large changes in the number of differentiated progeny. We further predict that the repertoire of HSC clones will evolve over time. Last, our results suggest that larger differences in cellular properties have to be assumed to account for genetically determined differences in HSC behavior as observed in different inbred mice strains. The model provides comprehensive systemic and quantitative insights into the clonal heterogeneity among HSCs with potential applications in predicting the behavior of malignant and/or genetically modified cells.

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Gupta, Saumya, Andrew Bortvin, Svetlana Vinogradova, Ramesh Shivdasani, and Alexander Gimelbrant. "CLONAL EPIGENETIC MOSAICISM: MECHANISM FOR CROHN’S DISEASE HETEROGENEITY." Gastroenterology 160, no. 3 (February 2021): S38. http://dx.doi.org/10.1053/j.gastro.2021.01.110.

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Gupta, Saumya, Andrew Bortvin, Svetlana Vinogradova, Ramesh Shivdasani, and Alexander Gimelbrant. "CLONAL EPIGENETIC MOSAICISM: MECHANISM FOR CROHN’S DISEASE HETEROGENEITY." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S28. http://dx.doi.org/10.1093/ibd/izaa347.066.

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Abstract Crohn’s disease is a chronic heterogenous disorder with patients showing complex phenotypes and highly variable response to therapies. GWAS studies have identified hundreds of genetic factors associated with the disease but the precise mechanism with which these genes cause variable phenotype in the disease are unknown. We observed an autosomal analog of X-chromosome inactivation causes clonally stable epigenetic mosaicism in intestinal organoids generated from mice. This epigenetic mosaicism was detected by measuring allele specific expression in organoids grown from different individuals and from spatially different regions of the mouse intestine. This epigenetic mechanism has been observed in more than 25% of autosomal genes in mouse and in human cell lines and is called autosomal monoallelic expression (MAE). Allelic imbalance in MAE genes is clonally stable, persisting for multiple organoid passages and is regulated partially by DNA methylation. Our findings suggest how non-genetic variation leads to formation of developmental clones (or patches) within an individual that could then cause a wide range of functional diversity, thereby driving phenotypic variability. This will point the ways to affect epigenetic differences in intestinal tissue for disease prevention.

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Xiao, Keyan, Dan Yu, Jinwang Wang, and Wen Xiong. "Clonal Plasticity ofVallisneria spiralisin Response to Substrate Heterogeneity." Journal of Freshwater Ecology 21, no. 1 (March 2006): 31–38. http://dx.doi.org/10.1080/02705060.2006.9664093.

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Haffner, Michael C., Angelo M. De Marzo, Srinivasan Yegnasubramanian, Jonathan I. Epstein, and H. Ballentine Carter. "Diagnostic Challenges of Clonal Heterogeneity in Prostate Cancer." Journal of Clinical Oncology 33, no. 7 (March 1, 2015): e38-e40. http://dx.doi.org/10.1200/jco.2013.50.3540.

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Landgren, Ola. "Serum protein markers of clonal heterogeneity in myeloma." Lancet Haematology 4, no. 12 (December 2017): e565-e566. http://dx.doi.org/10.1016/s2352-3026(17)30216-8.

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Bribián, A., M. Figueres-Oñate, E. Martín-López, and L. López-Mascaraque. "Decoding astrocyte heterogeneity: New tools for clonal analysis." Neuroscience 323 (May 2016): 10–19. http://dx.doi.org/10.1016/j.neuroscience.2015.04.036.

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Swanton, C. "Intrapatient Heterogeneity and Clonal Evolution: what Precision Medicine?" Annals of Oncology 25 (September 2014): iv37. http://dx.doi.org/10.1093/annonc/mdu313.3.

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Faltas, Bishoy, Himisha Beltran, Kenneth Eng, Chantal Pauli, Brian D. Robinson, Juan Miguel Mosquera, David M. Nanus, Scott T. Tagawa, Olivier Elemento, and Mark A. Rubin. "Clonal heterogeneity in platinum-resistant metastatic urothelial cancer." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 290. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.290.

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290 Background: Beyond platinum-based chemotherapy, there are currently no approved therapies for advanced PRUC. Our objective was to generate the first detailed genomic profile of metastatic PRUC to identify molecular changes critical to platinum-resistance and metastasis development. Methods: Following informed consent, we collected 50 urothelial cancer (UC) tissue samples, from 23 patients. Metastatic tumor samples were obtained from biopsies or metastatectomy. Germline samples were prospectively collected and matched archival formalin-fixed paraffin-embedded primary tumors from the same patients were retrieved. Our cohort comprises 23 metastatic samples, 37 PRUC samples and 18 trios of matched primary, metastatic and germline samples including 2 rapid autopsies yielding tumor samples from multiple sites. We performed whole exome sequencing of all tumor and germline samples followed by integrated analysis of somatic single nucleotide variants and copy-number alterations and to analyze clonality. We utilized DAVID bioinformatic tool for pathway analysis. Results: Advanced PRUC samples were enriched for several molecular alterations, we identified 414 recurrently mutated genes including common genes such as TP53 (45%) as well as actionable alterations in PIK3CA (11%) and TSC1 (19%). We also identified frequent alterations in novel genes such as DPCR1 (38%) and NIN (28%). Frequent copy number alterations included CDKN2A deletion (33%), E2F3 amplification (10%) and ERBB2 amplification (7%). Pathway analysis showed enrichment of mutations in the apoptosis (p=1.0E-7) and cell cycle regulation (p=1.6E-2) pathways compared to TCGA primary UC dataset. We reconstructed phylogenetic trees from matched primary, metastatic and germline trios. Variant allele frequencies of certain shared mutations increased from primary tumors to lymph node and visceral metastases revealing clonal selection of mutations present in primary tumors. Conclusions: This study generates a detailed profile of the genomic landscape of advanced PRUC revealing extensive heterogeneity and clonal selection underlying platinum-resistance and metastatic spread.

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Wu, Catherine J. "CLL clonal heterogeneity: an ecology of competing subpopulations." Blood 120, no. 20 (November 15, 2012): 4117–18. http://dx.doi.org/10.1182/blood-2012-09-452805.

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Gorunova, Ludmila, Bertil Johansson, Sigmund Dawiskiba, Åke Andrén-Sandberg, Nils Mandahl, Sverre Heim, and Felix Mitelman. "Cytogenetically detected clonal heterogeneity in a duodenal adenocarcinoma." Cancer Genetics and Cytogenetics 82, no. 2 (July 1995): 146–50. http://dx.doi.org/10.1016/0165-4608(95)00032-k.

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Ferraris, Anna Maria, Rosa Mangerini, Omar Racchi, Davide Rapezzi, Michela Rolfo, Salvatore Casciaro, and Gian Franco Gaetani. "Heterogeneity of clonal development in chronic myeloproliferative disorders." American Journal of Hematology 60, no. 2 (February 1999): 158–60. http://dx.doi.org/10.1002/(sici)1096-8652(199902)60:2<158::aid-ajh14>3.0.co;2-9.

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Vega, Francisco, Rajyalakshmi Luthra, L. Jeffrey Medeiros, Valerie Dunmire, Sang-Joon Lee, Madeleine Duvic, and Dan Jones. "Clonal heterogeneity in mycosis fungoides and its relationship to clinical course." Blood 100, no. 9 (November 1, 2002): 3369–73. http://dx.doi.org/10.1182/blood.v100.9.3369.

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Abstract Mycosis fungoides (MF) is a cutaneous T-cell lymphoma characterized by multifocal disease and protracted clinical course. The few studies that have assessed T-cell receptor (TCR) gene rearrangements (GRs) present at different anatomic sites in MF have generally reported a common clone. We used a previously validated 4-color polymerase chain reaction (PCR) assay to assess the size and V-family usage of TCR-γ GRs in 102 concurrent and/or sequential morphologically involved biopsy specimens (91 skin and 11 lymph nodes) from 39 MF patients. This assay detected TCR-γ clonal GRs in 89 samples (87%) from 36 patients (92%). In 24 patients (77%), an identical clonal GR was present in at least 2 skin samples. However, in one third of these patients, additional different clonal GRs were also noted. Four patients (13%) had clonal GRs that were distinct in different skin samples. In 3 patients (10%), no GR was detected in any sample. In a comparison of lymph node and skin samples, 8 patients had the identical clonal GRs at both sites, 2 patients had different clonal GRs, and 1 patient had no GR identified at either site. Independent of clinical stage, patients who had the same GR detected in multiple concurrent biopsy specimens at the time of diagnosis were more likely to have progressive disease than those who had different GRs (P = .04). Four-color TCR-γ PCR analysis can uncover multiple distinct clonal GRs in different samples consistent with multiclonal or oligoclonal disease in a significant proportion of MF patients. Demonstration of identical clonal GRs in multiple biopsy specimens at the time of diagnosis may provide prognostic information related to disease progression.

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Baslan, Timour, Jie Wu, Yee Him Cheung, Jonathan Bermeo, and Nevenka Dimitrova. "Defining the heterogeneity landscape of pancreatic cancer copy number alterations." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15776-e15776. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15776.

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e15776 Background: Pancreatic cancer (PDAC) is projected to become the second leading cause of cancer related mortality by 2030. Bulk whole genome sequencing studies of PDAC have characterized the landscape of clonal mutations and highlighted the prominence of copy number alterations (CNAs) in PDAC genomes. However, little is known with regards to the extent of sub-clonal heterogeneity of somatic CNAs and it is hypothesized that this heterogeneity is a contributing factor to the limited effectiveness of existing therapies. Methods: We retrieved absolute copy number information using bulk sparse whole genome sequencing of multi-region sampled PDAC samples as well as matching primary-metastasis tumor samples from over 100 patients. In addition, we analyzed copy number variations in a subset of these samples (n = 15) at single-cell resolution (~1000 cells in total). Results: We describe a detailed picture of sub-clonal CNAs genetic heterogeneity. Our results illustrate, among other findings, (1) extensive sub-clonal diversity of CNAs giving rise to many genetically unique sub-clonal cancer populations, (2) somatic mosaicism of chromosomal amplicons in single-cancer cells, (3) variation in the dosage of cancer genes, including the KRAS oncogene, in different tumor sub-clones and (4) somatic alterations, such as amplification of 8q11 containing the metastasis promoting gene IKBKB, associated with primary PDAC progression to liver metastasis. Conclusions: Our results offer an in-depth view of the sub-clonal heterogeneity of somatic CNAs in pancreatic cancer and illustrate ways in which such heterogeneity could lead to therapeutic resistance.

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Cao, Xiao-Xiao, Wei Xue, Ning-Fei Lei, and Fei-Hai Yu. "Effects of Clonal Integration on Foraging Behavior of Three Clonal Plants in Heterogeneous Soil Environments." Forests 13, no. 5 (April 29, 2022): 696. http://dx.doi.org/10.3390/f13050696.

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Environments are ubiquitously heterogeneous in nature, and clonal plants commonly benefit from both clonal integration and foraging responses in heterogeneous environments. While many studies have examined clonal integration and foraging responses separately, few have tested the effect of clonal integration on the foraging response of clonal plants to environmental heterogeneity. We grew offspring ramets of each of three clonal plants (Hydrocotyle vulgaris, Duchesnea indica, and Glechoma longituba) in both homogeneous and heterogenous soil environments and severed their stem connection to a mother ramet (to prevent clonal integration from the mother ramet) or kept it intact (to allow clonal integration). Without clonal integration from the mother ramet, soil heterogeneity had no effect on biomass or number of ramets for any of the three species. With clonal integration, soil heterogeneity also had no effect on biomass or number of ramets of D. indica and G. longituba, but significantly decreased biomass and marginally significantly decreased number of ramets of H. vulgaris. Without clonal integration, offspring ramets did not demonstrate either shoot or root foraging responses in terms of total, shoot and root biomass and ramet number in the heterogeneous soil environment in any of the three species. With integration, offspring ramets of H. vulgaris also did not demonstrate either root or shoot foraging responses, but offspring ramets of G. longituba demonstrated both root and shoot foraging responses, and those of D. indica demonstrated a root foraging response when they grew in the heterogeneous soil environment. We conclude that clonal integration can alter the foraging response of clonal plants, but this effect is species-specific. Our results also suggest that foraging responses of clonal plants in heterogeneous soil environments may not necessarily benefit the growth of clonal plants.

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Li, Yan, Yongli Shan, Ravi V. Desai, Kimberly H. Cox, Leor S. Weinberger, and Joseph S. Takahashi. "Noise-driven cellular heterogeneity in circadian periodicity." Proceedings of the National Academy of Sciences 117, no. 19 (May 1, 2020): 10350–56. http://dx.doi.org/10.1073/pnas.1922388117.

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Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.

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El Hussein, Siba, and Sanam Loghavi. "The Impact of Clonal Hierarchy and Heterogeneity on Phenotypic Manifestations of Myelodysplastic Neoplasms." Cancers 14, no. 22 (November 19, 2022): 5690. http://dx.doi.org/10.3390/cancers14225690.

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Until recently, conventional prognostication of myelodysplastic neoplasms (MDS) was performed using the revised International Prognostic Scoring System (IPSS-R), with additional adverse prognoses conferred by select mutations. Nonetheless, the clonal diversity and dynamics of coexisting mutations have been shown to alter the prognosis and treatment response in patients with MDS. Often in the process of clonal evolution, various initial hits are preferentially followed by a specific spectrum of secondary alterations, shaping the phenotypic and biologic features of MDS. Our ability to recapitulate the clonal ontology of MDS is a necessary step toward personalized therapy and the conceptualization of a better classification system, which ideally would take into consideration all genomic aberrations and their inferred clonal architecture in individual cases. In this review, we summarize our current understanding of the molecular landscape of MDS and the role of mutational combinations, clonal burden, and clonal hierarchy in defining the clinical fate of the disease.

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Passaro, Antonio, Umberto Malapelle, Marzia Del Re, Ilaria Attili, Alessandro Russo, Elena Guerini-Rocco, Caterina Fumagalli, et al. "Understanding EGFR heterogeneity in lung cancer." ESMO Open 5, no. 5 (October 2020): e000919. http://dx.doi.org/10.1136/esmoopen-2020-000919.

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The advances in understanding the inherited biological mechanisms of non-small cell lung cancer harbouring epidermal growth factor receptor (EGFR) mutations led to a significant improvement in the outcomes of patients treated with EGFR tyrosine kinase inhibitors. Despite these clinically impressive results, clinical results are not always uniform, suggesting the need for deepening the molecular heterogeneity of this molecularly defined subgroup of patients beyond the clinical and biological surface.The availability of tissue and blood-based tumour genotyping allows us to improve the understanding of molecular and genetic intratumor heterogeneity, driving the measurement of clonal evaluation in patients with lung cancer carrying EGFR mutations. Genetic diversification, clonal expansion and selection are highly variable patterns of genetic diversity, resulting in different biological entities, also a prerequisite for Darwinian selection and therapeutic failure.Such emerging pieces of evidence on the genetic diversity, including adaptive and immunomodulated aspects, provide further evidence for the role of the tumour microenvironment (TME) in drug-resistance and immune-mediated mechanisms. Matching in daily clinical practice, the detailed genomic profile of lung cancer disease and tracking the clonal evolution could be the way to individualise the further target treatments in EGFR-positive disease. Characterising the tumour and immune microenvironment during the time of the cancer evaluation could be the way forward for the qualitative leap needed from bench to bedside. Such a daring approach, aiming at personalising treatment selection in order to exploit the TME properties and weaken tumour adaptivity, should be integrated into clinical trial design to optimise patient outcome.

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Seco-Hidalgo, Víctor, Luis Miguel De Pablos, and Antonio Osuna. "Transcriptional and phenotypical heterogeneity of Trypanosoma cruzi cell populations." Open Biology 5, no. 12 (December 2015): 150190. http://dx.doi.org/10.1098/rsob.150190.

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Trypanosoma cruzi has a complex life cycle comprising pools of cell populations which circulate among humans, vectors, sylvatic reservoirs and domestic animals. Recent experimental evidence has demonstrated the importance of clonal variations for parasite population dynamics, survival and evolution. By limiting dilution assays, we have isolated seven isogenic clonal cell lines derived from the Pan4 strain of T. cruzi . Applying different molecular techniques, we have been able to provide a comprehensive characterization of the expression heterogeneity in the mucin-associated surface protein (MASP) gene family, where all the clonal isogenic populations were transcriptionally different. Hierarchical cluster analysis and sequence comparison among different MASP cDNA libraries showed that, despite the great variability in MASP expression, some members of the transcriptome (including MASP pseudogenes) are conserved, not only in the life-cycle stages but also among different strains of T. cruzi. Finally, other important aspects for the parasite, such as growth, spontaneous metacyclogenesis or excretion of different catabolites, were also compared among the clones, demonstrating that T. cruzi populations of cells are also phenotypically heterogeneous. Although the evolutionary strategy that sustains the MASP expression polymorphism remains unknown, we suggest that MASP clonal variability and phenotypic heterogeneities found in this study might provide an advantage, allowing a rapid response to environmental pressure or changes during the life cycle of T. cruzi .

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Colvin, Gerald A., Mark S. Dooner, Mehrdad Abedi, and Peter J. Quesenberry. "The Heterogeneity of Clonally Derived Purified Murine Marrow Stem Cell Colonies." Blood 104, no. 11 (November 16, 2004): 3215. http://dx.doi.org/10.1182/blood.v104.11.3215.3215.

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Abstract Clonal stem cells have been regarded as a semi-gold standard for stem cell studies and in some instances stem cell studies have been disregarded if they were not confirmed on a clonal basis. Thus, studies of populations of stem cells have been criticized if there were not also a clonal component. This appears to be inherently contradictory. Intuitively, divergent hematopoietic stem cell function would confer an evolutionary advantage to organisms as a survival mechanism protecting against catastrophic differentiation, apoptosis or necrosis. We have evaluated the heterogeneity of highly purified synchronized stem cells using single cell clonal cultures in cytokines and have used lineagenegativerhodaminelowHoeschtlow(LRH) murine marrow stem cells. As part of these studies, we evaluated the effect of cell cycle phase at the time of differentiation signaling using TPO, FLT3-ligand and steel factor for cycle initiation from resting G0–1 state and then serially subcultured cells on a clonal basis prior to cell division with single cell deposition into 96-well plates determining differentiation and colony formation 14-days later. Time zero cells went directly into the differentiation subculture. Initially, we clonally subcultured cells in a granulocyte-macrophage cocktail consisting of steel factor (SCF), G-CSF and GM-CSF. Additional experiments looked at different cytokine levels and included a megakaryocytic cocktail consisting of SCF, GM-CSF, G-CSF, IL-3, IL-6, IL-11 and TPO. We have determined (using propidium iodine, tritiated thymidine and cell doubling experiments) that LRH cells enter S-phase in a synchronized fashion at about 18hrs, and exit S-phase at 40–42hrs; they double between 44–48hrs. These studies showed a diversity of colony size, morphology and composition which was independent of cell cycle phase at time of differentiation subculture. We have analyzed a total of 800 colonies at the various time-points for morphology, cell type and cell number. We found that this “purified” population of LRH stem cells acted as individuals, i.e. snowflakes falling from the sky. There were no identical colonies. Growth in microtiter wells ranged from 0–864,600 cells (mean 77,450±296). Cloning efficiency was up to 62%, depending on cytokine concentration and combination. There was significant variability of colony size and number within as well as between time-points. In these studies, colonies were analyzed for the following differentiative hematopoietic cell lineages: neutrophilic (myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, segmented neutrophils), megakaryocytic, lymphocytic, plasmacytic, eosinophilic, basophilic, monocytic and erythocytic. We found colonies consisting of one to nine major cell types. An example highlighting the degree of heterogeneity seen, out of 55 colonies produced using SCF, GM-CSF, G-CSF at a particular time in culture and cytokine concentration, there were 33 colonies which were unique as to lineage composition. Altogether these studies show virtually complete heterogeneity of stem cells as characterized by clonal differentiation. The stem cell can probably not be defined on a single cell basis, but rather must be considered on a population basis.

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Jakubikova, Jana, Danka Cholujova, Teru Hideshima, Jacob P. Laubach, Nikhil C. Munshi, Steven P. Treon, Paul Richardson, Efstathios Kastritis, David M. Dorfman, and Kenneth C. Anderson. "Inter and Intra-Clonal Heterogeneity in Multiple Myeloma and Waldenstrom Macroglobulinemia." Blood 124, no. 21 (December 6, 2014): 2070. http://dx.doi.org/10.1182/blood.v124.21.2070.2070.

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Abstract Introduction: Intra-clonal heterogeneity in malignant plasma (PC) cells and B-cells has recently been reported in both multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM). Further phenotypic and molecular characterization of inter- and intra-clonal genetic complexity will enhance our understanding of disease pathogenesis and identify novel therapeutic strategies. Methods: In this study, we compared normal and malignant PC maturation-associated B-cell subsets using bone marrow samples from individuals with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), newly diagnosed MM, and relapsed/refractory MM versus age-matched healthy donors (HD). We also similarly analyzed WM. In addition to corrupted B-cell lineage, we examined phenotypic and molecular features of intra-clonal architecture (complexity) of malignant PC in MM and clonal B-cells in WM on a single cell level using time-of-flight mass cytometry (CyTOF) technology. CyTOF technology is based on rare stable earth elemental isotopes-bound to antibodies to target epitopes on and within cells: up to 40 different markers on a single cell can simultaneously assess including phenotype, transcription factors, regulatory signaling molecules and enzymes, as well as activation of signaling molecules. The resulting high-dimensional data were analyzed by SPADE, viSNE and Wanderlust software. Results: Our high-dimensional data of clustered analyses showed significantly decreased CD19+CD27- patient cells in MM with cytogenetic abnormalities (cytog+) including del(13q), t(4;14), t(14;16), t(3;14), +1q or t(11;14) versus patient cells in MM without any cytogenetic abnormalities (cytog-; P=0.013). In contrast, there was a significant increase of transitional B cells (CD19+CD27-IgM+CD10-IgDlow) in patients with MM cytog+ vs. MM cytog- (P=0.028). A significant increase of mature (naïve) B cells (CD19+CD27-IgM+CD10-IgD+) was also detected in MM cytog+ versus MM cytog- patients (P=0.013), but not in WM cytog- vs. WM cytog+ (46XY, -Y, +18q, +6p, 14q). Clonal PC (CD19-CD38++CD138+CD45-/dim; either cyk or cyl +) were significantly upregulated in MM cytog+ compared to MM cytog- (P=0.021) by CyTOF analyses. To investigate phenotypic profiles and molecular signature of intra-clonal heterogeneity of PC in MM, high-dimensional analyses by SPADE and viSNE revealed that clonal PC clustered separately from B cells by, virtue of high CD319 and CD47 expression; variable expression of CD52, CD56, CD81, CD44, CD200; and low expression of CD28, CD117, CD338, CD325, and CD243. For example, adhesion CD56 and anti-adhesion CD52 molecules were significantly increased in MM cytog+ compared to MM cytog-. Clonal PC highly expressed IFR4 and Notch1; variously expressed FGFR3, sXBP-1, KLF4 and c-Myc; and only minimally expressed Bcl-6, WHSC-1 (MMSET) and RARa2. sXBP-1 was significantly upregulated in all MM stages compared to HD. Furthermore, expression of stem cell markers including Sox-2, Oct3/4 and Nestin was detected only at low level in clonal PC, except for higher expression of Nanog. In WM, clonal B cells expressed Bcl-6 (4-36%) and MYD88 (2-27%) by CyTOF analyses. Finally, cluster analyses by SPADE and viSNE allows for detection of phenotypic and molecular changes not only in clonal populations but also at distinct B-lineage maturation stages, such as expression of Pax-5 and Bcl-2 on early B cell progenitors. This data represents a cohort of MM (N=35) and WM (N=15) patients; a significantly larger data set of MM (N=100) and WM (N=50) will be presented. Conclusion: This study characterizes the molecular and phenotypic profile associated with inter- and intra-clonal heterogeneity in MM and WM. It not only enhances our understanding of disease pathogenesis, but may allow for individualized targeted therapy. Disclosures No relevant conflicts of interest to declare.

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Danilenko, Marina, Masood Zaka, Claire Keeling, Stephen Crosier, Rafiqul Hussain, Edward Schwalbe, Dan Williamson, et al. "MBRS-59. SINGLE-CELL WHOLE-GENOME SEQUENCING DISSECTS INTRA-TUMOURAL GENOMIC HETEROGENEITY AND CLONAL EVOLUTION IN CHILDHOOD MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii408. http://dx.doi.org/10.1093/neuonc/noaa222.563.

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Abstract Medulloblastomas harbor clinically-significant intra-tumoral heterogeneity for key biomarkers (e.g. MYC/MYCN, β-catenin). Recent studies have characterized transcriptional heterogeneity at the single-cell level, however the underlying genomic copy number and mutational architecture remains to be resolved. We therefore sought to establish the intra-tumoural genomic heterogeneity of medulloblastoma at single-cell resolution. Copy number patterns were dissected by whole-genome sequencing in 1024 single cells isolated from multiple distinct tumour regions within 16 snap-frozen medulloblastomas, representing the major molecular subgroups (WNT, SHH, Group3, Group4) and genotypes (i.e. MYC amplification, TP53 mutation). Common copy number driver and subclonal events were identified, providing clear evidence of copy number evolution in medulloblastoma development. Moreover, subclonal whole-arm and focal copy number alterations covering important genomic loci (e.g. on chr10 of SHH patients) were detected in single tumour cells, yet undetectable at the bulk-tumor level. Spatial copy number heterogeneity was also common, with differences between clonal and subclonal events detected in distinct regions of individual tumours. Mutational analysis of the cells allowed dissection of spatial and clonal heterogeneity patterns for key medulloblastoma mutations (e.g. CTNNB1, TP53, SMARCA4, PTCH1) within our cohort. Integrated copy number and mutational analysis is underway to establish their inter-relationships and relative contributions to clonal evolution during tumourigenesis. In summary, single-cell analysis has enabled the resolution of common mutational and copy number drivers, alongside sub-clonal events and distinct patterns of clonal and spatial evolution, in medulloblastoma development. We anticipate these findings will provide a critical foundation for future improved biomarker selection, and the development of targeted therapies.

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Marjanovic, Nemanja D., Robert A. Weinberg, and Christine L. Chaffer. "Cell Plasticity and Heterogeneity in Cancer." Clinical Chemistry 59, no. 1 (January 1, 2013): 168–79. http://dx.doi.org/10.1373/clinchem.2012.184655.

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BACKGROUND Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor and from genetic and/or epigenetic differences amongst the cancer cells themselves. These factors conspire to create a disease with various phenotypes. There are 2 established models of cancer development and progression to metastatic disease. These are the clonal evolution and cancer stem cell models. CONTENT The clonal evolution theory suggests that successive mutations accumulating in a given cell generate clonal outgrowths that thrive in response to microenvironmental selection pressures, dictating the phenotype of the tumor. The alternative cancer stem cell (CSC) model suggests that cancer cells with similar genetic BACKGROUNDs can be hierarchically organized according to their tumorigenic potential. Accordingly, CSCs reside at the apex of the hierarchy and are thought to possess the majority of a cancer's tumor-initiating and metastatic ability. A defining feature of this model is its apparent unidirectional nature, whereby CSCs undergo symmetric division to replenish the CSC pool and irreversible asymmetric division to generate daughter cells (non-CSCs) with low tumorigenic potential. However, evolving evidence supports a new model of tumorigenicity, in which considerable plasticity exists between the non-CSC and CSC compartments, such that non-CSCs can reacquire a CSC phenotype. These findings suggest that some tumors may adhere to a plastic CSC model, in which bidirectional conversions are common and essential components of tumorigenicity. SUMMARY Accumulating evidence surrounding the plasticity of cancer cells, in particular, suggests that aggressive CSCs can be created de novo within a tumor. Given the current focus on therapeutic targeting of CSCs, we discuss the implications of non-CSC-to-CSC conversions on the development of future therapies.

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Qin, Xiaoqi, Gang An, Yu Qin, Yan Xu, Xiaoyan Feng, Meirong Zang, Weiwei Sui, et al. "Clonal Heterogeneityand Evolutional Paths in Multiple Myeloma Revealed By QM-FISH in Single Cell of Sequential Analysis." Blood 124, no. 21 (December 6, 2014): 3395. http://dx.doi.org/10.1182/blood.v124.21.3395.3395.

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Abstract Background: Clonal heterogeneity is a hallmark of many solid and hematologic malignancies. Clonal heterogeneity may foster clonal evolution and affect personalized care strategies in multiple myeloma(MM). In order to grasp this ubiquitous phenomenon and its effect on MM patients’ prognosis, we report on sequential analysis by quantitative multicolor-fluorescence in situ hybridization (QM-FISH) in single cell of myeloma patients who were longitudinally followed. Methods: Bacterial artificial chromosomes (BAC) clones that contain target genes including TP53, Rb1, CKS1B, CYLD and cIAP, which belonged to secondary genetic variation of MM and were searched in the data base UCSC Genome Bioinformatics. Multicolor FISH probes were prepared by linking fluorescein labeled dUTP and dCTP to target genes by nick translation. We performed QM-FISH in single cell of 42 specimen from 17 myeloma patients who were longitudinally followed and compared the difference between myeloma patients at initial diagnosis and progression of disease. Results: Sequential samples revealed that MM may follow three clonal evolution patterns in the course of disease progression. In these 17 patients, myeloma clone in 5 patients had no changes over the time, 6 patients acquired one or more molecular abnormalities and only one predominant clone over the course, 6 patients had more than 1 clone in the course and all clones competing and tiding, or acquired one or more molecular abnormalities resulted in new clones emerging and all involved clones waxing and waning. Furthermore, we analyzed clone architecture in samples at initial diagnosis and 15/17(88.2%) cases had multiple subclones architecture at initial diagnosis. 3 patients of the first group (3/5, 60%) had more than 1 subclone, and all patients of the latter two groups had multiple subclones at initial time. Clonal heterogeneity may contribute to clonal evolution Conclusions: The outcome of tracking clonal heterogeneity and evolutional paths by QM-FISH is effective and feasible. Myeloma patients may follow 1 of 3 pathways to progress. Clonal heterogeneitymay foster lonal evolution in the course of disease progression. Disclosures No relevant conflicts of interest to declare.

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Puig, Noemi, Isabel Conde, Cristina Jimenez, Maria E. Sarasquete, Ana Balanzategui, Miguel Alcoceba, Jonathan Quintero, et al. "Intraclonal Heterogeneity Associates with Clonal Stability in Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 3412. http://dx.doi.org/10.1182/blood.v124.21.3412.3412.

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Abstract Multiple myeloma (MM) pathogenesis has been explained for many years by the cancer biology dogma introduced by Peter Nowell: first, a single plasma cell would be immortalized by an error in the immunoglobulin genes rearrangement process; then, a progressive stepwise acquisition of somatic cell mutations would induce a sequential selection and domination by the fittest clone. In line with this idea of “myeloma stability”, SNP arrays studies in diagnostic-relapse paired samples have revealed the presence of common clonal characteristics. Biologically, the M-protein remains usually constant across MM evolution and further, the variable domain of the rearranged immunoglobulin heavy chain genes (or CDR3 region) has been used as a patient-specific myeloma fingerprint in minimal residual disease (MRD) studies. However, massive genome studies with Next Generation Sequencing (NGS) have challenged this concept, showing a significant intraclonal heterogeneity at diagnosis with the possible presence of several clonal progenitors or tumor-initiating cells. In this study, we have characterized and compared the CDR3 region in 52-paired samples from 26 MM patients aiming: 1) to assess mono-clonality in MM evolution through the analysis of the CDR3 sequence and, 2) to validate ASO RQ-PCR approaches for MRD in MM, based on the constancy and specificity of the CDR3 region. Samples were obtained at diagnosis and progression (19 pairs) or at 2 different timepoints of progressive disease (7 pairs). Median time between sampling was 2 years. M-protein subtype remained stable in all pairs but 1, associated with a light-chain escape phenomenon. All samples proceeded from bone marrow (BM) except for 2 pairs, composed by BM and extramedullary disease (spleen and testes). Two major cytogenetic changes were identified: increased 13q14 deletion (from 7 to 54%) in 1 pair and increased 17p (p53) deletion (from 5 to 87%) in a further one. Treatments administered between sampling included most of the current approaches used in MM (data not shown). Genomic DNA isolation, PCR amplification and sequencing were performed following conventional methods. Germline VH, DH and JH segments were identified by comparison with public databases. CDR3 region was first identified in all samples and then compared between the two samples in the 26 pairs: the sequence of nucleotides was constantly identical in each pair, including those associated with major cytogenetic changes, a light-chain escape, extramedullar vs. BM infiltration and relapsed (and therefore, treatment selected) vs. refractory disease. Therefore, we can first conclude that the main tumor clone in MM retains a specific signature across all stages of disease evolution that allows the identification of samples as evolutionary related. This major clone signature is not modified by clinical or biological changes in the disease nor under different treatment pressures and would thus identify disease relapse and progression. Our results have also a clear impact on the validity of molecular MRD techniques. The high rate of complete responses (up to 50-60%) currently achieved in MM has prompted the use of new techniques for disease assessment. Today, ASO RQ-PCR, based on the use of specific primers and probes complementary of the VDJH rearrangement, continues to be the most sensitive approach. One pitfall of this technique would be the potential instability of PCR targets over time, which would induce false negative results. In B-cell precursor ALL, this is estimated to happen in 30-40% of cases but has not been deeply evaluated in MM yet. With the present study, we can also conclude that the junction region of the VDJH rearrangement in MM constantly identifies the myeloma cells responsible for relapse and therefore can be used as a reliable target for MRD assessment by ASO RQ-PCR and more recently, by NGS methods. If the CDR3 region remains stable, the novel concept of clonal tiding in MM should not be interpreted as a poly- or oligoclonal but subclonal. In MM, tides can be subclonal, but the ocean remains monoclonal. Disclosures No relevant conflicts of interest to declare.

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Scaini, Maria Chiara, Jacopo Pigozzo, Marco Pizzi, Mariangela Manicone, Vanna Chiarion-Sileni, Pamela Zambenedetti, Massimo Rugge, et al. "Clonal heterogeneity of melanoma in a paradigmatic case study." Melanoma Research 29, no. 1 (February 2019): 89–94. http://dx.doi.org/10.1097/cmr.0000000000000510.

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Romer-Seibert, Jennifer S., and Sara E. Meyer. "Genetic heterogeneity and clonal evolution in acute myeloid leukemia." Current Opinion in Hematology 28, no. 1 (November 13, 2020): 64–70. http://dx.doi.org/10.1097/moh.0000000000000626.

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Campbell, Lauren L., and Kornelia Polyak. "Breast Tumor Heterogeneity: Cancer Stem Cells or Clonal Evolution?" Cell Cycle 6, no. 19 (October 2007): 2332–38. http://dx.doi.org/10.4161/cc.6.19.4914.

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Suguro, Miyuki, Noriaki Yoshida, Akira Umino, Harumi Kato, Hiroyuki Tagawa, Masao Nakagawa, Noriko Fukuhara, et al. "Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis." Cancer Science 105, no. 7 (July 2014): 897–904. http://dx.doi.org/10.1111/cas.12442.

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Palm, Margriet M., Marjet Elemans, and Joost B. Beltman. "Heritable tumor cell division rate heterogeneity induces clonal dominance." PLOS Computational Biology 14, no. 2 (February 12, 2018): e1005954. http://dx.doi.org/10.1371/journal.pcbi.1005954.

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Sun, Deming, and Christopher Coleclough. "Clonal heterogeneity of MBP-reactive rat encephalitogenic T cells." Journal of Neuroimmunology 54, no. 1-2 (October 1994): 200. http://dx.doi.org/10.1016/0165-5728(94)90549-5.

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Journal articles on the topic 'Clonal heterogeneity'

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