7 research outputs found
The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma
The development of sensitive and non-invasive
ââliquid biopsiesââ presents new opportunities for
longitudinal monitoring of tumor dissemination and
clonal evolution. The number of circulating tumor
cells (CTCs) is prognostic in multiple myeloma
(MM), but there is little information on their genetic
features. Here, we have analyzed the genomic landscape
of CTCs from 29 MM patients, including eight
cases with matched/paired bone marrow (BM) tumor
cells. Our results show that 100% of clonal mutations
in patient BM were detected in CTCs and that 99% of
clonal mutations in CTCs were present in BM MM.
These include typical driver mutations in MM such
as in KRAS, NRAS, or BRAF. These data suggest
that BM and CTC samples have similar clonal structures,
as discordances between the two were
restricted to subclonal mutations. Accordingly, our
results pave the way for potentially less invasive
mutation screening of MM patients through characterization
of CTCs
Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma
Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas
Circulating microRNAs and their role in multiple myeloma
Multiple myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow infiltration
of clonal plasma cells. The recent literature has clearly demonstrated clonal heterogeneity in terms
of both the genomic and transcriptomic signature of the tumor. Of note, novel studies have also
highlighted the importance of the functional cross-talk between the tumor clone and the surrounding
bone marrow milieu, as a relevant player of MM pathogenesis. These findings have certainly
enhanced our understanding of the underlying mechanisms supporting MM pathogenesis and
disease progression. Within the specific field of small non-coding RNA-research, recent studies have
provided evidence for considering microRNAs as a crucial regulator of MM biology and, in this
context, circulating microRNAs have been shown to potentially contribute to prognostic stratification
of MM patients. The present review will summarize the most recent studies within the specific topic
of microRNAs and circulating microRNAs in MM
The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma
The development of sensitive and non-invasive
ââliquid biopsiesââ presents new opportunities for
longitudinal monitoring of tumor dissemination and
clonal evolution. The number of circulating tumor
cells (CTCs) is prognostic in multiple myeloma
(MM), but there is little information on their genetic
features. Here, we have analyzed the genomic landscape
of CTCs from 29 MM patients, including eight
cases with matched/paired bone marrow (BM) tumor
cells. Our results show that 100% of clonal mutations
in patient BM were detected in CTCs and that 99% of
clonal mutations in CTCs were present in BM MM.
These include typical driver mutations in MM such
as in KRAS, NRAS, or BRAF. These data suggest
that BM and CTC samples have similar clonal structures,
as discordances between the two were
restricted to subclonal mutations. Accordingly, our
results pave the way for potentially less invasive
mutation screening of MM patients through characterization
of CTCs
FlowCT for the analysis of large immunophenotypic data sets and biomarker discovery in cancer immunology
Large-scale immune monitoring is becoming routinely used in clinical trials to identify determinants of treatment responsiveness, particularly to immunotherapies. Flow cytometry remains one of the most versatile and high throughput approaches for single-cell analysis; however, manual interpretation of multidimensional data poses a challenge when attempting to capture full cellular diversity and provide reproducible results. We present FlowCT, a semi-automated workspace empowered to analyze large data sets. It includes pre-processing, normalization, multiple dimensionality reduction techniques, automated clustering, and predictive modeling tools. As a proof of concept, we used FlowCT to compare the T-cell compartment in bone marrow (BM) with peripheral blood (PB) from patients with smoldering multiple myeloma (SMM), identify minimally invasive immune biomarkers of progression from smoldering to active MM, define prognostic T-cell subsets in the BM of patients with active MM after treatment intensification, and assess the longitudinal effect of maintenance therapy in BM T cells. A total of 354 samples were analyzed and immune signatures predictive of malignant transformation were identified in 150 patients with SMM (hazard ratio [HR], 1.7; P < .001). We also determined progression-free survival (HR, 4.09; P < .0001) and overall survival (HR, 3.12; P = .047) in 100 patients with active MM. New data also emerged about stem cell memory T cells, the concordance between immune profiles in BM and PB, and the immunomodulatory effect of maintenance therapy. FlowCT is a new open-source computational approach that can be readily implemented by research laboratories to perform quality control, analyze high-dimensional data, unveil cellular diversity, and objectively identify biomarkers in large immune monitoring studies. These trials were registered at www.clinicaltrials.gov as #NCT01916252 and #NCT02406144
FlowCT for the analysis of large immunophenotypic data sets and biomarker discovery in cancer immunology
Large-scale immune monitoring is becoming routinely used in clinical trials to identify determinants of treatment responsiveness, particularly to immunotherapies. Flow cytometry remains one of the most versatile and high throughput approaches for single-cell analysis; however, manual interpretation of multidimensional data poses a challenge when attempting to capture full cellular diversity and provide reproducible results. We present FlowCT, a semi-automated workspace empowered to analyze large data sets. It includes pre-processing, normalization, multiple dimensionality reduction techniques, automated clustering, and predictive modeling tools. As a proof of concept, we used FlowCT to compare the T-cell compartment in bone marrow (BM) with peripheral blood (PB) from patients with smoldering multiple myeloma (SMM), identify minimally invasive immune biomarkers of progression from smoldering to active MM, define prognostic T-cell subsets in the BM of patients with active MM after treatment intensification, and assess the longitudinal effect of maintenance therapy in BM T cells. A total of 354 samples were analyzed and immune signatures predictive of malignant transformation were identified in 150 patients with SMM (hazard ratio [HR], 1.7; P < .001). We also determined progression-free survival (HR, 4.09; P < .0001) and overall survival (HR, 3.12; P = .047) in 100 patients with active MM. New data also emerged about stem cell memory T cells, the concordance between immune profiles in BM and PB, and the immunomodulatory effect of maintenance therapy. FlowCT is a new open-source computational approach that can be readily implemented by research laboratories to perform quality control, analyze high-dimensional data, unveil cellular diversity, and objectively identify biomarkers in large immune monitoring studies. These trials were registered at www.clinicaltrials.gov as #NCT01916252 and #NCT02406144
Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma
Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas