scholarly journals Detection of Rare Germline Variants in the Genomes of B Cell Neoplasms

2021 ◽  
Author(s):  
Adrian Mosquera Orgueira ◽  
Miguel Cid Lopez ◽  
Andres Peleteiro Raindo ◽  
Jose Angel Diaz Arias ◽  
Beatriz Antelo Rodriguez ◽  
...  
Keyword(s):  
B Cell ◽  
Rare Variants ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Nucleic Acid Metabolism ◽  
Compound Heterozygous ◽  
Lymphoid Neoplasms ◽  
Study Results ◽  
Germline Variation ◽  
Compound Heterozygous Variants

Growing evidence has revealed the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of putatively disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment of 26 genes in germline protein truncating variants (PTVs), affecting cell signaling (MET, JAK2, ANGPT2), energy metabolism (ACO1) and nucleic acid metabolism and repair pathways (NT5E, DCK). Interestingly, some of these variants were restricted to either chronic lymphocytic leukemia (CLL) (i.e., ANGPT2 and AKR1C3) or B-cell lymphoma cases (PNMT, TPT1 and IGHMBP2). Additionally, we detected 1,675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were PTVs. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A and TSC2. Homozygous or compound heterozygous variants were detected in 28 cases; and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D and MYC. Finally, we observed that variants in the helicase gene WRN were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis, clinical presentation and disease outcome of B-cell lymphoid neoplasms.

scholarly journals Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1340
Author(s):  
Adrián Mosquera Orgueira ◽  
Miguel Cid López ◽  
Andrés Peleteiro Raíndo ◽  
José Ángel Díaz Arias ◽  
Beatriz Antelo Rodríguez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
B Cell ◽  
Rare Variants ◽  
Cancer Predisposition ◽  
Germline Variants ◽  
Lymphoid Neoplasms ◽  
Study Results ◽  
Germline Variation ◽  
Significant Enrichment ◽  
Double Hit

There is growing evidence indicating the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of likely disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment for two genes in rare dysfunctional variants, both of which participate in the regulation of oxidative stress pathways (CHMP6 and GSTA4). Additionally, we detected 1675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were protein-truncating variants. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A, and TSC2. Homozygous or germline double-hit variants were detected in 28 cases, and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D, and MYC. Finally, we observed that variants in six different genes were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis and prognosis of B-cell lymphoid neoplasms.

scholarly journals Variable Distribution of DOCK-D Proteins between Cytosol and Nucleoplasm in Cell Lines, Effect of Interleukin-4 on DOCK10 in B-Cell Lymphoid Neoplasms, and Validation of a New DOCK10 Antiserum for Immunofluorescence Studies

Antibodies ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 33
Author(s):  
Natalia Ruiz-Lafuente ◽  
Alfredo Minguela ◽  
Jose M. Moraleda ◽  
Manuel Muro ◽  
Antonio Parrado
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cellular Localization ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Interleukin 4 ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Lymphoid Neoplasms

Dedicator-of-cytokinesis (DOCK), a family of guanine-nucleotide exchange factors (GEFs), comprises four subfamilies, named from A to D. DOCK-D comprises DOCK9, DOCK10, and DOCK11. The GEF activity involves translocation from the cytoplasm to the plasma membrane (PM), as assessed by the transfection of tagged proteins. However, the cellular localization of endogenous DOCK proteins is poorly understood. In this paper, to gain a better understanding of the role of the DOCK-D proteins, we studied their distribution between cytosol and nucleoplasm in 11 cell lines. DOCK-D proteins were distributed with variable cytosolic or nuclear predominance, although the latter was common for DOCK9 and DOCK11. These results suggest that the DOCK-D proteins may perform new nuclear functions, which remain to be discovered. Furthermore, we found that DOCK10 levels are increased by interleukin-4 (IL-4) in B-cell lymphoid neoplasms other than chronic lymphocytic leukemia (CLL) such as mantle cell lymphoma and diffuse large B-cell lymphoma. We also found evidence for an induction of the cytosolic levels of DOCK10 by IL-4 in CLL. Finally, we obtained a valid DOCK10 antiserum for immunofluorescence (IF) microscopy that, as an antibody against the hemagglutinin (HA) tag, marked PM ruffles and filopodia in HeLa cells with inducible expression of HA-DOCK10.

scholarly journals Artificially and Sugar-Sweetened Carbonated Beverage Consumption Is Not Associated with Risk of Lymphoid Neoplasms in Older Men and Women

2014 ◽  
Vol 144 (12) ◽  
pp. 2041-2049 ◽  
Author(s):  
Marjorie L McCullough ◽  
Lauren R Teras ◽  
Roma Shah ◽  
W Ryan Diver ◽  
Mia M Gaudet ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Histologic Subtype ◽  
Men And Women ◽  
Beverage Consumption ◽  
Carbonated Beverages ◽  
Lymphoid Neoplasms ◽  
Carbonated Beverage

Abstract Background: Concern about the carcinogenic potential of aspartame was raised after an increase in lymphomas and leukemia was reported in an animal study at doses similar to human exposure. Two prospective cohort studies published after the report found inconsistent results for estimated aspartame intake, artificially sweetened beverage consumption, and risk of lymphoid neoplasms. Objective: The objective of this study was to examine associations of artificially and sugar-sweetened carbonated beverage consumption (for comparison) and aspartame intake with risk of non-Hodgkin lymphoma (NHL) overall and by major histologic subtype in the Cancer Prevention Study-II Nutrition Cohort. Methods: Among 100,442 adult men and women who provided information on diet and lifestyle factors in 1999, 1196 NHL cases were verified during a 10-y follow-up period. Cox proportional hazards regression was used to estimate multivariable-adjusted RRs and 95% CIs. Results: In women and men combined, there were no associations of consumption of ≥1 (355 mL) servings/d of artificially (RR: 0.92; 95% CI: 0.73, 1.17; P-trend: 0.14) or sugar- (RR: 1.10; 95% CI: 0.77, 1.58; P-trend: 0.62) sweetened carbonated beverages with NHL risk, compared to no consumption (P-heterogeneity by gender: 0.11–1.00). Similarly, aspartame intake was not associated with NHL risk (RR: 1.02; 95% CI: 0.84, 1.24; P-trend: 0.69, top vs. bottom quintile). Associations with NHL subtype (multiple myeloma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular and other B-cell lymphoma) were generally null. Conclusion: These findings do not support associations of daily consumption of artificially or sugar-sweetened carbonated beverages, or aspartame, with NHL risk.

scholarly journals Neoplastic lesions in domestic pigs detected at slaughter: literature review and a 20-year review (1998–2018) of carcass inspection in Catalonia

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Antonia Morey-Matamalas ◽  
Enric Vidal ◽  
Jorge Martínez ◽  
Jaume Alomar ◽  
Antonio Ramis ◽  
...  
Keyword(s):  
B Cell ◽  
Case Series ◽  
B Cell Lymphoma ◽  
Support Network ◽  
Published Data ◽  
Nerve Sheath Tumor ◽  
Lymphoid Leukemia ◽  
Lymphoid Neoplasms ◽  
Neoplastic Lesions ◽  
Slaughtered Pigs

Abstract Background The present paper reviews the occurrence of neoplasms in swine and presents a case series of 56 tumors submitted to the Slaughterhouse Support Network (Servei de Suport a Escorxadors [SESC] IRTA-CReSA]) from slaughtered pigs from 1998 to 2018 (April) in Catalonia (Spain). The aim of the study was to describe the spectrum of spontaneous neoplastic lesions found in slaughtered pigs and to compare the reported tumor cases with previous published data. Lymphoid neoplasms were characterized and classified using the WHO classification adapted for animals. Results The most reported neoplasm during this period was lymphoma (28). Within lymphomas, the B-cell type was the most common, being the diffuse large B-cell lymphoma (15/28) the most represented subtype. Other submitted non-lymphoid neoplasms included melanoma (7), nephroblastoma (3), mast cell tumor (2), liposarcoma (2), osteochondromatosis (2), papillary cystadenocarcinoma (1), peripheral nerve sheath tumor (1), lymphoid leukemia (1), fibropapilloma (1), hemangiosarcoma (1), hepatoma (1), histiocytic sarcoma (1), pheochromocytoma (1) and osteosarcoma (1). Conclusions The existence of a well-established Slaughterhouse Support Network allowed the compilation of comprehensive data for further epidemiological and pathological studies, particularly about less commonly reported lesions in livestock such as neoplasms in pigs.

scholarly journals Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1053
Author(s):  
Jasleen Dhaliwal ◽  
Ying Qiao ◽  
Kristina Calli ◽  
Sally Martell ◽  
Simone Race ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Variable Effect ◽  
Gabaergic Neurotransmission ◽  
High Heritability ◽  
Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

scholarly journals The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia

2016 ◽  
Vol 7 (6) ◽  
pp. 321-329 ◽  
Author(s):  
Valentín Ortíz-Maldonado ◽  
Pablo Mozas ◽  
Julio Delgado
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Therapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Hallmarks Of Cancer ◽  
Lymphoid Malignancies

B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.

U.S. budget impact analysis of biosimilar versus originator intravenous rituximab for the treatment of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18820-e18820
Author(s):  
Elizabeth James ◽  
Holly Trautman ◽  
Ali McBride ◽  
Azhar Choudhry ◽  
Stephen Thompson
Keyword(s):  
B Cell ◽  
Impact Analysis ◽  
Budget Impact ◽  
Drug Acquisition ◽  
B Cell Lymphoma ◽  
Economic Benefits ◽  
Lymphocytic Leukemia ◽  
Sensitivity Analyses ◽  
Cost Share ◽  
The Impact

e18820 Background: Rituximab-abbs is an anti-CD20 monoclonal antibody and an important immuno-oncology agent for the treatment of B-cell malignancies NHL (diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma [FL]) and CLL. It is also indicated for patients with RA, GPA, and MPA. Rituximab-abbs was the first rituximab biosimilar approved in the US and is expected to reduce drug acquisition costs. This budget impact model (BIM) estimated the impact of replacing a share of originator rituximab (IV-R-REF) use with rituximab-abbs (IV-R-BIOSIM) for NHL (DLBCL and FL), CLL, RA, GPA, and MPA. The objective was to project incremental annual cost differences between IV-R-BIOSIM and IV-R-REF for a hypothetical 1-million-member US healthcare insured (Medicare) population. Methods: An illustrative BIM estimated changes in 1-year drug and administration costs for an increased IV-R-BIOSIM uptake from 17.5% to 22.0%. Values for epidemiology, market share distribution, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Dosing was based on a mean patient body surface area of 1.8 m2. Annual dose counts per patient were: 10 untreated FL with maintenance; 8 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 6 CLL, and 4 for RA, GPA, or MPA. All treatments were assumed to infuse over 3 hours. Drug acquisition and administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. Patient cost share was based on 2020 Medicare Part B 20% cost-share for office visits and drug products. Univariate sensitivity analyses were conducted. A scenario analysis was performed to project 2-year costs for extended FL maintenance treatment. Results: Estimated total annual plan incremental savings for a 1-million-member payer after the utilization shift were $312,379, equating to $0.31 per enrolled member per year (PMPY). Per-patient incremental drug cost savings with IV-R-BIOSIM for 1-year were $5,474–$12,924 (Table). The model was most sensitive to IV-R-REF cost and proportion of patients with RA. Conclusions: This analysis estimated annual savings of over $310,000 ($0.31 PMPY) for a 1-million-member US payer following a 4.5% utilization shift from IV-R-REF to IV-R-BIOSIM, demonstrating that IV-R-BIOSIM may confer considerable economic benefits vs originator rituximab.[Table: see text]

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