Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+.

ViCloD, an interactive web tool for visualizing B cell repertoires and analyzing intraclonal diversities: application to human B-cell tumors.

High throughput sequencing of adaptive immune receptor repertoire (AIRR-seq) has provided numerous human immunoglobulin (IG) sequences allowing specific B cell receptor (BCR) studies such as the antigen-driven evolution of antibodies (soluble forms of the membrane-bound IG part of the BCR). AIRR-seq data allows researchers to examine intraclonal differences caused primarily by somatic hypermutations in IG genes and affinity maturation. Exploring this essential adaptive immunity process could help elucidate the generation of antibodies with high affinity or broadly neutralizing activities.

Reconstructing B cell lineage trees with minimum spanning tree and genotype abundances.

B cell receptor (BCR) genes exposed to an antigen undergo somatic hypermutations and Darwinian antigen selection, generating a large BCR-antibody diversity. This process, known as B cell affinity maturation, increases antibody affinity, forming a specific B cell lineage that includes the unmutated ancestor and mutated variants. In a B cell lineage, cells with a higher antigen affinity will undergo clonal expansion, while those with a lower affinity will not proliferate and probably be eliminated.

Evidence of somatic hypermutation in the antigen binding sites of patients with CLL harboring IGHV genes with 100% germline identity.

Classification of patients with chronic lymphocytic leukemia (CLL) based on the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene has established predictive and prognostic relevance. The SHM status is assessed based on the number of mutations within the IG heavy variable domain sequence, albeit only over the rearranged IGHV gene excluding the variable heavy complementarity determining region 3 (VH CDR3). This may lead to an underestimation of the actual impact of SHM, in fact overlooking the most critical region for antigen-antibody interactions, i.

A multi-objective based clustering for inferring BCR clonal lineages from high-throughput B cell repertoire data.

The adaptive B cell response is driven by the expansion, somatic hypermutation, and selection of B cell clonal lineages. A high number of clonal lineages in a B cell population indicates a highly diverse repertoire, while clonal size distribution and sequence diversity reflect antigen selective pressure. Identifying clonal lineages is fundamental to many repertoire studies, including repertoire comparisons, clonal tracking, and statistical analysis.

[Watch out for a second train].

We report the case of a man with a primary diagnosis of Waldenström macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques.

Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing.

Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend.

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers.

Introduction: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far.

Methods: We describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes.

TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS.

Posterior cortical atrophy as an extreme phenotype of GRN mutations.

Importance: Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described.

Observations: We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA.

Extensive white matter involvement in patients with frontotemporal lobar degeneration: think progranulin.

Importance: Mutations in the progranulin (GRN) gene are responsible for 20% of familial cases of frontotemporal dementias. All cause haploinsufficiency of progranulin, a protein involved in inflammation, tissue repair, and cancer. Carriers of the GRN mutation are characterized by a variable degree of asymmetric brain atrophy, predominantly in the frontal, temporal, and parietal lobes.

Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are adult-onset neurodegenerative diseases with overlapping clinical characteristics. They share common genetic causes and pathologic hallmarks such as TDP-43 neuronal accumulations. Recently, exome analysis identified mutations in matrin 3 (MATR3) gene in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease.

Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients.

Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment. CHCHD10 encodes a protein located in the mitochondrial intermembrane space and is likely involved in mitochondrial genome stability and maintenance of cristae junctions. However, the exact contribution of CHCHD10 in FTD and ALS diseases spectrum remains unknown.

A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V.

Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.

Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration.

Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date.

DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.

Importance: Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified.

Objective: To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype).

hnRNPA2B1 and hnRNPA1 mutations are rare in patients with "multisystem proteinopathy" and frontotemporal lobar degeneration phenotypes.

hnRNPA2B1 and hnRNPA1 mutations have been recently identified by exome sequencing in three families presenting with multisystem proteinopathy (MSP), a rare complex phenotype associating frontotemporal lobar degeneration (FTLD), Paget disease of bone (PDB), inclusion body myopathy (IBM), and amyotrophic lateral sclerosis (ALS). No study has evaluated the exact frequency of these genes in cohorts of MSP or FTD patients so far. We sequenced both genes in 17 patients with MSP phenotypes, and in 60 patients with FTLD and FTLD-ALS to test whether mutations could be implicated in the pathogenesis of these disorders.