Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non-Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk-stratification CLL model

Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis

Immunoglobulin light-chain amyloidosis (AL) and multiple myeloma (MM) are 2 distinct monoclonal gammopathies that involve the same cellular compartment: clonal plasma cells (PCs). Despite the fact that knowledge about MM PC biology has significantly increased in the last decade, the same does not apply for AL. Here, we used an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 24 newly diagnosed patients with AL. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and both monoclonal gammopathy of undetermined significance and MM PCs. However, in contrast to MM, highly purified fluorescence-activated cell-sorted clonal PCs from AL (n = 9) showed almost normal transcriptome, with only 38 deregulated genes vs normal PCs; these included a few tumor-suppressor (CDH1, RCAN) and proapoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11) were genomically unstable, with a median of 9 copy number alterations (CNAs) per case, many of such CNAs being similar to those found in MM. Whole-exome sequencing (WES) performed in 5 AL patients revealed a median of 15 nonrecurrent mutations per case. Altogether, our results show that in the absence of a unifying mutation by WES, clonal PCs in AL display phenotypic and CNA profiles similar to MM, but their transcriptome is remarkably similar to that of normal PCs

Estudio del perfil genético en pacientes con Amiloidosis de cadenas ligeras

Oral Presentation [CO-130] Introducción: Los estudios de secuenciación masiva (NGS) han permitido profundizar en el conocimiento de las gammapatías monoclonales tales como el mieloma múltiple (MM) y la macroglobulinemia de Waldesntröm’s (WM). Desafortunadamente, la baja incidencia de la amiloidosis de cadenas ligeras (AL) y la baja carga tumoral que presenta, a menudo enmascarada por un fondo policlonal de células plasmáticas (PC), explica la poca información que hay sobre la biología de la célula tumoral. Por ello, se desconoce si la AL presenta alguna mutación común como ocurre en la WM, si existen mutaciones recurrentes, y si estas podrían coincidir con las observadas en MM. Por lo tanto, el objetivo de este trabajo es realizar una secuenciación de exoma (WES) en una serie de pacientes con AL y comparar su perfil mutacional con el de MM. Métodos: En este estudio se incluyeron 28 pacientes con AL. Se realizó un WES, incluyendo las regiones reguladoras UTR (SureSelect Human All Exon V6 + UTRs (Agilent)) en 56 muestras pareadas sorteadas de células plasmáticas patológicas y sangre periférica como muestra control. Cada muestra tumoral fue capturada por triplicado y secuenciada en la plataforma NextSeq 500 (Illumina). Para el análisis de variantes somáticas se utilizaron los programas Strelka y ANNOVAR. . Las firmas mutacionales se analizaron con el software DeconstructSigs. Para comparar el perfil mutacional de AL con MM se utilizó la base de datos MMRF CoMMpass con 895 pacientes. Además, se han determinado los reordenamientos de los genes de las inmunoglobulinas (Igs) mediante NGS. Resultados: La cobertura media de secuenciación para las muestras de control y tumor fue de 64x y 186x, respectivamente. Se detectaron un total de 1983 SNV y 133 INDEL con una media de 71 (20-281) SNV y 5 (0-25) INDEL por paciente. Al comparar con MM (media 66 SNV y 2.5 INDEL) se observó una carga mutacional similar. Los únicos genes mutados tanto en AL como en MM fueron MUC16 (recurrencia 17% y 8%, respectivamente) e IGLL5 (recurrencia 17%, en ambas), siendo además los genes más frecuentemente mutados en AL Las firmas mutacionales más frecuentes que se identificaron fueron la 1 (desaminación espontánea de citosinas metiladas en sitios CpG), la 3 (fallo en la reparación de la ruptura de la doble cadena de ADN mediante recombinación homóloga), y la 9 (transveriones T> G en trinucleótidos ApTpN y TpTpN), identificadas en el 96%, 54% y 46% de los pacientes, respectivamente. Respecto al repertorio de los genes de las Igs, se observó que el 26% de los pacientes con AL presentan más de un clon, siendo esta heterogeneidad clonal similar a la encontrada en MM (23%). El gen IGHV3-30 fue identificado con mayor frecuencia tanto en AL como en MM, 10% y 12% de recurrencia, respectivamente. Conclusiones: Este es el primer estudio de WES en una serie de pacientes con AL. Los resultados muestran que no hay una mutación común driver en esta enfermedad, que podrían estar implicados múltiples procesos mutacionales, y que los genes descritos más frecuentemente mutados en AL y MM no coinciden. En conjunto, estos resultados suponen un avance en el entendimiento de la patogénesis de la AL

Measurement of the W+W- Production Cross Section in ppbar Collisions at sqrt(s)=1.96 TeV using Dilepton Events

We present a measurement of the W+W- production cross section using 184/pb of ppbar collisions at a center-of-mass energy of 1.96 TeV collected with the Collider Detector at Fermilab. Using the dilepton decay channel W+W- -> l+l-vvbar, where the charged leptons can be either electrons or muons, we find 17 candidate events compared to an expected background of 5.0+2.2-0.8 events. The resulting W+W- production cross section measurement of sigma(ppbar -> W+W-) = 14.6 +5.8 -5.1 (stat) +1.8 -3.0 (syst) +-0.9 (lum) pb agrees well with the Standard Model expectation.Comment: 8 pages, 2 figures, 2 tables. To be submitted to Physical Review Letter

Search for a W' boson decaying to a top and bottom quark pair in 1.8 TeV p(p)over-bar collisions

We report the results of a search for a W-' boson produced in p (p) over bar collisions at a center-of-mass energy of 1.8 TeV using a 106 pb(-1) data sample recorded by the Collider Detector at Fermilab. We observe no significant excess of events above background for a W' boson decaying to a top and bottom quark pair. In a model where this boson would mediate interactions involving a massive right-handed neutrino (nu(R)) and have standard model strength couplings, we use these data to exclude a W' boson with mass between 225 and 536 GeV/c(2) at 95% confidence level for M-W(') gt M-nuR and between 225 and 566 GeV/c(2) at 95% confidence level for M-W(') lt M-nuR

Measurement of B-meson lifetimes using fully reconstructed B decays produced in p(p)over-bar collisions at root s=1.8 TeV

We present an improved measurement of b-meson lifetimes using fully reconstructed B-decays produced in p(p) over bar collisions at roots = 1.8 TeV, using 114 pb(-1) of data collected at the Collider Detector at Fermilab. We obtain tau(B+) = 1.636+/-0.058(stat)+/-0.025(syst) ps, tau(B-0) = 1.497+/-0.073(stat)+/-0.032(syst) ps and for the lifetime ratio tau(B+)/tau(B-0) = 1.093+/-0.066(stat)+/-0.028(syst)

Search for radiative b-hadron decays in p(p)over-bar collisions at root s=1.8 TeV

We have performed a search for radiative b-hadron decays using events produced in p (p) over bar collisions at roots=1.8 TeV and collected by the Collider Detector at Fermilab. The decays we considered were (B) over bar (0)(d)→(K) over bar*(0)(→K(-)pi(+))gamma, (B) over bar (0)(s)→phi(→K+K-)gamma, Lambda(b)(0)→Lambda(→ppi(-))gamma, and their charge conjugates. Two independent methods to identify photons from such decays were employed. In the first method, the photon was detected in the electromagnetic calorimeter. In the second method, the photon was identified by an electron-positron pair produced through the external photon conversion before the tracking detector volume. By combining the two methods we obtain upper limits on the branching fractions for the (B) over bar (0)(d), (B) over bar (0)(s), and Lambda(b)(0) radiative decays which, at the 95% confidence level, are found to be B((B) over bar (0)(d)→(K) over bar*(0)gamma) lt 1.4x10(-4), B((B) over bar (0)(s)→phigamma) lt 1.6x10(-4), and B(Λ(0)(b)→Lambdagamma) lt 1.9x10(-3)

Search for W and Z bosons in the reaction (p)over-barp -> two jets plus gamma at root s=1.8 TeV

We present a study of the dijet invariant mass distribution for the reaction \pbp \to 2 jets$+\gamma+X$, at a center of mass energy of 1.8 TeV, using data collected by the CDF experiment. We compare the data to predictions for the production of a photon with two jets, together with the resonant processes \pbp \to W/Z+\gamma+X, in which the $W$ and $Z$ bosons decay hadronically. A fit is made to the dijet invariant mass distribution combining the non-resonant background and resonant processes. We use the result to establish a limit for the inclusive production cross section of $W/Z+\gamma$ with hadronic decay of the $W$ and $Z$ bosons.Comment: 9 pages, 6 figures. To be submitted to PR