The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Yelena Y Janjigian - One of the best experts on this subject based on the ideXlab platform.
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tumor Mutational Load predicts survival after immunotherapy across multiple cancer types
Nature Genetics, 2019Co-Authors: Robert M Samstein, Chunghan Lee, Alexander N Shoushtari, Matthew D Hellmann, Ronglai Shen, Yelena Y JanjigianAbstract:Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor Mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
Ricard V Sole - One of the best experts on this subject based on the ideXlab platform.
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tumour neoantigen heterogeneity thresholds provide a time window for combination immunotherapy
Journal of the Royal Society Interface, 2020Co-Authors: Guim Aguadegorgorio, Ricard V SoleAbstract:Following the advent of cancer immunotherapy, increasing insight has been gained on the role of Mutational Load and neoantigens as key ingredients in T cell recognition of malignancies. However, no...
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replication mode and landscape topology differentially affect rna virus Mutational Load and robustness
Journal of Virology, 2009Co-Authors: Josep Sardanyes, Ricard V Sole, Santiago F ElenaAbstract:Regardless of genome polarity, intermediaries of complementary sense must be synthesized and used as templates for the production of new genomic strands. Depending on whether these new genomic strands become themselves templates for producing extra antigenomic ones, thus giving rise to geometric growth, or only the firstly synthesized antigenomic strands can be used to this end, thus following Luria's stamping machine model, the abundances and distributions of mutant genomes will be different. Here we propose mathematical and bit string models that allow distinguishing between stamping machine and geometric replication. We have observed that, regardless the topology of the fitness landscape, the critical mutation rate at which the master sequence disappears increases as the mechanism of replication switches from purely geometric to stamping machine. We also found that, for a wide range of mutation rates, large-effect mutations do not accumulate regardless the scheme of replication. However, mild mutations accumulate more in the geometric model. Furthermore, at high mutation rates, geometric growth leads to a population collapse for intermediate values of Mutational effects at which the stamping machine still produces master genomes. We observed that the critical mutation rate was weakly dependent on the strength of antagonistic epistasis but strongly dependent on synergistic epistasis. In conclusion, we have shown that RNA viruses may increase their robustness against the accumulation of deleterious mutations by replicating as stamping machines and that the magnitude of this benefit depends on the topology of the fitness landscape assumed.
Timothy G Call - One of the best experts on this subject based on the ideXlab platform.
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tumor Mutational Load predicts time to first treatment in chronic lymphocytic leukemia cll and monoclonal b cell lymphocytosis beyond the cll international prognostic index
American Journal of Hematology, 2020Co-Authors: Geffen Kleinstern, Xing Li, Daniel R Obrien, Brian Kabat, Aaron D Norman, Nicholas J Boddicker, Shulan Tian, Celine M. Vachon, Kari G Rabe, Timothy G CallAbstract:Next-generation sequencing identified ~60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes [i.e., tumor Mutational Load (TML)] or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR=1.27 (CI:1.17-1.39, P=2.6x10(-8) ; c-statistic=0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR=1.54, CI:1.37-1.72, P=7.0x10(-14) ). Overall, 80% of low/intermediate CLL-IPI cases with 2+ mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR=1.53, CI:1.12-2.07, P=0.007; c-statistic=0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT. This article is protected by copyright. All rights reserved.
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tumor Mutational Load predicts time to first treatment in chronic lymphocytic leukemia cll and monoclonal b cell lymphocytosis beyond the cll international prognostic index
American Journal of Hematology, 2020Co-Authors: Geffen Kleinstern, Xing Li, Daniel R Obrien, Brian Kabat, Aaron D Norman, Nicholas J Boddicker, Shulan Tian, Celine M. Vachon, Kari G Rabe, Timothy G CallAbstract:Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor Mutational Load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10-8 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.
Jacques Izopet - One of the best experts on this subject based on the ideXlab platform.
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Impact of the Mutational Load on the virological response to a first-line rilpivirine-based regimen.
The Journal of antimicrobial chemotherapy, 2018Co-Authors: Chloé Dimeglio, Stéphanie Raymond, Florence Nicot, Nicolas Jeanne, Romain Carcenac, Caroline Lefebvre, Jacques IzopetAbstract:Author(s): Dimeglio, Chloe; Raymond, Stephanie; Nicot, Florence; Jeanne, Nicolas; Carcenac, Romain; Lefebvre, Caroline; Izopet, Jacques; French National Agency for Research on AIDS and Viral Hepatitis (ANRS) AC11 Resistance Study Group | Abstract: ObjectivesTo determine how the Load of rilpivirine-resistant variants (Mutational Load) influences the virological response (VR) of HIV-1-infected patients to a rilpivirine-based first-line regimen.Patients and methodsFour hundred and eighty-nine patients infected with HIV-1 whose reverse transcriptase gene had been successfully resistance genotyped using next-generation sequencing were given a first-line regimen containing rilpivirine. Variables associated with the VR at 12 months were identified using a logistic model. The results were used to build a multivariate model for each Mutational Load threshold and the R2 variations were analysed to identify the Mutational Load threshold that best predicted the VR.ResultsThe Mutational Load at baseline was the only variable linked to the VR at 12 months (P l 0.01). The VR at 12 months decreased from 96.9% to 83.4% when the Mutational Load was g1700 copies/mL and to 50% when the Mutational Load was g 9000 copies/mL. The threshold of 9000 copies/mL was associated with the VR at 12 months with an OR of 36.7 (95% CI 4.7-285.1). The threshold of 1700 copies/mL was associated with the VR at 12 months with an OR of 7.2 (95% CI 1.4-36.8).ConclusionsThere is quantifiable evidence that determining a Mutational Load threshold can be used to identify those patients on a first-line regimen containing rilpivirine who are at risk of virological failure. The clinical management of HIV-infected patients can be improved by evaluating the frequency of mutant variants at a threshold of l 20% together with the plasma HIV-1 viral Load at the time of resistance genotyping.
Howard M Cann - One of the best experts on this subject based on the ideXlab platform.
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distance from sub saharan africa predicts Mutational Load in diverse human genomes
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Brenna M Henn, Laura R Botigue, Stephan Peischl, Isabelle Dupanloup, Mikhail Lipatov, Brian K Maples, Alicia R Martin, Shaila Musharoff, Howard M CannAbstract:The Out-of-Africa (OOA) dispersal ∼ 50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of Mutational Load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation Load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.
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distance from sub saharan africa predicts Mutational Load in diverse human genomes
bioRxiv, 2015Co-Authors: Brenna M Henn, Laura R Botigue, Stephan Peischl, Isabelle Dupanloup, Mikhail Lipatov, Brian K Maples, Alicia R Martin, Shaila Musharoff, Howard M Cann, Michael SnyderAbstract:The Out-of-Africa (OOA) dispersal ~50,000 years ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of Mutational Load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from 7 geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation Load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.
