Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

Cell, Journal Year: 2017, Volume and Issue: 168(4), P. 613 - 628

Published: Feb. 1, 2017

Language: Английский

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Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Nature, Journal Year: 2017, Volume and Issue: 551(7681), P. 512 - 516

Published: Nov. 1, 2017

Language: Английский

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Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: Oct. 20, 2017

Abstract Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients metastatic melanoma, but the common mechanisms of primary and acquired resistance these agents remain incompletely characterized have yet be validated large cohorts. By analyzing longitudinal tumor biopsies from 17 melanoma treated CPB therapies, we observed point mutations, deletions or loss heterozygosity (LOH) beta-2-microglobulin ( B2M ), an essential component MHC class I antigen presentation, 29.4% progressing disease. In two independent cohorts anti-CTLA4 anti-PD1, respectively, find that LOH is enriched threefold non-responders (~30%) compared responders (~10%) associated poorer overall survival. Loss both copies found only non-responders. likely a mechanism targeting CTLA4 PD1.

Language: Английский

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A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy

Nature, Journal Year: 2017, Volume and Issue: 551(7681), P. 517 - 520

Published: Nov. 1, 2017

Language: Английский

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Molecular landmarks of tumor hypoxia across cancer types

Nature Genetics, Journal Year: 2019, Volume and Issue: 51(2), P. 308 - 318

Published: Jan. 7, 2019

Language: Английский

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Resolving genetic heterogeneity in cancer

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 20(7), P. 404 - 416

Published: March 27, 2019

Language: Английский

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Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas

Journal of Clinical Oncology, Journal Year: 2017, Volume and Issue: 35(26), P. 3065 - 3074

Published: May 12, 2017

Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell cancer (SCLC) has been described as one the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed TKI-resistant SCLCs. Among them, whole genome sequencing was applied nine tumors acquired at various time points from four to reconstruct their clonal evolutionary history and detect genetic predictors transformation. The findings validated by immunohistochemistry in 210 tissues. Results identified SCLCs share a common origin undergo branched trajectories. divergence SCLC ancestors LADC cells occurred before first TKI treatments, complete inactivation both RB1 TP53 observed early stages sequenced tumors. extended early-stage tissues 75 treated TKIs; Rb p53 strikingly more frequent small-cell-transformed group than nontransformed (82% v 3%; odds ratio, 131; 95% CI, 19.9 859). registered predefined cohort (n = 65), an harbored completely inactivated had 43× greater risk (relative risk, 42.8; 5.88 311). Branch-specific mutational signature analysis revealed apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced hypermutation branches toward Conclusion are out clones harbor TP53. evaluation status TKI-treated informative predicting

Language: Английский

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Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 2239 - 2254.e39

Published: April 1, 2021

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, drivers ITH across cancer types are poorly understood. To address this, we extensively characterize whole-genome sequences 2,658 samples spanning 38 types. Nearly all informative (95.1%) contain evidence distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection driver mutations most identify type-specific patterns gene mutations, fusions, structural variants, copy number alterations as well dynamic changes in mutational processes expansions. Our results underline importance its tumor evolution provide pan-cancer resource comprehensively annotated events from sequencing data.

Language: Английский

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Machine learning approaches to drug response prediction: challenges and recent progress

npj Precision Oncology, Journal Year: 2020, Volume and Issue: 4(1)

Published: June 15, 2020

Abstract Cancer is a leading cause of death worldwide. Identifying the best treatment using computational models to personalize drug response prediction holds great promise improve patient’s chances successful recovery. Unfortunately, task predicting very challenging, partially due limitations available data and algorithmic shortcomings. The recent advances in deep learning may open new chapter search for ultimately result more accurate tools therapy response. This review provides an overview challenges prediction, focuses on comparing machine techniques be utmost practical use clinicians non-experts. incorporation modalities such as single-cell profiling, along with that rapidly find effective combinations will likely instrumental improving cancer care.

Language: Английский

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Tumor evolution: Linear, branching, neutral or punctuated?

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2017, Volume and Issue: 1867(2), P. 151 - 161

Published: Jan. 19, 2017

Language: Английский

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