The Immune Landscape of Cancer

Immunity, Journal Year: 2018, Volume and Issue: 48(4), P. 812 - 830.e14

Published: April 1, 2018

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled TCGA. Across types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized differences in macrophage or signatures, Th1:Th2 cell ratio, extent intratumoral heterogeneity, aneuploidy, neoantigen load, overall proliferation, expression immunomodulatory genes, prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, IDH1) higher (BRAF, TP53, CASP8) leukocyte levels across all cancers. Multiple control modalities the intracellular extracellular networks (transcription, microRNAs, copy number, epigenetic processes) were involved tumor-immune interactions, both within subtypes. Our immunogenomics pipeline to characterize these heterogeneous resulting are intended serve as a resource for future targeted studies further advance field.

Language: Английский

---

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Cell, Journal Year: 2018, Volume and Issue: 173(2), P. 321 - 337.e10

Published: April 1, 2018

Highlights•Alteration map of 10 signaling pathways across 9,125 samples from 33 cancer types•Reusable, curated pathway templates that include a catalogue driver genes•57% tumors have at least one potentially actionable alteration in these pathways•Co-occurrence alterations suggests combination therapy opportunitiesSummaryGenetic control cell-cycle progression, apoptosis, and cell growth are common hallmarks cancer, but the extent, mechanisms, co-occurrence differ between individual tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions DNA methylation profiled by The Cancer Genome Atlas (TCGA), we analyzed mechanisms patterns somatic ten canonical pathways: cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 β-catenin/Wnt. We charted detailed landscape types, stratified into 64 subtypes, identified mutual exclusivity. Eighty-nine percent had pathways, 57% targetable currently available drugs. Thirty multiple alterations, indicating opportunities for therapy.Graphical abstract

Language: Английский

---

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

Cell, Journal Year: 2018, Volume and Issue: 173(2), P. 291 - 304.e6

Published: April 1, 2018

We conducted comprehensive integrative molecular analyses of the complete set tumors in The Cancer Genome Atlas (TCGA), consisting approximately 10,000 specimens and representing 33 types cancer. performed clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, miRNA expression levels reverse-phase protein arrays, which all, except for revealed primarily organized by histology, tissue type, or anatomic origin. influence cell type was evident DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative further emphasized dominant role cell-of-origin patterns. Molecular similarities among histologically anatomically related cancer provide a basis focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, pan-squamous cancers, those stemness features, turn may inform strategies future therapeutic development.

Language: Английский

---

State-of-the-art strategies for targeting the DNA damage response in cancer

Nature Reviews Clinical Oncology, Journal Year: 2018, Volume and Issue: 16(2), P. 81 - 104

Published: Oct. 24, 2018

Language: Английский

---

Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines

Cell Systems, Journal Year: 2018, Volume and Issue: 6(3), P. 271 - 281.e7

Published: March 1, 2018

The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling Multiple Cancers project, our effort to generate a comprehensive encyclopedia somatic mutation calls for TCGA enable robust cross-tumor-type analyses. Our approach accounts variance and batch effects introduced by rapid advancement DNA extraction, hybridization-capture, sequencing, analysis methods time. We present best practices applying an ensemble seven mutation-calling algorithms with scoring artifact filtering. created this 3.5 million variants forms basis PanCan papers. results have been made available research community along used them. This project is result collaboration from number institutes demonstrates how team science drives extremely large projects.

Language: Английский

---

Inflammatory microenvironment remodelling by tumour cells after radiotherapy

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(4), P. 203 - 217

Published: March 11, 2020

Language: Английский

---

RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

Science, Journal Year: 2019, Volume and Issue: 364(6444)

Published: June 6, 2019

How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 tissues revealed multiple variants, demonstrating that macroscopic clones can be found many tissues. We sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests environmental factors promote mosaicism. Mutation was associated with both age tissue-specific cell proliferation rate, highlighting over time number divisions. Finally, were to harbor known cancer genes hotspots. This study provides broad view clonal expansion human thus serving as foundation for associating factors, aging, risk disease.

Language: Английский

---

Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

European Urology, Journal Year: 2019, Volume and Issue: 76(4), P. 469 - 478

Published: July 22, 2019

Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility. To elucidate PC PSMA and associate this with defective DNA damage repair (DDR). Membranous (mPSMA) was scored immunohistochemically from metastatic castration-resistant (mCRPC) matching, same-patient, diagnostic biopsies, correlated next-generation sequencing (NGS) clinical outcome data. Expression of mPSMA quantitated by modified H-score. Patient tested NGS. Gene activity scores were determined mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival estimated Kaplan-Meier test, sample heterogeneity quantified Shannon's diversity index. at diagnosis associated higher Gleason grade (p = 0.04) worse overall 0.006). Overall, levels increased (median H-score [interquartile range]: castration-sensitive [CSPC] 17.5 [0.0–60.0] vs 55.0 [2.8–117.5]). Surprisingly, 42% (n 16) CSPC 27% tissues sampled had no detectable (H-score <10). Marked intratumour expression, foci containing PSMA, observed in all expressing (100%) 37 (84%) biopsies. Heterogeneous intrapatient between metastases also observed, the lowest liver metastases. Tumours DDR 0.016; 87.5 [25.0–247.5] 20 [0.3–98.8]; difference medians 60 [5.0–95.0]); validation cohort studies confirmed patients deleterious aberrations BRCA2 < 0.001; median H-score: 300 [165–300]; 195.0 [100.0–270.0]) ATM 0.005; 212.5 [136.3–300]; 140.0 [55.0–200]) than molecularly unselected biopsies (55.0 [2.75–117.5]). Validation using transcriptomes corroborated these findings, indicating that SOX2 high tumours have low expression. is upregulated some but not PCs, demonstrating marked inter- heterogeneity. are merit further evaluation as predictive biomarkers response for PSMA-targeted therapies larger, prospective cohorts. Through analysis samples, we report presence prostate-specific (PSMA) extremely variable both within one patient different patients. This may limit usefulness scans therapies. We show first time cancers produce more so respond better to PSMA-targeting treatments.

Language: Английский

---

Tumour lineage shapes BRCA-mediated phenotypes

Nature, Journal Year: 2019, Volume and Issue: 571(7766), P. 576 - 579

Published: July 1, 2019

Language: Английский

---

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

Cell, Journal Year: 2018, Volume and Issue: 173(2), P. 305 - 320.e10

Published: April 1, 2018

Highlights•An overview of PanCancer Atlas analyses on oncogenic molecular processes•Germline genome affects somatic genomic landscape in a pathway-dependent fashion•Genome mutations impact expression, signaling, and multi-omic profiles•Mutation burdens drivers influence immune-cell composition microenvironmentSummaryThe Cancer Genome (TCGA) has catalyzed systematic characterization diverse alterations underlying human cancers. At this historic junction marking the completion over 11,000 tumors from 33 cancer types, we present our current understanding processes governing oncogenesis. We illustrate insights into through synthesis findings TCGA project three facets oncogenesis: (1) driver mutations, germline pathogenic variants, their interactions tumor; (2) tumor epigenome transcriptome proteome; (3) relationship between microenvironment, including implications for drugs targeting events immunotherapies. These results will anchor future rare common primary relapsed tumors, cancers across ancestry groups guide deployment clinical sequencing.Graphical abstract

Language: Английский

---