Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours

AbstractAbout half of all cancers have somatic integrations of retrotransposons. To characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 37 histological cancer subtypes. We identified 19,166 somatically acquired retrotransposition events, affecting 35% of samples, and spanning a range of event types. L1 insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, sometimes removing tumour suppressor genes, as well as inducing complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications in the development of human tumours.

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Cancer metabolic subtypes and their association with molecular and clinical features

10.1101/2021.12.16.472974 ◽

2021 ◽

Author(s):

Enrico Moiso ◽

Paolo Provero

Keyword(s):

Clinical Data ◽

Large Scale ◽

Tumor Grade ◽

Point Of View ◽

General Point ◽

Protein Abundance ◽

Phenotypic Data ◽

Cancer Subtypes ◽

Molecular Features

Alteration of metabolic pathways in cancer has been investigated for many years, beginning way before the discovery of the role of oncogenes and tumor suppressors, and the last few years have witnessed a renewed interest in this topic. Large-scale molecular and clinical data on tens of thousands of samples allow us today to tackle the problem from a general point of view. Here we show that trancriptomic profiles of tumors can be exploited to define metabolic cancer subtypes, that can be systematically investigated for association with other molecular and clinical data. We find thousands of significant associations between metabolic subtypes and molecular features such as somatic mutations, structural variants, epigenetic modifications, protein abundance and activation; and with clinical/phenotypic data including survival probability, tumor grade, and histological types. Our work provides a methodological framework and a rich database of statistical associations, accessible from https://metaminer.unito.it, that will contribute to the understanding of the role of metabolic alterations in cancer and to the development of precision therapeutic strategies.

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Military profile rises but coup is unlikely in Brazil

Emerald Expert Briefings ◽

10.1108/oxan-db235754 ◽

2018 ◽

Keyword(s):

Large Scale ◽

Armed Forces ◽

Military Coup ◽

Content Type ◽

Political Role ◽

Military Members ◽

Senior Officers ◽

High Level ◽

The Military

Subject The political role of the armed forces. Significance The armed forces have recently assumed an unusually high political profile. The current government has appointed generals to high-level positions and ordered a large-scale intervention led by the army in Rio de Janeiro state security institutions. These measures, many of them unprecedented, are an attempt by President Michel Temer to boost his popularity as a ‘tough-on-crime’ leader. The armed forces are one of the few public institutions enjoying high levels of trust among Brazilians. Impacts Despite recent protest calls for a military coup, support for such a move is restricted to a radical minority. Resistance against further reliance on the military for domestic law enforcement will rise, including among senior officers. Bolsonaro will focus his message on crime, promising to bring more military members into his cabinet, including the Education Ministry.

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DriverPower: Combined burden and functional impact tests for cancer driver discovery

10.1101/215244 ◽

2017 ◽

Cited By ~ 4

Author(s):

Shimin Shuai ◽

Steven Gallinger ◽

Lincoln Stein ◽

Keyword(s):

Driver Mutations ◽

Functional Interpretation ◽

Functional Impact ◽

Genomic Features ◽

Cancer Driver ◽

Mutational Burden ◽

Mutation Model ◽

Whole Genomes ◽

Cancer Genomes ◽

Pan Cancer

AbstractWe describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify cancer driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1,373 genomic features derived from public sources, DriverPower’s background mutation model explains up to 93% of the regional variance in the mutation rate across a variety of tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2,583 cancer genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Group, DriverPower has the highest F1-score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.

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An Integrated Pan-Cancer Analysis and Structure-Based Virtual Screening of GPR15

International Journal of Molecular Sciences ◽

10.3390/ijms20246226 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6226 ◽

Cited By ~ 2

Author(s):

Yanjing Wang ◽

Xiangeng Wang ◽

Yi Xiong ◽

Cheng-Dong Li ◽

Qin Xu ◽

...

Keyword(s):

Virtual Screening ◽

G Protein ◽

Large Scale ◽

3D Structure ◽

Rectal Adenocarcinoma ◽

Squamous Carcinoma ◽

The Cancer Genome Atlas ◽

G Protein Coupled ◽

Pan Cancer

G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan G protein-coupled receptors (GPCRs) involving human immunodeficiency virus (HIV) infection, colonic inflammation, and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability to inhibit cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) than in normal tissues. Among 33 cancer types, GPR15 expression was significantly positively correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), and lung adenocarcinoma (LUAD) and significantly negatively correlated with stomach adenocarcinoma (STAD). This study also revealed that commonly upregulated gene sets in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD, and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted structure-based virtual screening. The top eight hit compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provides novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.

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Pan-cancer analysis of whole genomes

10.1101/162784 ◽

2017 ◽

Cited By ~ 75

Author(s):

Peter J Campbell ◽

Gaddy Getz ◽

Joshua M Stuart ◽

Jan O Korbel ◽

Lincoln D Stein

Keyword(s):

Structural Variation ◽

Integrative Analysis ◽

Background Information ◽

Cancer Driver ◽

Normal Tissues ◽

Whole Genomes ◽

Cancer Genomes ◽

Pan Cancer ◽

Events Study

We report the integrative analysis of more than 2,600 whole cancer genomes and their matching normal tissues across 39 distinct tumour types. By studying whole genomes we have been able to catalogue non-coding cancer driver events, study patterns of structural variation, infer tumour evolution, probe the interactions among variants in the germline genome, the tumour genome and the transcriptome, and derive an understanding of how coding and non-coding variations together contribute to driving individual patient's tumours. This work represents the most comprehensive look at cancer whole genomes to date. NOTE TO READERS: This is an incomplete draft of the marker paper for the Pan-Cancer Analysis of Whole Genomes Project, and is intended to provide the background information for a series of in-depth papers that will be posted to BioRixv during the summer of 2017.

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Looking Backward to Move Forward

Personality and Social Psychology Bulletin ◽

10.1177/0146167216689064 ◽

2017 ◽

Vol 43 (4) ◽

pp. 555-569 ◽

Cited By ~ 13

Author(s):

Boaz Hameiri ◽

Arie Nadler

Keyword(s):

Large Scale ◽

Field Experiments ◽

Emotional Needs ◽

Palestinian Authority ◽

Mediating Role ◽

Right Of Return ◽

Group Members ◽

The Right ◽

High Level

Two large-scale surveys conducted in Israel (Study 1A) and the Palestinian Authority (Study 1B) show that the belief by group members that people in the “enemy” group acknowledge their victimhood (i.e., Holocaust and Nakba for Jews and Palestinians, respectively) is associated with Israeli-Jews’ readiness to accept responsibility for Palestinian sufferings and offer apologies. For Palestinians, this belief is linked to a perceived higher likelihood of a reconciled future with Israelis. Three field experiments demonstrate that a manipulated high level of acknowledgment of Jewish victimhood by Palestinians (Studies 2 and 4) and of Palestinian victimhood by Israeli-Jews (Study 3) caused greater readiness to make concessions for the sake of peace on divisive issues (e.g., Jerusalem, the 1967 borders, the right of return) and increased conciliatory attitudes. Additional analyses indicate the mediating role of increased trust and reduced emotional needs in these relationships.

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Parallelized Latent Dirichlet Allocation Provides a Novel Interpretability of Mutation Signatures in Cancer Genomes

Genes ◽

10.3390/genes11101127 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1127

Author(s):

Taro Matsutani ◽

Michiaki Hamada

Keyword(s):

Latent Dirichlet Allocation ◽

Extended Model ◽

Tumor Type ◽

Whole Genomes ◽

Cancer Genomes ◽

The One ◽

Tumor Types ◽

Apobec Family ◽

Pan Cancer ◽

Dirichlet Allocation

Mutation signatures are defined as the distribution of specific mutations such as activity of AID/APOBEC family proteins. Previous studies have reported numerous signatures, using matrix factorization methods for mutation catalogs. Different mutation signatures are active in different tumor types; hence, signature activity varies greatly among tumor types and becomes sparse. Because of this, many previous methods require dividing mutation catalogs for each tumor type. Here, we propose parallelized latent Dirichlet allocation (PLDA), a novel Bayesian model to simultaneously predict mutation signatures with all mutation catalogs. PLDA is an extended model of latent Dirichlet allocation (LDA), which is one of the methods used for signature prediction. It has parallelized hyperparameters of Dirichlet distributions for LDA, and they represent the sparsity of signature activities for each tumor type, thus facilitating simultaneous analyses. First, we conducted a simulation experiment to compare PLDA with previous methods (including SigProfiler and SignatureAnalyzer) using artificial data and confirmed that PLDA could predict signature structures as accurately as previous methods without searching for the optimal hyperparameters. Next, we applied PLDA to PCAWG (Pan-Cancer Analysis of Whole Genomes) mutation catalogs and obtained a signature set different from the one predicted by SigProfiler. Further, we have shown that the mutation spectrum represented by the predicted signature with PLDA provides a novel interpretability through post-analyses.

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Framework for quality assessment of whole genome cancer sequences

Nature Communications ◽

10.1038/s41467-020-18688-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Justin P. Whalley ◽

Ivo Buchhalter ◽

Esther Rheinbay ◽

Keiran M. Raine ◽

Miranda D. Stobbe ◽

...

Keyword(s):

Molecular Mechanisms ◽

Quality Measures ◽

Poor Quality ◽

Rating System ◽

Test Case ◽

Whole Genome ◽

Whole Genomes ◽

Cancer Genomes ◽

Pan Cancer

Abstract Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2.

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Biallelic mutations in cancer genomes reveal local mutational determinants

10.1101/2021.03.29.437407 ◽

2021 ◽

Author(s):

Jonas Demeulemeester ◽

Stefan C Dentro ◽

Moritz Gerstung ◽

Peter Van Loo

Keyword(s):

Binding Sites ◽

Variant Calling ◽

Mutation Rates ◽

Uv Damage ◽

Sequencing Data ◽

Whole Genomes ◽

Cancer Genomes ◽

Infinite Sites Model ◽

Biallelic Mutations ◽

Pan Cancer

The infinite sites model of molecular evolution requires that every position in the genome is mutated at most once. It is a cornerstone of tumour phylogenetic analysis, and is often implied when calling, phasing and interpreting variants or studying the mutational landscape as a whole. Here we identify 20,555 biallelic mutations, where the same base is mutated independently on both parental copies, in 722 (26.0%) bulk sequencing samples from the Pan-Cancer Analysis of Whole Genomes study (PCAWG). Biallelic mutations reveal UV damage hotspots at ETS and NFAT binding sites, and hypermutable motifs in POLE-mutant and other cancers. We formulate recommendations for variant calling and provide frameworks to model and detect biallelic mutations. These results highlight the need for accurate models of mutation rates and tumour evolution, as well as their inference from sequencing data.

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Large-Scale Organization of the Hand Action Observation Network in Individuals Born Without Hands

Cerebral Cortex ◽

10.1093/cercor/bhy212 ◽

2018 ◽

Vol 29 (8) ◽

pp. 3434-3444 ◽

Cited By ~ 10

Author(s):

Gilles Vannuscorps ◽

Moritz F Wurm ◽

Ella Striem-Amit ◽

Alfonso Caramazza

Keyword(s):

Large Scale ◽

Action Observation ◽

Spatial Arrangement ◽

Upper Limbs ◽

Body Movements ◽

Action Observation Network ◽

Observation Network ◽

Pattern Similarity ◽

High Level

Abstract The human high-level visual cortex comprises regions specialized for the processing of distinct types of stimuli, such as objects, animals, and human actions. How does this specialization emerge? Here, we investigated the role of effector-specific visuomotor coupling experience in shaping the organization of the action observation network (AON) as a window on this question. Observed body movements are frequently coupled with corresponding motor codes, e.g., during monitoring one’s own movements and imitation, resulting in bidirectionally connected circuits between areas involved in body movements observation (e.g., of the hand) and the motor codes involved in their execution. If the organization of the AON is shaped by this effector-specific visuomotor coupling, then, it should not form for body movements that do not belong to individuals’ motor repertoire. To test this prediction, we used fMRI to investigate the spatial arrangement and functional properties of the hand and foot action observation circuits in individuals born without upper limbs. Multivoxel pattern decoding, pattern similarity, and univariate analyses revealed an intact hand AON in the individuals born without upper limbs. This suggests that the organization of the AON does not require effector-specific visuomotor coupling.

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