scholarly journals Comprehensive patient-level classification and quantification of driver events in TCGA PanCanAtlas cohorts

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1009996
Author(s):  
Alexey D. Vyatkin ◽  
Danila V. Otnyukov ◽  
Sergey V. Leonov ◽  
Aleksey V. Belikov
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Single Nucleotide ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Patient Level ◽  
Tumour Suppressors ◽  
Chromosome Arm ◽  
Cancer Mutations ◽  
Cancer Types

There is a growing need to develop novel therapeutics for targeted treatment of cancer. The prerequisite to success is the knowledge about which types of molecular alterations are predominantly driving tumorigenesis. To shed light onto this subject, we have utilized the largest database of human cancer mutations–TCGA PanCanAtlas, multiple established algorithms for cancer driver prediction (2020plus, CHASMplus, CompositeDriver, dNdScv, DriverNet, HotMAPS, OncodriveCLUSTL, OncodriveFML) and developed four novel computational pipelines: SNADRIF (Single Nucleotide Alteration DRIver Finder), GECNAV (Gene Expression-based Copy Number Alteration Validator), ANDRIF (ANeuploidy DRIver Finder) and PALDRIC (PAtient-Level DRIver Classifier). A unified workflow integrating all these pipelines, algorithms and datasets at cohort and patient levels was created. We have found that there are on average 12 driver events per tumour, of which 0.6 are single nucleotide alterations (SNAs) in oncogenes, 1.5 are amplifications of oncogenes, 1.2 are SNAs in tumour suppressors, 2.1 are deletions of tumour suppressors, 1.5 are driver chromosome losses, 1 is a driver chromosome gain, 2 are driver chromosome arm losses, and 1.5 are driver chromosome arm gains. The average number of driver events per tumour increases with age (from 7 to 15) and cancer stage (from 10 to 15) and varies strongly between cancer types (from 1 to 24). Patients with 1 and 7 driver events per tumour are the most frequent, and there are very few patients with more than 40 events. In tumours having only one driver event, this event is most often an SNA in an oncogene. However, with increasing number of driver events per tumour, the contribution of SNAs decreases, whereas the contribution of copy-number alterations and aneuploidy events increases.

scholarly journals Comprehensive patient-level classification and quantification of driver events in TCGA PanCanAtlas cohorts

2021 ◽  
Author(s):  
Alexey D. Vyatkin ◽  
Danila V. Otnyukov ◽  
Sergey V. Leonov ◽  
Aleksey V. Belikov
Keyword(s):  
Human Cancer ◽  
Point Mutations ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Patient Level ◽  
Tumour Suppressors ◽  
Chromosome Arm ◽  
Cancer Mutations ◽  
Cancer Types ◽  
And Gender

AbstractBackgroundThere is a growing need to develop novel therapeutics for targeted treatment of cancer. The prerequisite to success is the knowledge about which types of molecular alterations are predominantly driving tumorigenesis – single nucleotide (SNA) or copy number (CNA), in oncogenes or in tumour suppressors, gains or losses of full chromosomes or chromosomal arms (aneuploidy). However, the number and proportion of various types of driver events per tumour is still not clear, neither for cancer in general, nor for individual cancer types, stages and patient demographics (age and gender).MethodsTo shed light onto this subject, we have utilized the largest database of human cancer mutations – TCGA PanCanAtlas, multiple established algorithms for cancer driver prediction (2020plus, CHASMplus, CompositeDriver, dNdScv, DriverNet, HotMAPS, IntOGen Plus, OncodriveCLUSTL, OncodriveFML) and developed four novel computational pipelines: SNADRIF (SNA DRIver Finder), GECNAV (Gene Expression-based CNA Validator), ANDRIF (ANeuploidy DRIver Finder) and PALDRIC (PAtient-Level DRIver Classifier). A unified workflow integrating all these pipelines, algorithms and datasets at cohort and patient levels was created.ResultsBy integrating results of various driver prediction algorithms, we have found that there are on average 20 driver events per tumour, of which 1.5 are hyperactivating SNAs in oncogenes, 10.5 are amplifications of oncogenes, 2 are homozygous inactivating SNAs or deletions of tumour suppressors, 1.5 are driver chromosome losses, 2 are driver chromosome gains, 1 is a driver chromosome arm loss, and 1.5 are driver chromosome arm gains. The average number of driver events per tumour varies strongly between cancer types, from 1.7 in thyroid carcinoma to 42.4 in ovarian carcinoma. In females, the number of driver events increases most dramatically until the age of menopause (50 y.o.), whereas in males until 70 y.o. Moreover, in females, the number of driver events increases abruptly from Stage I to Stage II, after which stays more or less constant, and this increase is due to CNAs and aneuploidy but not due to SNAs. In tumours having only one driver event, this event is a SNA in an oncogene. However, with increasing number of driver events per tumour, the contribution of SNAs and tumour suppressor events decreases, whereas the contribution of oncogene amplifications and aneuploidy events increases. Patients with two driver events per tumour are the most frequent, and there are very few patients with more than 50 events.ConclusionsAs half of all driver events in a patient’s tumour appear to be amplifications of oncogenes, we suggest that future therapeutics development efforts should be focused on targeting this alteration type. Therapies aimed at gains and losses of chromosomal arms and whole chromosomes also appear very promising. On the other hand, drugs aiming at point mutations and tumour suppressors are predicted to be less successful. Overall, our results provide valuable insights into the extent of driver alterations of different types in human tumours and suggest optimal targets for candidate therapeutics.

scholarly journals Systematic identification of mutations and copy number alterations associated with cancer patient prognosis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Joan C Smith ◽  
Jason M Sheltzer
Keyword(s):  
Copy Number ◽  
Meta Analysis ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Driver Genes ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Patient Prognosis ◽  
Almost All ◽  
Systematic Identification

Successful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed the genomic profiles of 17,879 tumors from patients with known outcomes. We find that mutations in almost all cancer driver genes contain remarkably little information on patient prognosis. However, CNAs in these same driver genes harbor significant prognostic power. Focal CNAs are associated with worse outcomes than broad alterations, and CNAs in many driver genes remain prognostic when controlling for stage, grade, TP53 status, and total aneuploidy. By performing a meta-analysis across independent patient cohorts, we identify robust prognostic biomarkers in specific cancer types, and we demonstrate that a subset of these alterations also confer specific therapeutic vulnerabilities. In total, our analysis establishes a comprehensive resource for cancer biomarker identification and underscores the importance of gene copy number profiling in assessing clinical risk.

Abstract 5759: The landscape of copy-number changes across multiple human cancer types

2010 ◽  
Author(s):  
Rameen Beroukhim ◽  
Matthew Meyerson ◽  
Levi Garraway ◽  
John Prensner
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Cancer Types ◽  
Copy Number Changes

scholarly journals Identification of rare germline copy number variations over-represented in five human cancer types

2015 ◽  
Vol 14 (1) ◽  
Author(s):  
Richard W Park ◽  
Tae-Min Kim ◽  
Simon Kasif ◽  
Peter J Park
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Copy Number Variations ◽  
Cancer Types

scholarly journals Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

2018 ◽  
Author(s):  
Bin Zhang ◽  
Kamesh R. Babu ◽  
Chun You Lim ◽  
Zhi Hao Kwok ◽  
Jia Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Cancer ◽  
Mrna Splicing ◽  
Regulatory Mechanisms ◽  
Translation Machinery ◽  
The Core ◽  
Cancer Types

AbstractRNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis. Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.

scholarly journals Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Gaojianyong Wang ◽  
Dimitris Anastassiou
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Copy Number Alterations ◽  
Multiple Cancer ◽  
Cancer Driver ◽  
Large Gene ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Pan Cancer

Abstract Analysis of large gene expression datasets from biopsies of cancer patients can identify co-expression signatures representing particular biomolecular events in cancer. Some of these signatures involve genomically co-localized genes resulting from the presence of copy number alterations (CNAs), for which analysis of the expression of the underlying genes provides valuable information about their combined role as oncogenes or tumor suppressor genes. Here we focus on the discovery and interpretation of such signatures that are present in multiple cancer types due to driver amplifications and deletions in particular regions of the genome after doing a comprehensive analysis combining both gene expression and CNA data from The Cancer Genome Atlas.

scholarly journals Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

2018 ◽  
Author(s):  
Isidro Cortés-Ciriano ◽  
June-Koo Lee ◽  
Ruibin Xi ◽  
Dhawal Jain ◽  
Youngsook L. Jung ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
End Joining ◽  
Cancer Types ◽  
Non Homologous End Joining

SummaryChromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.

scholarly journals Comprehensive characterization and clinical relevance of the SWI/SNF copy number aberrations across human cancers

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zhiwei Xing ◽  
Buhuan Ma ◽  
Weiting Sun ◽  
Yimin Sun ◽  
Caixia Liu
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Therapy Resistance ◽  
The Cancer Genome Atlas ◽  
Dna Damage And Repair ◽  
Human Cancers ◽  
Oncogenic Pathways ◽  
Cancer Types ◽  
Tcga Dataset ◽  
The Impact

Abstract Background Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types. Methods We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers. Results CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types. Conclusion The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.

TCGA PanCanAtlas Data Analysis Suggests Multiple Possibilities for Personalized Cancer Therapy

2021 ◽  
Vol 7 (1) ◽  
pp. 11
Author(s):  
Aleksey V. Belikov ◽  
Alexey D. Vyatkin ◽  
Danila V. Otnykov ◽  
Sergey V. Leonov
Keyword(s):  
Targeted Therapy ◽  
Tumor Suppressors ◽  
Human Cancer ◽  
Point Mutations ◽  
Driver Mutations ◽  
Primary Tumors ◽  
Cancer Driver ◽  
Significant Difference ◽  
Chromosome Arm ◽  
Personalized Cancer

Personalized cancer medicine holds promise for the future of cancer treatment. One of the keys to success is the knowledge of exact molecular alterations that drive tumorigenesis in a given patient, so that a suitable targeted therapy can be selected. However, the extent of such alterations, i.e., number of various kinds of driver mutations per patient, is still not known. We have utilized the largest database of human cancer mutations—TCGA PanCanAtlas, multiple popular algorithms for cancer driver prediction and several custom scripts to estimate the number of various kinds of driver mutations in primary tumors. We have found that there are on average 12 driver mutations per patient’s tumor, of which 0.6 are hyperactivating point mutations in oncogenes, 1.5 are amplifications of oncogenes, 0.1 have both in the same oncogene, 1.2 are inactivating point mutations in tumor suppressors, 2.1 are deletions in tumor suppressors, 0.3 have both in the same tumor suppressor, 1.5 are driver chromosome losses, 1 is driver chromosome gain, 2 are driver chromosome arm losses, and 1.5 are driver chromosome arm gains. The number of driver mutations per tumor gradually increased with age, from 6.7 for < 25 y.o. to 14.9 for > 85 y.o., and cancer stage, from 10.0 to 15.2. There was no significant difference between genders (12.0 in males vs. 11.9 in females). The number of driver mutations per tumor varied strongly between cancer types, from 1.2 in thyroid carcinoma to 23.8 in bladder carcinoma. Overall, our results provide valuable insights into the extent of driver alterations in tumors and suggest that multiple possibilities to choose a suitable targeted therapy exist in each patient.

scholarly journals The genomic landscape of carcinomas with mucinous differentiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bastien Nguyen ◽  
Francisco Sanchez-Vega ◽  
Christopher J. Fong ◽  
Walid K. Chatila ◽  
Amir Momeni Boroujeni ◽  
...  
Keyword(s):  
Stomach Cancer ◽  
Copy Number ◽  
Biologically Relevant ◽  
Molecular Alterations ◽  
Genomic Landscape ◽  
Tumor Mutational Burden ◽  
Cancer Types ◽  
Pathology Reports ◽  
Dna Copy Number Alterations ◽  
Oncogenic Gene

AbstractMucinous carcinomas can arise in any organ with epithelial cells that produce mucus. While mucinous tumors from different organs are histologically similar, it remains to be elucidated whether they share molecular alterations. Here we analyzed a total of 902 patients across six cancer types by comparing mucinous and non-mucinous samples, integrating text mining of pathology reports, gene expression, methylation, mutational and copy-number profiling. We found that, in addition to genes involved in mucin processing and secretion, MUC2 up-regulation is a multi-cancer biomarker of mucinous histology and is regulated by DNA methylation in colorectal, breast and stomach cancer. The majority of carcinomas with mucinous differentiation had fewer DNA copy-number alterations than non-mucinous tumors. The tumor mutational burden was lower in breast and lung with mucinous differentiation compared to their non-mucinous counterparts. We found several differences in the frequency of oncogenic gene and pathway alterations between mucinous and non-mucinous carcinomas, including a lower frequency of p53 pathway alterations in colorectal and lung cancer, and a lower frequency of PI-3-Kinase/Akt pathway alterations in breast and stomach cancer with mucinous differentiation. This study shows that carcinomas with mucinous differentiation originating from different organs share transcriptomic and genomic similarities. These results might pave the way for a more biologically relevant taxonomy for these rare cancers.

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