Cross-species identification of cancer-resistance associated genes uncovers their relevance to human cancer risk

Cancer is an evolutionarily conserved disease that occurs in a wide variety of species. We applied a comparative genomics approach to systematically characterize the genes whose conservation levels significantly correlates positively (PC) or negatively (NC) with a broad spectrum of cancer-resistance estimates, computed across almost 200 vertebrate species. PC genes are enriched in pathways relevant to tumor suppression including cell cycle, DNA repair, and immune response, while NC genes are enriched with a host of metabolic pathways. The conservation levels of the PC and NC genes in a species serve to build the first genomics-based predictor of its cancer resistance score. We find that PC genes are less tolerant to loss of function (LoF) mutations, are enriched in cancer driver genes and are associated with germline mutations that increase human cancer risk. Furthermore, their expression levels are associated with lifetime cancer risk across human tissues. Finally, their knockout in mice results in increased cancer incidence. In sum, we find that many genes associated with cancer resistance across species are implicated in human cancers, pointing to several additional candidate genes that may have a functional role in human cancer.

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OncodriveROLE classifies cancer driver genes in loss of function and activating mode of action

Bioinformatics ◽

10.1093/bioinformatics/btu467 ◽

2014 ◽

Vol 30 (17) ◽

pp. i549-i555 ◽

Cited By ~ 38

Author(s):

Michael P. Schroeder ◽

Carlota Rubio-Perez ◽

David Tamborero ◽

Abel Gonzalez-Perez ◽

Nuria Lopez-Bigas

Keyword(s):

Mode Of Action ◽

Loss Of Function ◽

Driver Genes ◽

Cancer Driver ◽

Cancer Driver Genes

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Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

10.1101/2020.08.18.256362 ◽

2020 ◽

Author(s):

Alexander N. Gorelick ◽

Minsoo Kim ◽

Walid K. Chatila ◽

Konnor La ◽

A. Ari Hakimi ◽

...

Keyword(s):

Mitochondrial Genome ◽

Atp Synthesis ◽

Loss Of Function ◽

Sequencing Data ◽

Mtdna Mutation ◽

Driver Genes ◽

Cancer Driver ◽

Translational Machinery ◽

Synonymous Mutations ◽

Mtdna Mutations

AbstractMitochondrial DNA (mtDNA) encodes essential protein subunits and translational machinery for four distinct complexes of oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, we demonstrate that pathogenic mtDNA mutations arise in tumors at a rate comparable to the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumor lineages. Loss-of-function mutations accumulate at an elevated rate specifically in Complex I, and often arise at specific homopolymeric hotspots. In contrast, Complex V is depleted of all non-synonymous mutations, suggesting that mutations directly impacting ATP synthesis are under negative selection. Both common truncating mutations and rarer missense alleles are associated with a pan-lineage transcriptional program, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal adenocarcinoma patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with significant implications for patient stratification, prognosis and therapeutic development.

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Targeting STAT3 and STAT5 in Cancer

Cancers ◽

10.3390/cancers12082002 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2002 ◽

Cited By ~ 1

Author(s):

Elvin D. de Araujo ◽

György M. Keserű ◽

Patrick T. Gunning ◽

Richard Moriggl

Keyword(s):

Cancer Biology ◽

Human Cancer ◽

Cancer Genome ◽

Driver Genes ◽

Cancer Driver ◽

Mutational Landscape ◽

Coding Regions ◽

Cancer Driver Genes

Insights into the mutational landscape of the human cancer genome coding regions defined about 140 distinct cancer driver genes in 2013, which approximately doubled to 300 in 2018 following advances in systems cancer biology studies [...]

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Peto's paradox and human cancers

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0104 ◽

2015 ◽

Vol 370 (1673) ◽

pp. 20150104 ◽

Cited By ~ 40

Author(s):

Robert Noble ◽

Oliver Kaltz ◽

Michael E. Hochberg

Keyword(s):

Stem Cell ◽

Natural Selection ◽

Cancer Risk ◽

Cancer Incidence ◽

Human Cancer ◽

Independent Effect ◽

Anatomical Site ◽

Lifetime Cancer Risk ◽

Cell Divisions ◽

Stem Cell Divisions

Peto's paradox is the lack of the expected trend in cancer incidence as a function of body size and lifespan across species. The leading hypothesis to explain this pattern is natural selection for differential cancer prevention in larger, longer lived species. We evaluate whether a similar effect exists within species, specifically humans. We begin by reanalysing a recently published dataset to separate the effects of stem cell number and replication rate, and show that each has an independent effect on cancer risk. When considering the lifetime number of stem cell divisions in an extended dataset, and removing cases associated with other diseases or carcinogens, we find that lifetime cancer risk per tissue saturates at approximately 0.3–1.3% for the types considered. We further demonstrate that grouping by anatomical site explains most of the remaining variation. Our results indicate that cancer risk depends not only on the number of stem cell divisions but varies enormously (approx. 10 000 times) depending on anatomical site. We conclude that variation in risk of human cancer types is analogous to the paradoxical lack of variation in cancer incidence among animal species and may likewise be understood as a result of evolution by natural selection.

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Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer

10.1101/354324 ◽

2018 ◽

Author(s):

Giorgio Mattiuz ◽

Salvatore Di Giorgio ◽

Lorenzo Tofani ◽

Antonio Frandi ◽

Francesco Donati ◽

...

Keyword(s):

Cancer Progression ◽

Somatic Mutations ◽

Driver Mutations ◽

Cancer Evolution ◽

Loss Of Function ◽

Driver Genes ◽

Cancer Driver ◽

Cancer Genomes ◽

Passenger Mutations ◽

Mutational Processes

AbstractAlterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.

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Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity

10.1101/818922 ◽

2019 ◽

Author(s):

Kuoyuan Cheng ◽

Nishanth Ulhas Nair ◽

Joo Sang Lee ◽

Eytan Ruppin

Keyword(s):

Tumor Suppressor ◽

Cancer Risk ◽

Tissue Specificity ◽

Synthetic Lethality ◽

Driver Genes ◽

Lifetime Cancer Risk ◽

Normal Tissues ◽

Gene Pairs ◽

Stem Cell Divisions

AbstractVarious characteristics of cancers exhibit tissue-specificity, including lifetime cancer risk, onset age and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels occurring in them. Here we study the role of another potentially important factor, synthetic lethality, in cancer risk. Analyzing transcriptomics data in the GTEx compendium we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs in normal tissues and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. We also show that the tissue-specificity of numerous tumor suppressor genes is strongly associated with the expression of their cSL partner genes in the corresponding normal tissues. Overall, our findings uncover the role of synthetic lethality as a novel important factor involved in tumorigenesis.

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Convergent mutations in tissue-specific regulatory regions reveal novel cancer drivers

10.1101/2020.08.21.239954 ◽

2020 ◽

Author(s):

Nasa Sinnott-Armstrong ◽

Jose A. Seoane ◽

Richard Sallari ◽

Jonathan K. Pritchard ◽

Christina Curtis ◽

...

Keyword(s):

Human Cancer ◽

Cell Type ◽

Multiple Cancer ◽

Driver Genes ◽

Regulatory Regions ◽

Tissue Specific ◽

Cancer Driver ◽

Regulatory Mutations ◽

Cancer Types ◽

Promoter Mutations

AbstractAlthough much effort has been devoted to identifying coding mutations across cancer types, regulatory mutations remain poorly characterized. Here, we describe a framework to identify non-coding drivers by aggregating mutations in cell-type specific regulatory regions for each gene. Application of this approach to 2,634 patients across 11 human cancer types identified 60 pan-cancer, 22 pan-breast and 192 cancer specific candidate driver genes that were enriched for expression changes. Analysis of high-throughput CRISPR knockout screens revealed large, cancer specific growth effects for these genes, on par with coding mutations and exceeding that for promoter mutations. Amongst the five candidate drivers selected for further analysis, four (IPO9, MED8, PLEKHA6, and OXNAD1) were associated with survival across multiple cancer types. These studies demonstrate the power of our cell-type aware, convergent regulatory framework to define novel tissue specific cancer driver genes, considerably expanding evidence of functional non-coding mutations in cancer.

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Technical advance in targeted NGS analysis enables identification of lung cancer risk-associated low frequency TP53, PIK3CA, and BRAF mutations in airway epithelial cells

BMC Cancer ◽

10.1186/s12885-019-6313-x ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Daniel J. Craig ◽

Thomas Morrison ◽

Sadik A. Khuder ◽

Erin L. Crawford ◽

Leihong Wu ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Lung Cancer Risk ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Braf Mutations ◽

Driver Genes ◽

Internal Standards ◽

Cancer Driver ◽

Synthetic Dna

Abstract Background Standardized Nucleic Acid Quantification for SEQuencing (SNAQ-SEQ) is a novel method that utilizes synthetic DNA internal standards spiked into each sample prior to next generation sequencing (NGS) library preparation. This method was applied to analysis of normal appearing airway epithelial cells (AEC) obtained by bronchoscopy in an effort to define a somatic mutation field effect associated with lung cancer risk. There is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effective screening by annual low dose CT. The purpose of this study was to test the hypothesis that lung cancer risk is characterized by increased prevalence of low variant allele frequency (VAF) somatic mutations in lung cancer driver genes in AEC. Methods Synthetic DNA internal standards (IS) were prepared for 11 lung cancer driver genes and mixed with each AEC genomic (g) DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach identified nucleotide-specific sequencing error and enabled reliable detection of specimen mutations with VAF as low as 5 × 10− 4 (0.05%). This method was applied in a retrospective case-control study of AEC specimens collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested. Results TP53 mutations with 0.05–1.0% VAF were more prevalent (p < 0.05) and also enriched for tobacco smoke and age-associated mutation signatures in normal AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls. Conclusions Application of SNAQ-SEQ to measure mutations in the 0.05–1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes.

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The Genomic Landscape of Serrated Lesion of the Colorectum: Similarities and Differences With Tubular and Tubulovillous Adenomas

Frontiers in Oncology ◽

10.3389/fonc.2021.668466 ◽

2021 ◽

Vol 11 ◽

Author(s):

Luigi Tornillo ◽

Frank Serge Lehmann ◽

Andrea Garofoli ◽

Viola Paradiso ◽

Charlotte K. Y. Ng ◽

...

Keyword(s):

Somatic Mutations ◽

Bioinformatic Analysis ◽

Genetic Alterations ◽

University Hospital ◽

Library Preparation ◽

Loss Of Function ◽

Driver Genes ◽

Cancer Driver ◽

Genomic Landscape ◽

Serrated Lesions

Serrated lesions of the colorectum are the precursors of 15–30% of colorectal cancers (CRCs). These lesions have a peculiar morphological appearance, and they are more difficult to detect than conventional adenomatous polyps. In this study, we sought to define the genomic landscape of these lesions using high-depth targeted sequencing. Eight sessile serrated lesions without dysplasia (SSL), three sessile serrated lesions with dysplasia (SSL/D), two traditional serrated adenomas (TSA), and three tubular adenomas (TA) were retrieved from the files of the Institute of Pathology of the University Hospital Basel and from the GILAB AG, Allschwil, Switzerland. Samples were microdissected together with the matched normal counterpart, and DNA was extracted for library preparation. Library preparation was performed using the Oncomine Comprehensive Assay targeting 161 common cancer driver genes. Somatic genetic alterations were defined using state-of-the-art bioinformatic analysis. Most SSLs, as well as all SSL/Ds and TSAs, showed the classical BRAF p.V600E mutation. The BRAF-mutant TSAs showed additional alterations in CTNNB1, NF1, TP53, NRAS, PIK3CA, while TA showed a consistently different profile, with mutations in ARID1A (two cases), SMAD4, CDK12, ERBB3, and KRAS. In conclusion, our results provide evidence that SSL/D and TSA are similar in somatic mutations with the BRAF hotspot somatic mutation as a major driver of the disease. On the other hand, TAs show a different constellation of somatic mutations such as ARID1A loss of function.

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