scholarly journals Universal patterns of selection in cancer and somatic tissues

2017 ◽  
Author(s):  
Iñigo Martincorena ◽  
Keiran M. Raine ◽  
Moritz Gerstung ◽  
Kevin J. Dawson ◽  
Kerstin Haase ◽  
...  
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Clonal Selection ◽  
Purifying Selection ◽  
Driver Mutations ◽  
Base Substitution ◽  
List Type ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Mutation Burden

ABSTRACTCancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection only detected for truncating mutations in essential genes in haploid regions. This allows exome-wide enumeration of all driver mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.HIGHLIGHTSUnlike the germline, somatic cells evolve predominantly by positive selectionNearly all (∼99%) coding mutations are tolerated and escape negative selectionFirst exome-wide estimates of the total number of driver coding mutations per tumor1-10 coding driver mutations per tumor; half occurring outside known cancer genes

scholarly journals DOP50 The landscape of somatic mutations in non-neoplastic IBD-affected colon

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S088-S089
Author(s):  
S Olafsson ◽  
R E McIntyre ◽  
T Coorens ◽  
T Butler ◽  
P Robinson ◽  
...  
Keyword(s):  
Positive Selection ◽  
Somatic Mutations ◽  
Intestinal Inflammation ◽  
Base Substitution ◽  
Interleukin 17 ◽  
Clonal Structure ◽  
Normal Colon ◽  
Colonic Crypts ◽  
Mutation Burden ◽  
Chronic Intestinal Inflammation

Abstract Background Under normal physiological conditions, colonic crypts accrue ~40 somatic mutations for every year of life. That somatic mutations contribute to the development of cancer is well established, but their patterns, burden and functional consequences in diseases other than cancer have not been extensively studied and our understanding of the effects of chronic inflammation on the mutational profile and clonal structure of the colon is limited. Here, we investigated how the recurrent cycles of inflammation, ulceration and regeneration seen in IBD impact the mutational and clonal structure of intestinal epithelia. Methods We isolated and whole-genome sequenced ~400 individual colonic crypts from 46 IBD patients and compared these to ~400 crypts from 41 non-IBD controls. We compared the mutation burden, mutational signature exposure, clonal structure and cancer driver mutation landscape in crypts from actively and previously inflamed regions with crypts dissected from controls. Results We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon (Figure 1), and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimetre-scale clonal expansions, even in the absence of mutations in KRAS, TP53 and APC (Figure 2). We discovered that mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients (Figure 3). With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. A previously published mouse model of ZC3H12A suggests that LoF mutations in this gene may facilitate healing of affected mucosa without promoting tumorigenesis. This could make the encoded protein an attractive drug target. The observed enrichment of mutations in PIGR and IL17 and TLR pathways suggests that somatic mutations may initiate, maintain or perpetuate IBD pathogenesis through disruption of microbe-epithelial homeostasis. Conclusion Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia. We identify the mutagens driving the increase in mutation burden and mutations which are under positive selection in the context of inflammation. Our results suggest that studying somatic mutations in the colon can reveal putative drug targets and pathogenic mechanisms for IBD.

scholarly journals Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

2020 ◽  
Author(s):  
László Bányai ◽  
Mária Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

AbstractA major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes that are positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. In the present work we have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations. Oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

scholarly journals Selective pressures on human cancer genes along the evolution of mammals

2018 ◽  
Author(s):  
Alberto Vicens ◽  
David Posada
Keyword(s):  
Positive Selection ◽  
Hereditary Cancer ◽  
Clonal Selection ◽  
Human Cancer ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Potential Association ◽  
Show Evidence ◽  
Mammalian Genomes ◽  
Evolution Of Mammals

AbstractCancer is a disease of the genome caused by somatic mutation and subsequent clonal selection. Several genes associated to cancer in humans, hereafter cancer genes, also show evidence of (germline) positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for statistically significant signatures of positive selection using dN/dS models in a list of 430 cancer genes. Among these, we identified 63 genes under putative positive selection in mammals, which are significantly enriched in processes like crosslinking DNA repair. We also found evidence of a higher incidence of positive selection in cancer genes bearing germline mutations, like BRCA2, where positively selected residues are physically linked with known pathogenic variants, suggesting a potential association between germline positive selection and risk of hereditary cancer. Overall, our results suggest that genes associated with hereditary cancer have less selective constraints than genes related to sporadic cancer. Also, that the adaptive evolution of human cancer genes in mammals has been most likely driven by adaptive changes in important traits not directly related to cancer.

Analysis of mutation detection of POLD1/pole in pan-cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3142-3142
Author(s):  
Gao Yang ◽  
Jian'An Huang ◽  
Yukun Zu ◽  
Yan Zhang ◽  
Pingping Dai ◽  
...  
Keyword(s):  
Driver Mutation ◽  
Driver Mutations ◽  
Base Substitution ◽  
Tumor Mutation Burden ◽  
Target Capture ◽  
Mutation Burden ◽  
Substitution Mutations ◽  
High Level ◽  
Pan Cancer ◽  
Generation Sequencing

3142 Background: Previous studies proved that mutation of POLD1 and POLE elevates base-substitution mutations and lead to the elevation of tumor mutation burden (TMB). Other signature needs to explore to identify driver mutations in these two genes. Methods: Using gene-panel target-capture next generation sequencing, we analyzed the TMB and POLD1/POLE mutation in 17383 tumor tissue or plasma ctDNA samples from different patients. Results: Tumor mutation burdens were calculated of all the 17383 samples. According to the present research and our panel, we use 10 and 100 Mut/Mb to define hypermutation and ultra-hypermutation. Samples with hypermutation possessed 18.8% (n = 3268) and ultra-hypermutation possessed 0.3% (n = 58). In unselected, hypermutation and ultra-hypermutation group, POLD1 or/and POLE mutations were identified in 3.5% (n = 625), 56.1% (n = 32) and 87.9%(n = 372) samples. There were 0.5% (n = 81), 17.0% (n = 73) and 87.7%(n = 51) identified more than one mutation. These results showed that POLD1 or/and POLE mutations were enriched in samples with high TMB. We screened every known POLE and POLD1 driver mutations. There were 22 ultra-hypermutation samples identified these mutations, including A456P(3), P286R(10), V411L(6), M444K(1), S459F(1) in POLE and R1016H(1) in POLD1. Interestingly, all of them were identified in microsatellite stable (MSS) samples, which suggest that driver mutation may enriched in MSS samples. These already known driver mutation was not detect in 24 high-level microsatellite instability (MSI-H) and ultra-hypermutation samples. We further analyzed 10 POLD1/POLE mutations in other 5 MSS and ultra-hypermutation samples. POLE L424V was a pathogenic germline mutation but not defined as a driver mutation clearly before. POLE P286C had not been biochemically characterized but had different residue with P286R in the same position. Others had not been biochemically characterized (R232H, A234T, V945M, S1064I, Y467H in POLD1, D462N and R749Q, E1956D in POLE). These mutations were potential driver mutations and further research need to be support. Conclusions: We found that not only POLD1 or/and POLE mutations were enriched in samples with high TMB, but also driver mutations were enriched in microsatellite stable tumors. Further researches need to continue to identify more driver mutations of POLD1 and POLE.

scholarly journals Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution

2019 ◽  
Author(s):  
Saioa López ◽  
Emilia Lim ◽  
Ariana Huebner ◽  
Michelle Dietzen ◽  
Thanos Mourikis ◽  
...  
Keyword(s):  
Negative Selection ◽  
Chromosome Complement ◽  
Essential Genes ◽  
Tumour Suppressor Genes ◽  
Whole Genome ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Strong Negative Selection

AbstractWhole genome doubling (WGD) is a prevalent macro-evolutionary event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and clinical prognostic relevance, the evolutionary selection pressures for WGD have not been investigated. Here, we explored whether WGD may act to mitigate the irreversible, inexorable ratchet-like, accumulation of deleterious mutations in essential genes. Utilizing 1050 tumor regions from 816 non-small cell lung cancers (NSCLC), we temporally dissect mutations to determine their temporal acquisition in relation to WGD. We find evidence for strong negative selection against homozygous loss of essential cancer genes prior to WGD. However, mutations in essential genes occurring after duplication were not subject to significant negative selection, consistent with WGD providing a buffering effect, decreasing the likelihood of homozygous loss. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify signals of positive selection in lung, breast, colorectal cancer and other cancer types, enabling the elucidation of novel tumour suppressor genes and a deeper characterization of known cancer genes.

scholarly journals Evolution of subgenomic RNA shapes dengue virus adaptation and epidemiological fitness

2018 ◽  
Author(s):  
Esteban Finol ◽  
Eng Eong Ooi
Keyword(s):  
Dengue Virus ◽  
Positive Selection ◽  
Protein Interactions ◽  
Untranslated Region ◽  
Sequence Divergence ◽  
Purifying Selection ◽  
Viral Fitness ◽  
List Type ◽  
Nucleotide Substitutions ◽  
Genetic Changes

AbstractGenetic changes in the dengue virus (DENV) genome affects viral fitness both clinically and epidemiologically. Even in the 3’ untranslated region (3’UTR), mutations could impact the formation of subgenomic flaviviral RNA (sfRNA) and the specificity of sfRNA in inhibiting host proteins necessary for successful viral replication. Indeed, we have recently shown that mutations in the 3’UTR of DENV2 affected its ability to inhibit TRIM25 E3 ligase activity to reduce interferon (IFN) expression, which potentially contributed to the emergence of a new viral clade during the 1994 dengue epidemic in Puerto Rico. However, whether differences in 3’UTRs shaped DENV evolution on a larger scale remains incompletely understood. Herein, we combined RNA phylogeny with phylogenetics to gain insights on sfRNA evolution. We found that sfRNA structures are under purifying selection and highly conserved despite sequence divergence. Interestingly, only the second flaviviral Nuclease-resistant RNA (fNR2) structure of DENV-2 has undergone strong positive selection. Epidemiological reports also suggest that nucleotide substitutions in fNR2 may drive DENV-2 epidemiological fitness, possibly through sfRNA-protein interactions. Collectively, our findings indicate that 3’UTRs are important determinants of DENV fitness in human-mosquito cycles.HighlightsDengue viruses (DENV) preserve RNA elements in their 3’ untranslated region (UTR).Site-specific quantification of natural selection revealed positive selection on DENV2 sfRNA.Flaviviral nuclease-resistant RNA (fNR) structures in DENV 3’UTRs contribute to DENV speciation.A highly evolving fNR structure appears to increase DENV-2 epidemiological fitness.

scholarly journals Interpreting dN/dS under different selective regimes in cancer evolution

2021 ◽  
Author(s):  
Andrés Pérez-Figueroa ◽  
David Posada
Keyword(s):  
Negative Selection ◽  
Mutation Detection ◽  
Cancer Genomics ◽  
Detection Threshold ◽  
Cancer Genes ◽  
Selection Coefficient ◽  
Cancer Evolution ◽  
Synonymous Mutations ◽  
Somatic Evolution ◽  
The Relationship

The standard relationship between the dN/dS statistic and the selection coefficient is contingent upon the computation of the rate of fixation of non-synonymous and synonymous mutations among divergent lineages (substitutions). In cancer genomics, however, dN/dS is typically calculated by including mutations that are still segregating in the cell population. The interpretation of dN/dS within sexual populations has been shown to be problematic. Here we used a simple model of somatic evolution to study the relationship between dN/dS and the selection coefficient in the presence of deleterious, neutral, and beneficial mutations in cancer. We found that dN/dS can be used to distinguish cancer genes under positive or negative selection, but it is not always informative about the magnitude of the selection coefficient. In particular, under the asexual scenario simulated, dN/dS is insensitive to negative selection strength. Furthermore, the relationship between dN/dS and the positive selection coefficient depends on the mutation detection threshold, and, in particular scenarios, it can become non-linear. Our results warn about the necessary caution when interpreting the results drawn from dN/dS estimates in cancer.

scholarly journals Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
László Bányai ◽  
Maria Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

A major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. We have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations, oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

scholarly journals Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

2015 ◽  
Vol 7 (283) ◽  
pp. 283ra54-283ra54 ◽  
Author(s):  
Nicholas McGranahan ◽  
Francesco Favero ◽  
Elza C. de Bruin ◽  
Nicolai Juul Birkbak ◽  
Zoltan Szallasi ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Cells ◽  
Mitogen Activated Protein Kinase ◽  
Driver Mutations ◽  
Intratumor Heterogeneity ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Signaling Axis ◽  
Mutational Processes

Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.

scholarly journals Somatically Mutated Genes Under Positive and Negative Selection Found by Transcriptome Sequence Analysis Include Oncogene and Tumor Suppressor Candidates

2018 ◽  
Author(s):  
Casey W. Drubin ◽  
Avinash Ramu ◽  
Nicole B. Rockweiler ◽  
Donald F. Conrad
Keyword(s):  
Somatic Mutation ◽  
Negative Selection ◽  
Somatic Mutations ◽  
Clonal Selection ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Genome Wide ◽  
Mutation Burden

AbstractIntroductionOncogenic somatic mutations confer proliferative advantage and undergo positive clonal selection. We developed software and applied new analytical approaches to identify: (1) somatic mutations in diverse tissues, (2) somatically mutated genes under positive and negative selection, (3) post-transcriptional modifications in the mitochondrial transcriptome, and (4) inherited germline alleles predisposing people to higher somatic mutation burden or higher levels of post-transcriptional modification.MethodsTranscriptome sequence data (Genotype Tissue Expression project) for 7051 tissue samples from 549 postmortem donors and representing 44 tissue types were used. Germline mutations were inferred from whole-exome DNA sequencing and SNP arrays. DNA somatic mutations were inferred from variant allele frequencies (VAF) in RNA-seq data. Post-transcriptional modifications were inferred from Polymorphism Information Content (PIC) at the p9 sites of mitochondrial tRNA sequences. Positive and negative clonal selection was evaluated using a nonsynonomous/synonomous mutation rate (dN/dS) model. Genome-wide association studies (GWAS) were assessed with mitochondrial PIC for post-transcriptional modification level, or using the total number of somatic mutations observed per donor for somatic mutation burden.ResultsOur dN/dS model identified 78 genes under negative selection for somatic mutations (dN/dS < 1, padj< 0.05) and 14 under positive selection (dN/dS > 1, padj<0.05). Our GWAS identified 2 sites associated with post-transcriptional modification (1 approaching significance with p=5.99×10−8, 1 with p<5×10−8) and ∼20 sites associated with somatic mutation burden (p<5×10−8).ConclusionsTo our knowledge these are the first genome-wide association studies on normal somatic mutation burden. These studies were an attempt to increase understanding of the somatic mutation process. Our work identified somatic mutations at the global organismal level that may promote cell proliferation in a tissue-specific manner. By identifying tissue-specific mutations in actively expressed genes that appear before cancer phenotype is detected, this work also identifies gene candidates that might initiate tumorigenesis.

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