mutational hotspots
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2022 ◽  
Vol 13 (1) ◽  
Author(s):  
John K. L. Wong ◽  
Christian Aichmüller ◽  
Markus Schulze ◽  
Mario Hlevnjak ◽  
Shaymaa Elgaafary ◽  
...  

AbstractCancer driving mutations are difficult to identify especially in the non-coding part of the genome. Here, we present sigDriver, an algorithm dedicated to call driver mutations. Using 3813 whole-genome sequenced tumors from International Cancer Genome Consortium, The Cancer Genome Atlas Program, and a childhood pan-cancer cohort, we employ mutational signatures based on single-base substitution in the context of tri- and penta-nucleotide motifs for hotspot discovery. Knowledge-based annotations on mutational hotspots reveal enrichment in coding regions and regulatory elements for 6 mutational signatures, including APOBEC and somatic hypermutation signatures. APOBEC activity is associated with 32 hotspots of which 11 are known and 11 are putative regulatory drivers. Somatic single nucleotide variants clusters detected at hypermutation-associated hotspots are distinct from translocation or gene amplifications. Patients carrying APOBEC induced PIK3CA driver mutations show lower occurrence of signature SBS39. In summary, sigDriver uncovers mutational processes associated with known and putative tumor drivers and hotspots particularly in the non-coding regions of the genome.


BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Michael Wessolly ◽  
Susann Stephan-Falkenau ◽  
Anna Streubel ◽  
Marcel Wiesweg ◽  
Sabrina Borchert ◽  
...  

Abstract Background Immune checkpoint inhibitors (ICIs) are currently one of the most promising therapy options in the field of oncology. Although the first pivotal ICI trial results were published in 2011, few biomarkers exist to predict their therapy outcome. PD-L1 expression and tumor mutational burden (TMB) were proven to be sometimes-unreliable biomarkers. We have previously suggested the analysis of processing escapes, a qualitative measurement of epitope structure alterations under immune system pressure, to provide predictive information on ICI response. Here, we sought to further validate this approach and characterize interactions with different forms of immune pressure. Methods We identified a cohort consisting of 48 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab as ICI monotherapy. Tumor samples were subjected to targeted amplicon-based sequencing using a panel of 22 cancer-associated genes covering 98 mutational hotspots. Altered antigen processing was predicted by NetChop, and MHC binding verified by NetMHC. The NanoString nCounter® platform was utilized to provide gene expression data of 770 immune-related genes. Patient data from 408 patients with NSCLC were retrieved from The Cancer Genome Atlas (TCGA) as a validation cohort. Results The two immune escape mechanisms of PD-L1 expression (TPS score) (n = 18) and presence of altered antigen processing (n = 10) are mutually non-exclusive and can occur in the same patient (n = 6). Both mechanisms have exclusive influence on different genes and pathways, according to differential gene expression analysis and gene set enrichment analysis, respectively. Interestingly, gene expression patterns associated with altered processing were enriched in T cell and NK cell immune activity. Though both mechanisms influence different genes, they are similarly linked to increased immune activity. Conclusion Pressure from the immune system will lay the foundations for escape mechanisms, leading to acquisition of resistance under therapy. Both PD-L1 expression and altered antigen processing are induced similarly by pronounced immunoactivity but in different context. The present data help to deepen our understanding of the underlying mechanisms behind those immune escapes.


2022 ◽  
Vol 2 (1) ◽  
pp. 10-27
Author(s):  
Deepankar Chakroborty ◽  
Veera K. Ojala ◽  
Anna M. Knittle ◽  
Jasmin Drexler ◽  
Mahlet Z. Tamirat ◽  
...  

Despite the relatively high frequency of somatic ERBB4 mutations in various cancer types, only a few activating ERBB4 mutations have been characterized, primarily due to lack of mutational hotspots in the ERBB4 gene. Here, we utilized our previously published pipeline, an in vitro screen for activating mutations, to perform an unbiased functional screen to identify potential activating ERBB4 mutations from a randomly mutated ERBB4 expression library. Ten potentially activating ERBB4 mutations were identified and subjected to validation by functional and structural analyses. Two of the 10 ERBB4 mutants, E715K and R687K, demonstrated hyperactivity in all tested cell models and promoted cellular growth under two-dimensional and three-dimensional culture conditions. ERBB4 E715K also promoted tumor growth in in vivo Ba/F3 cell mouse allografts. Importantly, all tested ERBB4 mutants were sensitive to the pan-ERBB tyrosine kinase inhibitors afatinib, neratinib, and dacomitinib. Our data indicate that rare ERBB4 mutations are potential candidates for ERBB4-targeted therapy with pan-ERBB inhibitors. Statement of Significance: ERBB4 is a member of the ERBB family of oncogenes that is frequently mutated in different cancer types but the functional impact of its somatic mutations remains unknown. Here, we have analyzed the function of over 8,000 randomly mutated ERBB4 variants in an unbiased functional genetics screen. The data indicate the presence of rare activating ERBB4 mutations in cancer, with potential to be targeted with clinically approved pan-ERBB inhibitors.


2021 ◽  
Author(s):  
Siwei Chen ◽  
Yuan Liu ◽  
Yingying Zhang ◽  
Shayne D. Wierbowski ◽  
Steven M. Lipkin ◽  
...  

Rapid accumulation of cancer genomic data has led to the identification of an increasing number of mutational hotspots with uncharacterized significance. Here we present a biologically informed computational framework that characterizes the functional relevance of all 1107 published mutational hotspots identified in approximately 25,000 tumor samples across 41 cancer types in the context of a human 3D interactome network, in which the interface of each interaction is mapped at residue resolution. Hotspots reside in network hub proteins and are enriched on protein interaction interfaces, suggesting that alteration of specific protein–protein interactions is critical for the oncogenicity of many hotspot mutations. Our framework enables, for the first time, systematic identification of specific protein interactions affected by hotspot mutations at the full proteome scale. Furthermore, by constructing a hotspot-affected network that connects all hotspot-affected interactions throughout the whole-human interactome, we uncover genome-wide relationships among hotspots and implicate novel cancer proteins that do not harbor hotspot mutations themselves. Moreover, applying our network-based framework to specific cancer types identifies clinically significant hotspots that can be used for prognosis and therapy targets. Overall, we show that our framework bridges the gap between the statistical significance of mutational hotspots and their biological and clinical significance in human cancers.


2021 ◽  
Author(s):  
Yan-Xia Wu ◽  
Wen-Li Zhang ◽  
Tong-Min Wang ◽  
Ying Liao ◽  
Yi-Jun Zhang ◽  
...  

Epstein-Barr virus (EBV) infection is associated with multiple malignancies, including pulmonary lymphoepithelioma-like carcinoma (pLELC), a particular subtype of primary lung cancer. However, the genomic characteristics of EBV related to pLELC remain unclear. Here, we obtained the whole-genome dataset of EBV isolated from 78 pLELC patients and 37 healthy controls using EBV-captured sequencing. Compared to the reference genome (NC_007605), a total of 3995 variations were detected across pLELC-derived EBV sequences, with the mutational hotspots located in latent genes. Combined with 180 published EBV sequences derived from healthy people in Southern China, we performed a genome-wide association study and identified 32 variations significantly related to pLELC ( p < 2.56×10 −05 , Bonferroni correction), with the top signal of SNP coordinate T7327C (OR = 1.22, p = 2.39×10 −15 ) locating in the origin of plasmid replication (OriP). The results of population structure analysis of EBV isolates in East Asian showed the EBV strains derived from pLELC were more similar to those from nasopharyngeal carcinoma (NPC) than other EBV-associated diseases. In addition, typical latency type-II infection were recognized for EBV of pLELC at both transcription and methylation levels. Taken together, we defined the global view of EBV genomic profiles in pLELC patients for the first time, providing new insights to deepening our understanding of this rare EBV-associated primary lung carcinoma. Importance Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rarely distinctive subtype of primary lung cancer closely associated with Epstein-Barr virus (EBV) infection. Here, we gave the first overview of pLELC-derived EBV at the level of genome, methylation and transcription. We obtained the EBV sequences dataset from 78 primary pLELC patients, and revealed the sequences diversity across EBV genome and detected variability in known immune epitopes. Genome-wide association analysis combining 217 healthy controls identifies significant variations related to the risk of pLELC. Meanwhile, we characterized the integration landscapes of EBV at the genome-wide level. These results provided new insight for understanding EBV’s role in pLELC tumorigenesis.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shujie Dong ◽  
Zhiqi Ying ◽  
Shuisheng Yu ◽  
Qirui Wang ◽  
Guanghui Liao ◽  
...  

Abstract Background The Stephania tetrandra S. Moore (S. tetrandra) is a medicinal plant belonging to the family Menispermaceae that has high medicinal value and is well worth doing further exploration. The wild resources of S. tetrandra were widely distributed in tropical and subtropical regions of China, generating potential genetic diversity and unique population structures. The geographical origin of S. tetrandra is an important factor influencing its quality and price in the market. In addition, the species relationship within Stephania genus still remains uncertain due to high morphological similarity and low support values of molecular analysis approach. The complete chloroplast (cp) genome data has become a promising strategy to determine geographical origin and understand species evolution for closely related plant species. Herein, we sequenced the complete cp genome of S. tetrandra from Zhejiang Province and conducted a comparative analysis within Stephania plants to reveal the structural variations, informative markers and phylogenetic relationship of Stephania species. Results The cp genome of S. tetrandra voucher ZJ was 157,725 bp, consisting of a large single copy region (89,468 bp), a small single copy region (19,685 bp) and a pair of inverted repeat regions (24,286 bp each). A total of 134 genes were identified in the cp genome of S. tetrandra, including 87 protein-coding genes, 8 rRNA genes, 37 tRNA genes and 2 pseudogene copies (ycf1 and rps19). The gene order and GC content were highly consistent in the Stephania species according to the comparative analysis results, with the highest RSCU value in arginine (1.79) and lowest RSCU value in serine of S. tetrandra, respectively. A total of 90 SSRs have been identified in the cp genome of S. tetrandra, where repeats that consisting of A or T bases were much higher than that of G or C bases. In addition, 92 potential RNA editing sites were identified in 25 protein-coding genes, with the most predicted RNA editing sites in ndhB gene. The variations on length and expansion extent to the junction of ycf1 gene were observed between S. tetrandra vouchers from different regions, indicating potential markers for further geographical origin discrimination. Moreover, the values of transition to transversion ratio (Ts/Tv) in the Stephania species were significantly higher than 1 using Pericampylus glaucus as reference. Comparative analysis of the Stephania cp genomes revealed 5 highly variable regions, including 3 intergenic regions (trnH-psbA, trnD-trnY, trnP) and two protein coding genes (rps16 and ndhA). The identified mutational hotspots of Stephania plants exhibited multiple SNP sites and Gaps, as well as different Ka/Ks ratio values. In addition, five pairs of specific primers targeting the divergence regions were accordingly designed, which could be utilized as potential molecular markers for species identification, population genetic and phylogenetic analysis in Stephania species. Phylogenetic tree analysis based on the conserved chloroplast protein coding genes indicated a sister relationship between S. tetrandra and the monophyletic group of S. japonica and S. kwangsiensis with high support values, suggesting a close genetic relationship within Stephania plants. However, two S. tetrandra vouches from different regions failed to cluster into one clade, confirming the occurrences of genetic diversities and requiring further investigation for geographical tracing strategy. Conclusions Overall, we provided comprehensive and detailed information on the complete chloroplast genome and identified nucleotide diversity hotspots of Stephania species. The obtained genetic resource of S. tetrandra from Zhejiang Province would facilitate future studies in DNA barcode, species discrimination, the intraspecific and interspecific variability and the phylogenetic relationships of Stephania plants.


2021 ◽  
Author(s):  
han zheng ◽  
Chongbiao Huang

Abstract Purpose: With the increasing prevalence of pulmonary ground-glass nodules (GGNs) among younger population, its clinicopathologic performance, lung cancer-associated genetic mutation, and immune landscape features between pre-invasive adenocarcinoma and invasive adenocarcinoma (IAC) need to be get well known.Methods: We retrospectively reviewed basic clinical information, analyzed radiological characteristics, and then evaluated the status of mutational hotspots and tumor mutational burden by sequencing genome in tissue. Programmed death ligand 1 (PD-L1) expression was detected by immunohistochemistry staining. Results: Nodules vastly increased the probability of IAC when the diameter of GGNs was more than 1.15 mm or the consolidation-to-tumor ratio was at least 8.5%, with the latter predictor having a better diagnostic specificity. Tumors positive for exon 19 deletion and exon 21 L858R in EGFR mutation had a higher prevalence in IAC. However, there was no difference in PD-L1 expression. As expected, tumor mutational burden in IAC was higher, despite a low background mutational burden as a whole. Conclusions: GGNs should be pay high attention when several aggressive behaviors showed in radiology and inner solid components increased gradually, providing more evidence apt to a diagnosis of IAC. We found that GGNs of IAC performed early genomic alternations events during the slow growth carcinogenesis stage of GGNs, including the most common proto-oncogene EGFR activation, which mainly concentrates on IAC. Indolent GGNs at an early stage usually have negative PD-L1 expression.


2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yetian Dong ◽  
Tong Dai ◽  
Bin Wang ◽  
Lei Zhang ◽  
Ling-hui Zeng ◽  
...  

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). To halt the pandemic, multiple SARS-CoV-2 vaccines have been developed and several have been allowed for emergency use and rollout worldwide. With novel SARS-CoV-2 variants emerging and circulating widely, whether the original vaccines that were designed based on the wild-type SARS-CoV-2 were effective against these variants has been a contentious discussion. Moreover, some studies revealed the long-term changes of immune responses post SARS-CoV-2 infection or vaccination and the factors that might impact the vaccine-induced immunity. Thus, in this review, we have summarized the influence of mutational hotspots on the vaccine efficacy and characteristics of variants of interest and concern. We have also discussed the reasons that might result in discrepancies in the efficacy of different vaccines estimated in different trials. Furthermore, we provided an overview of the duration of immune responses after natural infection or vaccination and shed light on the factors that may affect the immunity induced by the vaccines, such as special disease conditions, sex, and pre-existing immunity, with the aim of aiding in combating COVID-19 and distributing SARS-CoV-2 vaccines under the prevalence of diverse SARS-CoV-2 variants.


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