Explore the vast range of titles available.

Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis. The genomes of cancer cells contain mutations that are not present in normal cells. Some of these prevent cells from repairing their DNA, while others give rise to tumours by causing cells to multiply uncontrollably. Moreover, some of the mutations in breast cancer cells occur in clusters—a phenomenon known as kataegis (from the Greek for ‘thunderstorm’). Kataegic mutations occur almost exclusively at a cytosine preceded by a thymine. This suggests that a family of proteins called AID/APOBEC enzymes—which remove amine groups from cytosines—may be involved in generating these mutations. In this study, Taylor et al. confirm this possibility by showing that expressing individual members of the AID/APOBEC family of enzymes in yeast cells increases the mutation frequency and induces kataegis. The kataegis triggered by the AID/APOBEC enzymes could be localised through the introduction of double-stranded breaks into the DNA: Taylor et al. suggest that this might happen because repairing the breaks exposes single-stranded DNA, which the AID/APOBEC enzymes then act upon. By comparing the mutations induced in the yeast cells with those observed in breast cancer cells, Taylor et al. identified APOBEC3B as the enzyme most likely to be responsible for kataegis in breast cancer (with APOBEC3A also a strong candidate in some cancers). Moreover, they showed that APOBEC3B was highly expressed in breast cancer cell lines, and that APOBEC3B and APOBEC3A can also cause DNA damage in human cells. Taken together, the findings provide key insights into the mechanism by which kataegis arises, and identify two proteins likely to contribute to the mutations seen in breast cancer. Further work is now required to determine whether these enzymes also give rise to mutations in other forms of cancer.

BackgroundOvarian clear cell carcinoma (OCCC) arises from endometriosis and represents a difficult-to-treat gynaecological malignancy, in part, because its spatial intratumour heterogeneity and temporal evolutionary trajectories have not been explicitly defined.MethodsWe performed whole-genome sequencing on six pathologically confirmed patients with OCCC. An R package named KataegisPortal was developed to identify and annotate loci of localised hypermutations. Immunohistochemical staining was conducted on a tissue microarray containing 143 OCCC specimens.ResultsMultiregion analysis demonstrated considerable degrees of subclonal diversification, ascribable to dynamic mutagenic processes, as well as macroevolutionary events including the acquisition of aneuploidy and chromoplexy. KataegisPortal unveiled APOBEC-mediated kataegis in the early phases of OCCC pathogenesis. We further showed evidence that APOBEC3A and APOBEC3B were frequently expressed in OCCC and possibly regulated by the MAPK pathway. Notably, APOBEC3B-expressing OCCC displayed favourable prognosis and appreciable immunogenicity manifested by marked cytotoxic T-cell infiltration.ConclusionsThese results point to an appealing model of punctuated tumour evolution underlying OCCC neoplastic transformation and progression, which may pose formidable challenges of early detection and intervention, and indicate the intratumour heterogeneity of cancer-driving alterations, yielding important implications for molecular diagnosis and targeted treatment of this lethal disease.

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

BackgroundSkin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles and thus, patient outcome, in skin melanoma.MethodsWe explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC.ResultsMetastatic skin melanomas had significantly higher CYT levels compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C > T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring chromothriptic events, contained a higher number of cancer genes. SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display a clinical benefit upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients.ConclusionsOverall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which might affect the patients' relapse rate or their acquisition of resistance to immune checkpoint inhibition therapies.

Background The classical genetic model of colorectal cancer presents APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of genomic alterations, such as genomic rearrangements, are still unclear. Results Here, we perform comprehensive bioinformatic analysis to dissect the relative timing of somatic genetic alterations in 63 colorectal cancers with whole-genome sequencing data. Utilizing allele fractions of somatic single nucleotide variants as molecular clocks while accounting for the presence of copy number changes and structural alterations, we identify key events in the evolution of colorectal tumors. We find that driver point mutations, gene fusions, and arm-level copy losses typically arise early in tumorigenesis; different mechanisms act on distinct genomic regions to drive DNA copy changes; and chromothripsis—clustered rearrangements previously thought to occur as a single catastrophic event—is frequent and may occur multiple times independently in the same tumor through different mechanisms. Furthermore, our computational approach reveals that, in contrast to recent studies, selection is often present on subclones and that multiple evolutionary models can operate in a single tumor at different stages. Conclusion Combining these results, we present a refined tumor progression model which significantly expands our understanding of the tumorigenic process of human colorectal cancer.

We carried out an integrated analysis based on multiple-dimensional types of data from cohorts of bladder cancer patients to identify multi-omics perspective (genomics and transcriptomics) on the tumor microenvironment on the bases of the programmed cell death 1 ligand (PD-L1) and CD8 T-cell infiltration in urothelial carcinoma. Multiple-dimensional types of data, including clinical, genomic and transcriptomic data of 408 bladder cancer patients were retrieved from the Cancer Genome Atlas database. Based on the median values of and , the tumor samples were grouped into four tumor microenvironment immune types (TMIT). The RNA sequencing profiles, somatic mutation and amplification data of bladder cancer were analyzed by different TMITs. Our research demonstrated that 36.8% of the evaluated bladder cancer belonged to TMIT I (high /high ). TIMT subtypes were not significantly associated with overall survival or disease free survival in urothelial cancer. TMIT I facilitates CD8+ T-cell infiltration and activates T-effector and interferon gamma ( ) associated gene signature. The number of somatic mutations, cytolytic activity, mRNA expression and mRNA expression in TMIT I was remarkably higher than those in other TMIT groups. Our results showed a high rate of C>T transversion and a high rate of transition/transversion (Ti/Tv) in TMIT I bladder tumors. The mutation was significantly associated with TMIT I bladder cancer and be significantly co-occurring with the mutation. However, mutation and mutation were mutually exclusive in TMIT II bladder tumors. More importantly, different amino acid changes by mutations were also found between TMIT I and TMIT II bladder cancer, such as amino acid changes in \"Immunoglobulin I-set domain (260-356)\"and \"Protein tyrosine kinase (472-748)\". We also detected 9 genes as significantly cancer-associated genes in TMIT I bladder cancer, of which, has been reported to play an important role in DNA damage responses. Further analysis concentrated on the potential molecular mechanism found that TMIT I was significantly associated with anti-tumor immune-related signaling pathway, and was present on chromosome 21 in TMIT I bladder tumors. The classification of bladder cancer into four TMITs on the bases of the expression and the CD8+ CTLs statuses is an appropriate approach for bladder tumor immunotherapy. TMIT I (high /high ) is significantly correlated with more somatic mutation burden, and facilitates CD8+ T-cell infiltration and activates T-effector and associated gene signature. Alteration landscape for somatic variants was different between TMIT I and TMIT II (low /low ).

Background Genomic localized hypermutation regions were found in cancers, which were reported to be related to the prognosis of cancers. This genomic localized hypermutation is quite different from the usual somatic mutations in the frequency of occurrence and genomic density. It is like a mutations “violent storm”, which is just what the Greek word “kataegis” means. Results There are needs for a light-weighted and simple-to-use toolkit to identify and visualize the localized hypermutation regions in genome. Thus we developed the R package “kataegis” to meet these needs. The package used only three steps to identify the genomic hypermutation regions, i.e., i) read in the variation files in standard formats; ii) calculate the inter-mutational distances; iii) identify the hypermutation regions with appropriate parameters, and finally one step to visualize the nucleotide contents and spectra of both the foci and flanking regions, and the genomic landscape of these regions. Conclusions The kataegis package is available on Bionconductor/Github ( https://github.com/flosalbizziae/kataegis ), which provides a light-weighted and simple-to-use toolkit for quickly identifying and visualizing the genomic hypermuation regions.

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.

Clusters of localized hypermutation in human breast cancer genomes, named “kataegis” (from the Greek for thunderstorm), are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins. However, a direct link between APOBECs and kataegis is still lacking. We have sequenced the genomes of yeast mutants induced in diploids by expression of the gene for PmCDA1, a hypermutagenic deaminase from sea lamprey. Analysis of the distribution of 5,138 induced mutations revealed localized clusters very similar to those found in tumors. Our data provide evidence that unleashed cytosine deaminase activity is an evolutionary conserved, prominent source of genome-wide kataegis events. Reviewers This article was reviewed by: Professor Sandor Pongor, Professor Shamil R. Sunyaev, and Dr Vladimir Kuznetsov.

Background Cancer genomes harbor hundreds to thousands of somatic nonsynonymous mutations. DNA damage and deficiency of DNA repair systems are two major forces to cause somatic mutations, marking cancer genomes with specific somatic mutation patterns. Recently, several pan-cancer genome studies revealed more than 20 mutation signatures across multiple cancer types. However, detailed cancer-type specific mutation signatures and their different features within (intra-) and between (inter-) cancer types remain largely unexplored. Methods We employed a matrix decomposition algorithm, namely Non-negative Matrix Factorization, to survey the somatic mutations in nine major human cancers, involving a total of ~2100 genomes. Results Our results revealed 3-5 independent mutational signatures in each cancer, implying that a range of 3-5 predominant mutational processes likely underlie each cancer genome. Both mutagen exposure (tobacco and sun) and changes in DNA repair systems (APOBEC family, POLE , and MLH1 ) were found as mutagenesis forces, each of which marks the genome with an evident mutational signature. We studied the features of several signatures and their combinatory patterns within and across cancers. On one hand, we found each signature may influence a cancer genome with different influential magnitudes even in the same cancer type and the signature-specific load reflects intra-cancer heterogeneity (e.g., the smoking-related signature in lung cancer smokers and never smokers). On the other hand, inter-cancer heterogeneity is characterized by combinatory patterns of mutational signatures, where no cancers share the same signature profile, even between two lung cancer subtypes (lung adenocarcinoma and squamous cell lung cancer). Conclusions Our work provides a detailed overview of the mutational characteristics in each of nine major cancers and highlights that the mutational signature profile is representative of each cancer.