Explore the vast range of titles available.

A high tumour mutational burden (hypermutation) is observed in some gliomas 1 – 5 ; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer. Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.

Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.

Olive (Olea europaea ssp. europaea) is the most important oil fruit crop in temperate areas, but the origin of the cultivated olive remains unclear. The existence of one or several domestication events in the Mediterranean Basin (MB) is still debated. We analyzed a dataset of 387 cultivated and wild accessions that were genotyped at 25 simple‐sequence repeat (SSR) loci. The sample represented genetic diversity at the geographic extremes of the MB. We inferred relationships among samples and also applied approximate Bayesian computation to estimate the most probable demographic model of our samples. Cultivated olives clustered into three different gene pools (Q1, Q2 and Q3), corresponding loosely to the west, central and eastern MB, respectively. Q1 consisted primarily of accessions from southern Spain, retained the fingerprint of a genetic bottleneck, and was closely related to accessions from the eastern MB. Q2 showed signs of recent admixture with wild olives and may derive from a local domestication event in the central MB. Overall our results suggest that admixture shaped olive germplasm and perhaps also local domestication events.

PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice. A more significant inhibition of tumor growth and a prolongation of survival were observed in the CT26 mouse model after treatment with a combination of PD-1 blockade and decitabine than in mice treated with decitabine or PD-1 blockade alone. The anti-tumor effect of the PD-1 blockade was enhanced by low-dose decitabine. The results of RNA sequencing and whole-genome bisulfite sequencing of decitabine-treated CT26 cells and tumor samples with microsatellite stability from the patient tumor-derived xenograft model have shown that many immune-related genes, including antigen-processing and antigen-presenting genes, were upregulated, whereas the promoter demethylation was downregulated after decitabine exposure. Therefore, decitabine-based tumor microenvironment re-modulation could improve the effect of the PD-1 blockade. The application of decitabine in PD-1 blockade-based immunotherapy may elicit more potent immune responses, which can provide clinical benefits to the colorectal cancer patients with low microsatellite instability or stable microsatellites.

Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch .

Programmed death-ligand 1 (PD-L1) is a key factor influencing cancer immunotherapy; however, the regulation of PD-L1 expression in cancer cells remains unclear, particularly regarding DNA damage, repair and its signalling. Herein, we demonstrate that oxidative DNA damage induced by exogenously applied hydrogen peroxide (H 2 O 2 ) upregulates PD-L1 expression in cancer cells. Further, depletion of the base excision repair (BER) enzyme DNA glycosylase augments PD-L1 upregulation in response to H 2 O 2 . PD-L1 upregulation in BER-depleted cells requires ATR/Chk1 kinase activities, demonstrating that PD-L1 upregulation is mediated by DNA damage signalling. Further analysis of The Cancer Genome Atlas revealed that the expression of PD-L1 is negatively correlated with that of the BER/single-strand break repair (SSBR) and tumours with low BER/SSBR gene expression show high microsatellite instability and neoantigen production. Hence, these results suggest that PD-L1 expression is regulated in cancer cells via the DNA damage signalling and neoantigen–interferon-γ pathway under oxidative stress. Highlights Exogenous oxidative DNA damage upregulates PD-L1 expression in cancer cells. BER deficiency augments PD-L1 upregulation following oxidative DNA damage. Tumour samples with BER/SSBR mutations show high microsatellite instability, neoantigen and PD-L1 expression. PD-L1 and BER/SSBR gene expressions are negatively correlated in clinical specimens.

Background A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. Data about the prevalence of high-level microsatellite instability in cholangiocarcinoma (CCA) has been conflicting. Methods We employed a cohort comprising 308 Western-world, non-liver fluke-associated CCAs (159 intrahepatic, 106 perihilar, and 43 distal). We analysed the mononucleotide microsatellite instability marker panel consisting of BAT25, BAT26, and CAT25 and detected MSI-H in 4/308 CCAs (1.3%). Results Patients affected by MSI-H CCA had mostly an atypical histomorphology ( p  = 0.004), showed a longer overall survival, although having a high tumour stage, and were of younger age. Correlation analysis of microsatellite instability status with tumour-infiltrating immune cells, MHC I, and PD-L1 expression in the same cholangiocarcinoma cohort showed higher numbers of CD8 + T cells, FOXP3 + regulatory T cells, CD20 + B cells and high or at least moderate MHC I expression levels in MSI-H CCAs. Conclusions Even though the overall number of MSI-H CCAs is low, the dismal prognosis of the disease and the therapeutic option of immune checkpoint blockade in the respective patients justify MSI testing of cholangiocarcinoma, particularly in younger patients showing an atypical histomorphology.

Abstract Background and Aims Spatial distribution of species genetic diversity is often driven by geographical distance (isolation by distance) or environmental conditions (isolation by environment), especially under climate change scenarios such as Quaternary glaciations. Here, we used coalescent analyses coupled with ecological niche modelling (ENM), spatially explicit quantile regression analyses and the multiple matrix regression with randomization (MMRR) approach to unravel the patterns of genetic differentiation in the widely distributed Neotropical savanna tree, Hancornia speciosa (Apocynaceae). Due to its high morphological differentiation, the species was originally classified into six botanical varieties by Monachino, and has recently been recognized as only two varieties by Flora do Brasil 2020. Thus, H. speciosa is a good biological model for learning about evolution of phenotypic plasticity under genetic and ecological effects, and predicting their responses to changing environmental conditions. Methods We sampled 28 populations (777 individuals) of Monachino’s four varieties of H. speciosa and used seven microsatellite loci to genotype them. Key Results Bayesian clustering showed five distinct genetic groups (K = 5) with high admixture among Monachino’s varieties, mainly among populations in the central area of the species geographical range. Genetic differentiation among Monachino’s varieties was lower than the genetic differentiation among populations within varieties, with higher within-population inbreeding. A high historical connectivity among populations of the central Cerrado shown by coalescent analyses may explain the high admixture among varieties. In addition, areas of higher climatic suitability also presented higher genetic diversity in such a way that the wide historical refugium across central Brazil might have promoted the long-term connectivity among populations. Yet, FST was significantly related to geographic distances, but not to environmental distances, and coalescent analyses and ENM predicted a demographical scenario of quasi-stability through time. Conclusions Our findings show that demographical history and isolation by distance, but not isolation by environment, drove genetic differentiation of populations. Finally, the genetic clusters do not support the two recently recognized botanical varieties of H. speciosa, but partially support Monachino’s classification at least for the four sampled varieties, similar to morphological variation.

Background The ubiquitous presence of short tandem repeats (STRs) in virtually all genomes implicates their functional relevance, while a widely-accepted definition of STR is yet to be established. Previous studies majorly focus on relatively longer STRs, while shorter repeats were generally excluded. Herein, we have adopted a more generous criteria to define shorter repeats, which has led to the definition of a much larger number of STRs that lack prior analysis. Using this definition, we analyzed the short repeats in 55 randomly selected segments in 55 randomly selected genomic sequences from a fairly wide range of species covering animals, plants, fungi, protozoa, bacteria, archaea and viruses. Results Our analysis reveals a high percentage of short repeats in all 55 randomly selected segments, indicating that the universal presence of high-content short repeats could be a common characteristic of genomes across all biological kingdoms. Therefore, it is reasonable to assume a mechanism for continuous production of repeats that can make the replicating process relatively semi-conservative. We have proposed a folded replication slippage model that considers the geometric space of nucleotides and hydrogen bond stability to explain the mechanism more explicitly, with improving the existing straight-line slippage model. The folded slippage model can explain the expansion and contraction of mono- to hexa- nucleotide repeats with proper folding angles. Analysis of external forces in the folding template strands also suggests that expansion exists more commonly than contraction in the short tandem repeats. Conclusion The folded replication slippage model provides a reasonable explanation for the continuous occurrences of simple sequence repeats in genomes. This model also contributes to the explanation of STR-to-genome evolution and is an alternative model that complements semi-conservative replication.

The mutation process ultimately defines the genetic features of all populations and, hence, has a bearing on a wide range of issues involving evolutionary genetics, inheritance, and genetic disorders, including the predisposition to cancer. Nevertheless, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. Here, we report on the use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae. Our results confirm some findings previously obtained by indirect methods but also yield numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion, a very high rate of segmental duplication and deletion in the nuclear genome, and substantial deviations in the mutational profile among various model organisms.