Instability Phenotype Research Articles

Identification of Molecular Subtypes and Prognostic Traits Based on Chromosomal Instability Phenotype-Related Genes in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) exhibits significant molecular heterogeneity; however, previous studies have not fully explored its classification into distinct molecular subtypes. Here, we identified LUAD-significant chromosomal instability (CIN) phenotype genes (n = 24) using a TCGA-LUAD cohort (n = 592) and evaluated their ability to predict pathologic grade. Unsupervised clustering and principal component analysis revealed that LUAD patients could be classified into CIN phenotype-related subtypes (GroupLow, GroupModerate, and GroupHigh), each exhibiting distinct transcriptomic patterns. Notably, the GroupHigh showed significantly poor overall survival [OS; hazard ratio (HR) = 1.43, p-value < 10-3] and disease-free survival (DFS; HR = 1.27, p-value < 10-3). Univariate and multivariate analysis confirmed that its expression status was an independent prognostic predictor (p-value < 10-3, HR = 2.18, 95% C.I = 1.26-3.76) of the clinical outcomes, outperforming pathologic grade (p-value < 10-3, HR = 1.2, 95% C.I = 1.08-1.33). Moreover, analysis of surfactant metabolism-related genes revealed higher expression in the GroupLow, which was associated with a favorable prognosis. By integrating multiple independent cohorts (n = 779), we validated these findings and confirmed that CIN phenotype gene status serves as a critical prognostic marker in LUAD. Furthermore, genomic profiling showed that the GroupHigh exhibited frequent mutations in key genes such as KEAP1, LYST, SETD2, and TP53, with oncogenes in this group preferentially showing copy number gains. Our study highlights the significance of CIN phenotype gene status as a predictor of LUAD prognosis and its association with transcriptomic and genomic alterations, paving the way for further clinical validation and potential therapeutic interventions.

Mini-Review: Tregs as a Tool for Therapy—Obvious and Non-Obvious Challenges and Solutions

Tregs have the potential to be utilized as a novel therapeutic agent for the treatment of various chronic diseases, including diabetes, Alzheimer’s disease, asthma, and rheumatoid arthritis. One of the challenges associated with developing a therapeutic product based on Tregs is the non-selectivity of polyclonal cells. A potential solution to this issue is a generation of antigen-specific CAR-Tregs. Other challenges associated with developing a therapeutic product based on Tregs include the phenotypic instability of these cells in an inflammatory microenvironment, discrepancies between engineered Treg-like cells and natural Tregs, and the expression of dysfunctional isoforms of Treg marker genes. This review presents a summary of proposed strategies for addressing these challenges.

Genome-Wide Association Studies for Key Agronomic and Quality Traits in Potato (Solanum tuberosum L.)

Deciphering the genetic mechanisms underlying key agronomic and quality traits in potato (Solanum tuberosum L.) is essential for advancing varietal improvement. Phenotypic instability in early clonal generations and inbreeding depression, coupled with the complexity of tetrasomic inheritance, pose significant challenges in constructing mapping populations for the genetic dissection of complex traits. Genome-wide association studies (GWASs) offer an efficient method to establish trait–genome associations by analyzing genetic recombination and mutation events in natural populations. This review systematically examines the application of GWASs in identifying agronomic traits in potato, such as plant architecture, yield components, tuber shape, and resistance to early and late blight and nematodes, as well as quality traits including dry matter, starch, and glycoalkaloid content. Some key chromosomal hotspots identified through GWASs include chromosome 5 associated with tuber yield, starch content, and late blight resistance; chromosome 4 and 10 associations with tuber shape and starch content; chromosomes 1, 9, and 11 associated with plant height, tuber number, glycoalkaloid content, and pest resistance. It elucidates the advantages and limitations of GWASs for genetic loci identification in this autotetraploid crop, providing theoretical insights and a reference framework for the precise localization of key genetic loci and the discovery of underlying genes using GWASs.

Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer

BackgroundThis study aimed to reveal the effect of TP53 status on clinical outcomes and underlying mechanism in gastric cancer (GC) patients.MethodsTP53 status was divided into three groups according to genome sequencing, namely clonal mutations with LOH (C-LOH), clonal diploid or subclonal mutations (CD-SC), and wild type (WT). The p53 protein activity was divided into over-expression (OE), Null and WT according to immunohistochemical staining. Four cohorts, including the TCGA, SMC, ZSHS and FUSCC cohort, were analyzed for association between TP53 mutation status and clinical outcomes and the underlying mechanism.ResultsIn TCGA cohort, TP53 CD-SC were associated with superior overall survival compared to TP53 C-LOH cases. GC patients could benefit from ACT only in TP53 CD-SC/ p53 OE and TP53/ p53 WT subgroups, and TP53 C-LOH subgroup demonstrated the worst response to pembrolizumab among three subgroups. Genomic and immunophenotypic deconvolution revealed that TP53 C-LOH, CD-SC and WT differed for genomic and immune-related features.ConclusionsTP53 C-LOH GCs with genomic instability and immune evasion phenotype have poor clinical outcomes in patients treated with ACT or immunotherapy.

Clinical features of COVID-19 infection in patients with myasthenia gravis: a real-world retrospective study.

We investigated the risk factors associated with severe or critical Coronavirus disease 2019 (COVID-19) infection due to the Omicron variant in patients with myasthenia gravis (MG) and determined the potential effect of COVID-19 on myasthenic exacerbation during the Omicron pandemic. This retrospective study included 287 patients with MG in Tianjin, China. Clinical data of the patients were collected using electronic questionnaires, databases, and clinical records. The overall infection rate was 84.7%. Advanced age, comorbidities, generalized phenotype, and MG instability were drivers of COVID-19 severity, and post-COVID-19 myasthenic exacerbation. The concurrent use of a steroid-sparing agent did not affect COVID-19 susceptibility or severity. It did lower the risk of myasthenic exacerbation after COVID-19 infection. Patients with severe COVID-19 experienced myasthenic exacerbation earlier than patients with non-severe infection (p < 0.001). The severity of COVID-19 (Hazards Ratio = 3.04, 95% CI: 1.41-6.54, p = 0.004) and the clinical phenotype (Hazards Ratio = 3.29, 95% CI: 1.63-6.63, p < 0.001) emerged as independent risk factors for early MG exacerbation. Generally, patients with MG appear to be susceptible to the Omicron strains. Immunotherapy for MG did not increase COVID-19 susceptibility or severity. We do not advocate an immediate cessation of ongoing immunosuppressive treatments once a COVID-19 infection is diagnosed. Instead, a judicious evaluation of the risks and benefits, tailored to each individual, is recommended.

Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells.

ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.

(Epi)mutation Rates and the Evolution of Composite Trait Architectures.

AbstractMutation rates vary widely along genomes and across inheritance systems. This suggests that complex traits-resulting from the contributions of multiple determinants-might be composite in terms of the underlying mutation rates. Here we investigate through mathematical modeling whether such a heterogeneity may drive changes in a trait's architecture, especially in fluctuating environments, where phenotypic instability can be beneficial. We first identify a convexity principle related to the shape of the trait's fitness function, setting conditions under which composite architectures should be adaptive or, conversely and more commonly, should be selected against. Simulations reveal, however, that applying this principle to realistic evolving populations requires taking into account pervasive epistatic interactions that take place in the system. Indeed, the fate of a mutation affecting the architecture depends on the (epi)genetic background, which itself depends on the current architecture in the population. We tackle this problem by borrowing the adaptive dynamics framework from evolutionary ecology-where it is routinely used to deal with such resident/mutant dependencies-and find that the principle excluding composite architectures generally prevails. Yet the predicted evolutionary trajectories will typically depend on the initial architecture, possibly resulting in historical contingencies. Finally, by relaxing the large population size assumption, we unexpectedly find that not only the strength of selection on a trait's architecture but also its direction depend on population size, revealing a new occurrence of the recently identified phenomenon coined "sign inversion."

Competitive fitness and stability of ammonium-excreting Azotobacter vinelandii strains in the soil

Non-symbiotic N2-fixation would greatly increase the versatility of N-biofertilizers for sustainable agriculture. Genetic modification of diazotrophic bacteria has successfully enhanced NH4+ release. In this study, we compared the competitive fitness of A. vinelandii mutant strains, which allowed us to analyze the burden of NH4+ release under a broad dynamic range. Long-term competition assays under regular culture conditions confirmed a large burden for NH4+ release, exclusion by the wt strain, phenotypic instability, and loss of the ability to release NH4+. In contrast, co-inoculation in mild autoclaved soil showed a much longer co-existence with the wt strain and a stable NH4+ release phenotype. All genetically modified strains increased the N content and changed its chemical speciation in the soil. This study contributes one step forward towards bridging a knowledge gap between molecular biology laboratory research and the incorporation of N from the air into the soil in a molecular species suitable for plant nutrition, a crucial requirement for developing improved bacterial inoculants for economic and environmentally sustainable agriculture.Key points• Genetic engineering for NH4+ excretion imposes a fitness burden on the culture medium• Large phenotypic instability for NH4+-excreting bacteria in culture medium• Lower fitness burden and phenotypic instability for NH4+-excreting bacteria in soil

Single-cell sequencing advances in research on mesenchymal stem/stromal cells.

Mesenchymal stem/stromal cells (MSCs), originating from the mesoderm, represent a multifunctional stem cell population capable of differentiating into diverse cell types and exhibiting a wide range of biological functions. Despite more than half a century of research, MSCs continue to be among the most extensively studied cell types in clinical research projects globally. However, their significant heterogeneity and phenotypic instability have significantly hindered their exploration and application. Single-cell sequencing technology emerges as a powerful tool to address these challenges, offering precise dissection of complex cellular samples. It uncovers the genetic structure and gene expression status of individual contained cells on a massive scale and reveals the heterogeneity among these cells. It links the molecular characteristics of MSCs with their clinical applications, contributing to the advancement of regenerative medicine. With the development and cost reduction of single-cell analysis techniques, sequencing technology is now widely applied in fundamental research and clinical trials. This study aimed to review the application of single-cell sequencing in MSC research and assess its prospects.

From genetic mosaicism to tumorigenesis through indirect genetic effects.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.

A Review on Plant Taxonomy

The Identification and naming of plants has attracted a lot of attention throughout history. The science that investigates, identifies, describes, naming of the plant and classifies all plants. Plant taxonomy includes the description of the variation of plants, the observation of the characters like morphological, anatomical and phylogenic characters of the plants, variation, comparison and the manipulation of the data obtained from the previous information/ data is useful to arrange plants in a system of classification. The 3 aspects of the taxonomy are Identification, Nomenclature, classification are the main activates of the taxonomy. Taxonomy means law full arrangement of plants and it is a process of grouping the plants and other organisms. In ancient days plants the classification of plants was very easier and the classification of made by taking consideration of one or two morphological characters which is known as artificial classification but in course of time the classification of plants underwent many medications were taken place because of technological development. But end the end of 19th century the system of classification based on external morphological characters especially based on floral characters because floral characters are stable when compare to morphological characters while growth of the plants, this system of classification is classical/ alpha taxonomy. In course of time the classification of organisms/plants taken consideration of the multiple allied disciplines like the evidences from Anatomy, Embryology, Palynology, Cytology and Genetics. This type of classification is used to resolve taxonomic problems in addition to morphology this classification special significance which is called as biosystematics. Of course an insufficient number of experts, and the instability of phenotypes, which are easily affected by environmental factors, made this classification meet difficulties. With the advent evidences of the fields of phylogenetic, cladistics, experimental botanical gardens, field study, herbariums, keys, museums, computers and systematics, the artificial classification have progressed to a system of modern/ Phylogenic system of biological classification based on consideration of the evolutionary relationships between organisms and both biotic and abiotic factors. Here, I discussed the history of Identification, nomenclature classification and its different systems, for the identification of plants, the development of various molecular techniques that generate molecular markers has made it possible to accurately identify plants. Here I referred the reviews which gives information of the modern techniques and traditional methods that can be used for identification plant species through genotypic studies based on DNA barcoding.

Loss-of-function variants affecting the STAGA complex component SUPT7L cause a developmental disorder with generalized lipodystrophy

Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we found altered expression of genes encoding DNA repair pathway components. This pathway was further investigated and an increased rate of DNA damage was detected in proband-derived fibroblasts and genome-edited HeLa cells. Finally, we performed transient overexpression of wildtype SUPT7L in both cellular systems, which normalizes the number of DNA damage events. Our findings suggest SUPT7L as a novel disease gene and underline the link between genome instability and progeroid phenotypes.

Genetic determinants of micronucleus formation in vivo

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR–Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

Short tandem repeat mutations regulate gene expression in colorectal cancer

Short tandem repeat (STR) mutations are prevalent in colorectal cancer (CRC), especially in tumours with the microsatellite instability (MSI) phenotype. While STR length variations are known to regulate gene expression under physiological conditions, the functional impact of STR mutations in CRC remains unclear. Here, we integrate STR mutation data with clinical information and gene expression data to study the gene regulatory effects of STR mutations in CRC. We confirm that STR mutability in CRC highly depends on the MSI status, repeat unit size, and repeat length. Furthermore, we present a set of 1244 putative expression STRs (eSTRs) for which the STR length is associated with gene expression levels in CRC tumours. The length of 73 eSTRs is associated with expression levels of cancer-related genes, nine of which are CRC-specific genes. We show that linear models describing eSTR-gene expression relationships allow for predictions of gene expression changes in response to eSTR mutations. Moreover, we found an increased mutability of eSTRs in MSI tumours. Our evidence of gene regulatory roles for eSTRs in CRC highlights a mostly overlooked way through which tumours may modulate their phenotypes. Future extensions of these findings could uncover new STR-based targets in the treatment of cancer.

Instability of Healthy Overweight and Obesity Phenotypes over the Long Term in Young Participants in the HARVEST Study: Influence of Sex.

Whether healthy metabolic status is stable or only temporary is still controversial. The aim of the present study was to determine the frequency of the transition from metabolically healthy to metabolically unhealthy status, or vice versa, over the long term. We examined 970 individuals of 18 to 45 years of age. The participants' mean age was 33.1 ± 8.6 years and mean BP was 145.5 ± 10.6/93.5 ± 5.7 mmHg. Participants were classified into four groups according to whether they had normal weight or overweight/obesity (OwOb) and were metabolically healthy or unhealthy. After 7.5 years, 24.3% of men and 41.9% of women in the metabolically healthy normal-weight group remained metabolically healthy (p < 0.0001). Among the metabolically healthy OwOb participants, 31.9% remained metabolically healthy, with a similar frequency in men and women. However, more OwOb women (19.1%) than men (5.7%) achieved normal weight (p < 0.0001). Among the metabolically unhealthy OwOb subjects, 81.8% of men and 69.3% of women remained metabolically unhealthy, 7.4% of men and 12.0% of women transitioned to OwOb healthy status, and 10.7% of men and 18.7% of women achieved normal weight (men versus women, p < 0.0001). Predictors of transition to unhealthy status were high BP, high BMI, and smoking. Male sex was a borderline predictor of progression to unhealthy status in OwOb participants (p = 0.073). These data show that metabolically healthy status is a highly unstable condition in both normal-weight and OwOb individuals. The impairment of metabolic status was more frequent in men than in women. Lifestyle counseling produced beneficial effects in almost one-third of metabolically unhealthy OwOb women and in less than one-fifth of men.

Enrichment of Bacteroides fragilis and enterotoxigenic Bacteroides fragilis in CpG island methylator phenotype-high colorectal carcinoma

ObjectivesData support that enterotoxigenic Bacteroides fragilis (ETBF) harbouring the Bacteroides fragilis toxin (bft) gene may promote colorectal tumourigenesis through the serrated neoplasia pathway. We hypothesized that ETBF may be enriched in colorectal carcinoma subtypes with high-level CpG island methylator phenotype (CIMP-high), BRAF mutation, and high-level microsatellite instability (MSI-high). MethodsQuantitative PCR assays were designed to quantify DNA amounts of Bacteroides fragilis, ETBF, and each bft gene isotype (bft-1, bft-2, or bft-3) in colorectal carcinomas in the Health Professionals Follow-up Study and Nurses' Health Study. We used multivariable-adjusted logistic regression models with the inverse probability weighting method. ResultsWe documented 4476 colorectal cancer cases, including 1232 cases with available bacterial data. High DNA amounts of Bacteroides fragilis and ETBF were positively associated with BRAF mutation (p ≤ 0.0003), CIMP-high (p ≤ 0.0002), and MSI-high (p < 0.0001 and p = 0.01, respectively). Multivariable-adjusted odds ratios (with 95% confidence interval) for high Bacteroides fragilis were 1.40 (1.06–1.85) for CIMP-high and 2.14 (1.65–2.77) for MSI-high, but 1.02 (0.78–1.35) for BRAF mutation. Multivariable-adjusted odds ratios for high ETBF were 2.00 (1.16–3.45) for CIMP-high and 2.86 (1.64–5.00) for BRAF mutation, but 1.09 (0.67–1.76) for MSI-high. Neither Bacteroides fragilis nor ETBF was associated with colorectal cancer-specific or overall survival. DiscussionThe tissue abundance of Bacteroides fragilis is associated with CIMP-high and MSI-high, whereas ETBF abundance is associated with CIMP-high and BRAF mutation in colorectal carcinoma. Our findings support the aetiological relevance of Bacteroides fragilis and ETBF in the serrated neoplasia pathway.

Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype

Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.

Fungicide sensitivity of isolates of Sclerotinia sclerotiorum from different hosts and regions in Brazil and phenotypic instability of thiophanate-methyl resistant isolates

Fungicide sensitivity of isolates of Sclerotinia sclerotiorum from different hosts and regions in Brazil and phenotypic instability of thiophanate-methyl resistant isolates

Clinical Features of Cytokine Storm Syndrome.

Cytokine storm syndrome (CSS) is a severe life-threatening condition characterized by a clinical phenotype of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multiple organ failure (MOF), and, if untreated, it can potentially lead to death. The hallmark of CSS is an uncontrolled and dysfunctional immune response involving the continual activation and expansion of lymphocytes and macrophages, which secrete large amounts of cytokines, causing a cytokine storm. Many clinical features of CSS can be explained by the effects of pro-inflammatory cytokines, such as interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-18 [1-7]. These cytokines are elevated in most patients with CSS as well as in animal models of CSS [8, 9]. A constellation of symptoms, signs, and laboratory abnormalities occurs that depends on the severity of the syndrome, the underlying predisposing conditions, and the triggering agent.

Deficient mismatch repair/microsatellite unstable colorectal cancer: therapeutic advances and questions.

The microsatellite instability (MSI) phenotype is related to a deficiency of the DNA mismatch repair (dMMR) system and is observed in 5% of metastatic colorectal cancers (mCRCs). MSI/dMMR phenotype testing should be routine for all CRCs regardless of stage. Two complementary techniques with a high concordance (90-97%) allow us to determine the MSI/dMMR status of a tumor: immunohistochemistry and polymerase chain reaction. Since 2020 and the results of the phase III KEYNOTE 177 trial, pembrolizumab [anti-programmed cell death protein 1 (PD1)] is the new standard of care in first-line MSI/dMMR mCRC. To date, no combination of chemtotherapy ± targeted therapy with immune checkpoint inhibitors (ICIs) has been validated in the management of MSI/dMMR mCRC, and it is not known whether this combination would be beneficial. It is also unclear whether dual therapy with two ICIs is more effective than monotherapy. Several phase III trials are ongoing to answer these questions. Despite a high response rate and long-term benefit of a first line by anti-PD1, 30-50% of patients with MSI/dMMR mCRC experience an early or secondary progression. There are currently no validated predictive biomarkers of anti-PD1 ± anti-cytotoxic T lymphocyte antigen-4 resistance in patients with MSI/dMMR mCRC. In case of early progression on ICIs, the first two questions to consider are the possibility of pseudoprogression and the correct diagnosis of MSI/dMMR status. To date, there are no data on the use of adjuvant ICIs for MSI/dMMR resected colon cancers. By contrast, data are accumulating regarding the efficacy of neoadjuvant ICIs, with at least two-thirds of patients in the different trials in pathological complete response, making it possible to envisage 'Watch and wait' strategies in future.