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Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.
The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Replication-associated mechanisms contribute to an increased CpG > TpG mutation burden in mismatch repair-deficient cancers
Abstract Background Single base substitution (SBS) mutations, particularly C > T and T > C, are increased owing to unrepaired DNA replication errors in mismatch repair-deficient (MMRd) cancers. Excess CpG > TpG mutations have been reported in MMRd cancers defective in mismatch detection (dMutSα), but not in mismatch correction (dMutLα). Somatic CpG > TpG mutations conventionally result from unrepaired spontaneous deamination of 5’-methylcytosine throughout the cell cycle, causing T:G mismatches and signature SBS1. It has been proposed that MutSα detects those mismatches, prior to error correction by base excision repair (BER). However, other evidence appears inconsistent with that hypothesis: for example, MutSα is specifically expressed in S/G2 phases of the cell cycle, and defects in replicative DNA polymerase proofreading specifically cause excess CpG > TpG mutations in signature SBS10b. Methods We analysed mutation spectra and COSMIC mutation signatures in whole-genome sequencing data from 1803 colorectal cancers (164 dMutLα, 20 dMutSα) and 596 endometrial cancers (103 dMutLα, 9 dMutSα) from the UK 100,000 Genomes Project. We mapped each C > T mutation to its genomic features, including normal DNA methylation state, replication timing, transcription strand, and replication strand, to investigate the mechanism(s) by which these mutations arise. Results We confirmed that dMutSα tumours specifically had higher CpG > TpG burdens than dMutLα tumours. We could fully reconstitute the observed dMutSα CpG > TpG mutation spectrum by adding CpG > TpG mutations in proportion to their SBS1 activity to the dMutLα spectrum. However, other evidence indicated that the SBS1 excess in dMutSα cancers did not come from 5’-methylcytosine deamination alone: non-CpG C > T mutations were also increased in dMutSα cancers; and, in contrast to tumours deficient in BER, CpG > TpG mutations were biased to the leading DNA replication strand, at similar levels in dMutSα and dMutLα cancers, suggesting an origin in DNA replication. Other substitution mutations usually corrected by BER were not increased in dMutSα tumours. Conclusions There is a CpG > TpG and SBS1 excess specific to dMutSα MMRd tumours, consistent with previous reports, and we find a general increase in somatic C > T mutations. Contrary to some other studies, the similar leading replication strand bias in both dMutSα and dMutLα tumours indicates that at least some of the excess CpG > TpG mutations arise via DNA replication errors, and not primarily via the replication-independent deamination of 5’-methylcytosine.
Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair.
DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20-150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.
Utilization of Fetal Hemoglobin Parameters in Predicting Clinical Severity of Sickle Cell Disease: Retrospective Study From a Tanzanian Cohort.
BackgroundFetal hemoglobin (HbF) is found at a measurable amount in red blood cells (RBCs) called F cells. High fetal hemoglobin (HbF) levels are linked with milder forms of sickle cell disease (SCD). However, some patients with high HbF levels still have severe symptoms. This variability has been associated with HbF per F cell (HbF/F cell) concentration; thus, it is hypothesized that high HbF/F cell (≥10 pg) is crucial in determining SCD disease severity rather than the overall HbF and F cell levels. This study assessed the utility of these three HbF parameters as predictors of SCD clinical events in Tanzania.MethodsA retrospective cohort study was conducted at Muhimbili University of Health and Allied Sciences, involving 92 SCD individuals aged ≥6 years, not on hydroxyurea, between September 2022 and February 2023. Data was collected from the Sickle Pan-African Research Consortium (SPARCO)-Tanzania registry. HbF/F cell was calculated as: HbF/F cell = (HbF% × MCH pg)/F cell%. STATA version 15 was used to analyze the association between HbF parameters and clinical events measured by ordinal logistic regression. A p-value <0.05 was considered statistically significant.ResultsOf the 92 SCD participants, the median age was 16 (IQR: 10-21) years, 53 (57.6%) were below 18 years, and males were 48 (52.2%). Eighty-two patients (89.1%) had HbF/F cells below 10pg. Males had significantly higher HbF/F cell levels with a median of 6.4 (IQR: 4.3-9.5) pg compared to females 5.3 (IQR: 3.5-6.5) pg (p-value = 0.004). Although, we did not observe a statistically significant association between HbF/F cell with clinical parameters, increased HbF and F cell percentages correlated with reduced odds of multiple blood transfusions by 11% (p-value = 0.016) and 3% (p-value = 0.020), respectively.ConclusionIn this cohort, HbF and F cell levels remain important predictors of disease severity, as higher levels predicted reduced requirement for multiple blood transfusions in SCD patients, while HbF/F cells did not correlate with SCD clinical events.
Generation of synthetic tomographic images from biplanar X-ray: a narrative review of history, methods, and the state of the art
This narrative review presents deep learning-based strategies for generating synthetic 3D CT-like images from biplanar or multiplanar 2D X-ray data. Current limitations of conventional CT imaging are discussed, hence emphasizing the potential of synthetic CT reconstruction as an alternative technique in certain scenarios. Previous non deep learning approaches for 3D reconstruction from 2D X-rays are presented, indicating their weaknesses and thus pointing out the potential benefits of deep learning techniques. Convolutional neural networks (CNNs), generative adversarial networks (GANs), and conditional diffusion processing (CDP) are introduced, as they demonstrate great potential for synthetic CT generation in multiple studies over the last few years. The review further presents the potential clinical applications, existing challenges and latest research advancements of deep learning strategies for 3D reconstruction from 2D X-rays.
Pelvic stereotactic ablative body radiotherapy (SABR) reirradiation: UK SABR consortium guidance for use in routine clinical care.
Stereotactic ablative body radiotherapy (SABR) is routinely used for the management of oligometastatic disease. Increasingly, there is overlap of targets or organs at risk with previous radiotherapy fields. As substantial variation in delivery of clinical practice exists, the UK SABR Consortium worked with a collaborative national group to develop pelvic SABR re-irradiation consensus guidelines. The scope of the guidance includes patient selection criteria, pre-treatment considerations, delineation guidelines, dose prescription, calculations of cumulative dose constraints, and optimal planning technique. This guidance is part of an ongoing national prospective audit in collaboration with the Royal College of Radiologists and EORTC ReCare.
Charting New Paths in Cancer Research: Insights from the Frontiers in Cancer Science Conference 2024.
The 16th annual Frontiers in Cancer Science conference convened leading experts to discuss the latest developments in cancer research. Key research themes included mechanisms of treatment resistance and innovative strategies to target resistant cancer cells, metabolic plasticity and its therapeutic vulnerabilities, modulation of the tumor microenvironment to enhance therapeutic efficacy, recent advances in immunotherapies and engineered immune cells, and strategies to overcome tumor immune evasion. The conference also highlighted the development of advanced spatial transcriptomic technologies as a powerful tool to decipher tumor heterogeneity and identify novel therapeutic targets. Additionally, the transformative potential of artificial intelligence and machine learning was explored in optimizing therapy selection, refining prognostication models, and improving patient outcomes, with a focus on advancing personalized, cost-effective cancer care. These collective insights underscore the rapid progress in the field and the potential for translating these discoveries into effective clinical interventions, marking a significant step toward addressing the complexities of cancer biology and enhancing patient care worldwide.
Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.
Diagnosing Burkitt Lymphoma in Sub-Saharan Africa by Sequencing of Circulating Tumor DNA: A Comparative Microcosting Study.
OBJECTIVES: Determining the cost of diagnosis of Burkitt lymphoma by DNA sequencing from a blood sample, compared with current histopathology. Estimating future sequencing costs at increased scale and exploring the effect of positivity rate on per-case cost. METHODS: We conducted a microcosting of both diagnostics. Resource use information was derived from standard operating procedures and interviews with staff. Unit cost data were from salary scales, purchase records, and publicly available prices. Costs were collected during 2021 and 2022, in the currency of purchase, and converted to common year (2024) and currency (US dollar [$]), with a discount rate of 5%. For increased scale, we assumed simple scaling up of current sample preparation and higher-capacity sequencing machines running at least once a week to maintain turnaround times. RESULTS: We estimated a cost of $185.01 per patient for histopathology, with the main cost drivers being staining ($87.20, largely immunohistochemistry consumables, including $34.52 for antibodies) and the biopsy procedure ($72.29). The cost of the sequencing-based diagnostic was $710.15 at current throughput, with the largest contribution from the sequencing step because of the cost of sequencing reagents ($175.48 per sample). Costs are sensitive to throughput, reagent costs, and efficiency of utilization of equipment. At the current prevalence, cost per positive case is 2-fold higher at a positivity rate of 25% compared with 75%. CONCLUSIONS: With the current technology and throughput, sequencing is likely to increase the cost of diagnosis compared with current pathology. Costs will reduce with increased scale, which requires establishing local reagent supply and maintenance capability.
Research training, barriers, and career development needs of early-career investigators in oncology: an EORTC survey-based study
Background: The increasing complexity of cancer research presents significant challenges for early-career oncologists in establishing independent research careers. Although dedicated support platforms have emerged in recent years, a thorough evaluation of the research training needs and barriers faced by the current generation of trainees and early-career oncologists has been lacking. This study aimed to assess the research backgrounds, needs, and career aspirations of early-career researchers in oncology. Methods: An online survey was distributed between September and October 2024 among young and early-career investigator (Y-ECI) members of the European Organisation for Research and Treatment of Cancer (EORTC) and other professionals meeting the EORTC Y-ECI criteria. The questionnaire collected information on research experience, challenges, and expectations from the newly launched EORTC Y-ECI community. Results: Among 301 respondents, 200 (66.7%) met Y-ECI criteria and participated in the survey. Most were female (62.4%), aged 31-35 years (38.7%), medical oncologists (69.6%), and working in academic settings (58.8%). While 73.7% had published research, 75.8% reported challenges in conducting and publishing their work. The main barriers included lack of protected research time (77.0%), limited funding (48.2%), and insufficient grant application support (47.1%). Female researchers were seven times more likely to report gender-related barriers (odds ratio 7.14, 95% confidence interval 1.14-79.22). Most (84.3%) expressed interest in joining the EORTC Y-ECIs community, with research training, mentorship, and funding opportunities rated as the most valuable initiatives. Conclusions: This study provides comprehensive insights into the research needs of early-career oncologists and supports the EORTC investment in structured training programmes to cultivate a strong, next-generation research workforce.
Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer.
BACKGROUND: Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is a standard therapy for resectable gastric and gastroesophageal junction adenocarcinomas, but recurrence rates remain high. Immunotherapy plus chemotherapy may improve outcomes. METHODS: In a phase 3, multinational, double-blind, randomized trial, we assigned participants with resectable gastric or gastroesophageal junction adenocarcinoma, in a 1:1 ratio, to receive durvalumab at a dose of 1500 mg or placebo every 4 weeks plus FLOT for 4 cycles (2 cycles each of neoadjuvant and adjuvant therapy), followed by durvalumab or placebo every 4 weeks for 10 cycles. The primary end point was event-free survival; secondary end points included overall survival and pathological complete response. RESULTS: A total of 474 participants were randomly assigned to the durvalumab group, and 474 to the placebo group (median follow-up, 31.5 months; interquartile range, 26.7 to 36.6). Two-year event-free survival (Kaplan-Meier estimate) was 67.4% among the participants in the durvalumab group and 58.5% among those in the placebo group (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001). Two-year overall survival was 75.7% in the durvalumab group and 70.4% in the placebo group (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], and during the period from month 12 onward, 0.67 [95% CI, 0.50 to 0.90]; P = 0.03 by a stratified log-rank test [exceeding the significance threshold of P<0.0001]). The percentage of participants with a pathological complete response was 19.2% in the durvalumab group and 7.2% in the placebo group (relative risk, 2.69 [95% CI, 1.86 to 3.90]). Adverse events with a maximum grade of 3 or 4 were reported in 340 participants (71.6%) in the durvalumab group and in 334 (71.2%) in the placebo group. The percentage of participants with delayed surgery was 10.1% and 10.8%, respectively, and the percentage with delayed initiation of adjuvant treatment was 2.3% and 4.6%. CONCLUSIONS: Perioperative durvalumab plus FLOT led to significantly better event-free survival outcomes than FLOT alone among participants with resectable gastric or gastroesophageal junction adenocarcinoma. (Funded by AstraZeneca; MATTERHORN ClinicalTrials.gov number, NCT04592913.).
Gastric cancer
Gastric cancer (GC) is the fifth most common cancer worldwide and is a poor prognosis disease. GC is diagnosed by endoscopic biopsy and staged with CT scan, endoscopic ultrasound, and laparoscopy. An MDT approach is of major importance to plan a tailored-made treatment for GC patients. Very early GCs are treated with endoscopic resection, while locally advanced GCs are treated with radical surgery accompanied by perioperative chemotherapy or adjuvant chemotherapy or chemoradiotherapy when appropriate. The management of advanced GCs is based on sequential lines of systemic treatments that include combination of chemotherapies, targeted therapies, or immunotherapies. The possible benefit of local treatments in advanced disease still needs to be clarified.
PD-L1 as a response biomarker to chemotherapy plus immune checkpoint inhibitors in operable gastroesophageal adenocarcinoma: a meta-analysis of neoadjuvant clinical trials
Background: Perioperative chemoimmunotherapy [i.e. chemotherapy plus immune checkpoint inhibitor (ICI) (ChT–ICI)] is an investigational treatment for operable gastroesophageal adenocarcinoma (GEA) with unclear outcomes in an unselected population. We aimed to assess the cumulative treatment effect of ChT–ICI on pathological response rates, the surrogacy of pathological response rates on overall survival (OS), and the value of programmed death-ligand 1 (PD-L1) as a biomarker of response to ICIs in operable GEA. Methods: We conducted a systematic review and meta-analysis of randomised clinical trials (RCTs) of ChT with or without ICIs with the primary outcome being pathological response rates [pathological complete response (pCR) and similar metrics]. A weighted linear regression model quantified the relationship between pathological response rates and OS using a determination coefficient (R2). A second meta-regression analysed the predictive effect of PD-L1 on pCR in trials of ICIs with ChT or chemoradiotherapy (CRT). Results: A total of 18 records from 15 RCTs were included. Of 6624 patients, 5291 received ChT and 1333 ChT–ICI. ChT–ICI significantly improved pathological response rates [pooled odds ratio 3.18, 95% confidence interval (CI) 2.42-4.18, P < 0.0001] compared with ChT (pooled odds ratio 1.66, 95% CI 1.33-2.07, P < 0.0001). The correlation between pathological response and OS was low (R2 = 0.12) but improved in recent trials (R2 = 0.51) and those with ChT–biological agents, including ICIs (R2 = 0.79). In the second analysis (11 studies, 633 patients), PD-L1 ≥5 was a significant predictor of response both individually (estimate: 0.73, 95% CI 0.28-1.18, P = 0.001) and after accounting for the backbone treatment (estimate: 0.80, 95% CI 0.28-1.33, P = 0.003). Conclusions: Perioperative ChT–ICI improves pathological response rates in operable GEA and PD-L1 ≥5 is a significant biomarker of pCR, supporting stratification by PD-L1 and the design of biomarker-selected trials.
Current practices and challenges in implementing precision medicine for upper gastrointestinal cancers in European academic centers: an EORTC survey
Background: Precision oncology is gaining momentum in managing patients with gastrointestinal cancers. This study examines the implementation of personalized medicine technologies in upper gastrointestinal (UGI) oncology across European academic centers. Material and methods: Forty-five oncology specialists from 41 European institutions completed a survey designed by the Personalized Medicine Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Working Group, providing insights into molecular testing, timing, availability of targeted therapies, funding sources, and utilization of molecular tumor boards (MTBs) for patients with UGI cancers. Frequencies and percentages were calculated. Results: Routine testing for human epidermal growth factor receptor 2 (HER2, 100%), programmed death-ligand 1 (PD-L1, 89%), and DNA mismatch repair (MMR, 91%) is implemented in most centers. Comprehensive gene panels on tumor tissue are frequently utilized, especially in biliary tract cancer, with almost all centers incorporating them into routine practice. Blood-based sequencing is increasingly employed, and half of centers carry out comprehensive gene panels for circulating tumor DNA analyses. MTBs are regularly held in 76% of centers, predominantly utilizing ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)-based recommendations for tissue molecular alterations. The translation of genomic information into prescribed treatments remains limited, however, with the majority of centers reporting ∼25% of molecularly stratified treatment decisions following comprehensive genetic testing. Conclusion: This survey provides important insights into current personalized medicine practice in European academic clinical centers for UGI oncology. Despite widespread adoption of molecular testing and implementation of MTBs, further efforts are needed to optimize the integration of personalized medicine into clinical practice.
Role of the microbiome in the development and treatment of gastric cancer: an overview of the biological and clinical landscape
For decades, the stomach was considered a sterile organ, due to the acid environment. However, starting from the discovery of Helicobacter pylori, this concept has progressively refined. By damaging the hydrochloric acid-secreting glands, H. pylori infection primes the progression from acute to chronic inflammation in gastric mucosa resulting in atrophic gastritis, intestinal metaplasia, dysplasia and ultimately gastric cancer (GC). Due to the challenging identification of culturing bacteria, the carcinogenic role of gastric microbial community, other than H. pylori, remains underestimated. More recently, a growing body of evidence has pointed out the dynamism of gastric microbiota as a crucial step for GC development, besides elucidating some additional activity in modulating the efficacy of cancer treatments. In turn, anticancer therapies can shape gastric microbiota with consequent dysbiosis and a potential correlation with drug-related toxicity. In conclusion, the current review aims to deepen the role of gut microbiota as a key factor in gastric disease at multiple levels, from carcinogenesis to the metastatic phase. It also provides novel insights on gastric microbiota as potential target for tailoring multimodal strategies, either surgical or oncological, to finally provide our patients with more individualized treatment options.
Integration of genomic aberrations to predict clinical outcomes for patients with gastroesophageal adenocarcinoma receiving neoadjuvant chemotherapy
Background: Esophageal cancer [esophagogastric adenocarcinoma (OGA)] shows heterogeneity at the molecular level, leading to lower efficacy rates and highlighting the need for personalized treatment strategies. We have developed a computational model that uses both mechanistic and statistical approaches to integrate a patient's genomic aberrations, revealing signaling pathway dysregulation and variable drug response. The model output, Therapy Response Index (TRI), has been used to predict therapeutic outcomes in this study. Design: TRI's ability to predict patient outcomes was retrospectively evaluated in a prospectively collected cohort of patients with operable OGA from the UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium receiving neoadjuvant chemotherapy. Stratified random sampling was used to split the data into training and validation subsets. Multivariate Cox proportional hazard and proportional odds models were used to predict survival and pathological response as a function of TRI and clinical thresholds compared with clinical factors. Results: A total of 270 patients with OGA were selected who had 50× whole genome sequencing carried out on tissue derived from either biopsy or resection. Patients were treated with chemotherapy drugs or regimens according to UK clinical guidelines. The association of TRI with overall survival (OS) was significant above and beyond standard clinical factors (P = 0.0012). A significant association was also observed with disease-free survival (DFS; P = 0.0288). A TRI optimized for tumor regression grade also displayed a significant association (P = 0.0011). Conclusions: TRI was predictive of OS and DFS beyond clinical factors. These positive results suggest the potential utility of personalized biosimulation-informed therapy selection and that further assessment in prospective clinical studies is warranted.
Nanotechnology for immuno-oncology.
Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.