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Cancer Prevention Research... Sep 2023Major advances in our understanding of the tumor immune microenvironment (TIME) in established cancer have been made, including the influence of host-intrinsic (host... (Review)
Review
Major advances in our understanding of the tumor immune microenvironment (TIME) in established cancer have been made, including the influence of host-intrinsic (host genomics) and -extrinsic factors (such as diet and the microbiome) on treatment response. Nonetheless, the immune and microbiome milieu across the spectrum of precancerous tissue and early neoplasia is a growing area of interest. There are emerging data describing the contribution of the immune microenvironment and microbiota on benign and premalignant tissues, with opportunities to target these factors in cancer prevention and interception. Throughout this review, we provide rationale for not only the critical need to further elucidate the premalignant immune microenvironment, but also for the utility of pharmacologic and lifestyle interventions to alter the immune microenvironment of early lesions to reverse carcinogenesis. Novel research methodologies, such as implementing spatial transcriptomics and proteomics, in combination with innovative sampling methods will advance precision targeting of the premalignant immune microenvironment. Additional studies defining the continuum of immune and microbiome evolution, which emerges in parallel with tumor development, will provide novel opportunities for cancer interception at the earliest steps in carcinogenesis.
Topics: Humans; Precancerous Conditions; Carcinogenesis; Tumor Microenvironment; Microbiota; Genomics
PubMed: 37428011
DOI: 10.1158/1940-6207.CAPR-23-0087 -
Modern Pathology : An Official Journal... Dec 2023Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate...
Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials from ADC precursors. Here, we employed state-of-the-art deep learning and artificial intelligence techniques to robustly segment and recognize cells on routinely used hematoxylin and eosin histopathology images and extracted 9 biology-relevant pathomic features to decode lung preneoplasia evolution. We analyzed 3 distinct cohorts (Japan, China, and United States) covering 98 patients, 162 slides, and 669 regions of interest, including 143 normal, 129 atypical adenomatous hyperplasia, 94 AIS, 98 MIA, and 205 ADC. Extracted pathomic features revealed progressive increase of atypical epithelial cells and progressive decrease of lymphocytic cells from normal to AAH, AIS, MIA, and ADC, consistent with the results from tissue-consuming and expensive molecular/immune profiling. Furthermore, pathomics analysis manifested progressively increasing cellular intratumor heterogeneity along with the evolution from normal lung to invasive ADC. These findings demonstrated the feasibility and substantial potential of pathomics in studying lung cancer carcinogenesis directly from the low-cost routine hematoxylin and eosin staining.
Topics: Humans; Hyperplasia; Artificial Intelligence; Eosine Yellowish-(YS); Hematoxylin; Adenocarcinoma; Lung; Lung Neoplasms; Adenocarcinoma in Situ; Precancerous Conditions; Evolution, Molecular; Carcinogenesis
PubMed: 37678674
DOI: 10.1016/j.modpat.2023.100326 -
Saudi Journal of Gastroenterology :... 2023Since the emergence of artificial intelligence (AI) in medicine, endoscopy applications in gastroenterology have been at the forefront of innovations. The... (Review)
Review
Since the emergence of artificial intelligence (AI) in medicine, endoscopy applications in gastroenterology have been at the forefront of innovations. The ever-increasing number of studies necessitates the need to organize and classify applications in a useful way. Separating AI capabilities by computer aided detection (CADe), diagnosis (CADx), and quality assessment (CADq) allows for a systematic evaluation of each application. CADe studies have shown promise in accurate detection of esophageal, gastric and colonic neoplasia as well as identifying sources of bleeding and Crohn's disease in the small bowel. While more advanced CADx applications employ optical biopsies to give further information to characterize neoplasia and grade inflammatory disease, diverse CADq applications ensure quality and increase the efficiency of procedures. Future applications show promise in advanced therapeutic modalities and integrated systems that provide multimodal capabilities. AI is set to revolutionize clinical decision making and performance of endoscopy.
Topics: Humans; Artificial Intelligence; Colonic Neoplasms; Crohn Disease; Endoscopy; Endoscopy, Gastrointestinal; Gastroenterology; Barrett Esophagus
PubMed: 37787347
DOI: 10.4103/sjg.sjg_286_23 -
Nature Communications Aug 2023The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and...
The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.
Topics: Humans; Animals; Mice; Carcinoma, Squamous Cell; Skin Neoplasms; Cell Differentiation; Disease Progression; Gene Expression Profiling; Keratosis, Actinic
PubMed: 37626054
DOI: 10.1038/s41467-023-40822-9 -
Proceedings of the National Academy of... Aug 2023Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by...
Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes. A gradient of TF expression changes forms a basis for the subtypes of abnormal DNA methylation, termed CpG-island promoter DNA methylation phenotypes (CIMPs), in CRCs and other cancers. CIMP is tightly correlated with cancer-specific hypermethylation at enhancers, which we term CpG-enhancer methylation phenotype (CEMP). Coordinated promoter and enhancer methylation appears to be driven by downregulation of TFs with common binding sites at the hypermethylated enhancers and promoters. The altered expression of TFs related to hypermethylator subtypes occurs early during CRC development, detectable in premalignant adenomas. TF-based profiling further identifies patients with worse overall survival. Importantly, altered expression of these TFs discriminates the transcriptome-based consensus molecular subtypes (CMS), thus providing a common basis for CIMP and CMS subtypes.
Topics: Humans; Transcription Factors; Gene Expression Regulation; DNA Methylation; Precancerous Conditions; Colorectal Neoplasms; Epigenesis, Genetic
PubMed: 37487069
DOI: 10.1073/pnas.2301536120 -
Cells Jan 2024Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their... (Review)
Review
Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their mutation frequency in premalignant tissue is expected to exceed the basal mutation rate. In old terms, that translates to "the survival of the fittest" and implies that a selective process underlies the frequency of cancer driver mutations. In that sense, each tissue is its own niche that creates a molecular selective pressure that may favor the propagation of a mutation or not. At the heart of this stands one of the biggest riddles in cancer biology: the tissue-predisposition to cancer driver mutations. The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.
Topics: Humans; Precancerous Conditions; Disease Susceptibility; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Mutation Rate
PubMed: 38247798
DOI: 10.3390/cells13020106 -
Nature Communications Oct 2023The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly...
The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.
Topics: Humans; Barrett Esophagus; Esophageal Neoplasms; Adenocarcinoma; Chromosomal Instability; Precancerous Conditions; Genomics; Disease Progression
PubMed: 37794034
DOI: 10.1038/s41467-023-41805-6 -
Scientific Reports Sep 2023Using advanced bioinformatics techniques, we conducted an analysis of ferroptosis-related genes (FRGs) in precancerous lesions of gastric cancer (PLGC). We also...
Using advanced bioinformatics techniques, we conducted an analysis of ferroptosis-related genes (FRGs) in precancerous lesions of gastric cancer (PLGC). We also investigated their connection to immune cell infiltration and diagnostic value, ultimately identifying new molecular targets that could be used for PLGC patient treatment. The Gene Expression Omnibus (GEO) and FerrDb V2 databases were used to identify FRGs. These genes were analysed via ClueGO pathways and Gene Ontology (GO) enrichment analysis, as well as single-cell dataset GSE134520 analysis. A machine learning model was applied to identify hub genes associated with ferroptosis in PLGC patients. Receiver Operating Characteristics (ROC) curve analysis was conducted to verify the diagnostic efficacy of these genes, and a PLGC diagnosis model nomogram was established based on hub genes. R software was utilized to conduct functional, pathway, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) on the identified diagnostic genes. Hub gene expression levels and survival times in gastric cancer were analysed using online databases to determine the prognostic value of these genes. MCPcounter and single-sample gene set enrichment analysis (ssGSEA) algorithms were used to investigate the correlation between hub genes and immune cells. Finally, noncoding RNA regulatory mechanisms and transcription factor regulatory networks for hub genes were mapped using multiple databases. Eventually, we identified 23 ferroptosis-related genes in PLGC. Enrichment analyses showed that ferroptosis-related genes were closely associated with iron uptake and transport and ferroptosis in the development of PLGC. After differential analysis using machine learning algorithms, we identified four hub genes in PLGC patients, including MYB, CYB5R1, LIFR and DPP4. Consequently, we established a ferroptosis diagnosis model nomogram. GSVA and GSEA mutual verification analysis helped uncover potential regulatory mechanisms of hub genes. MCPcounter and ssGSEA analysed immune infiltration in the disease and indicated that B cells and parainflammation played an important role in disease progression. Finally, we constructed noncoding RNA regulatory networks and transcription factor regulatory networks. Our study identified ferroptosis-related diagnostic genes and therapeutic targets for PLGC, providing novel insights and a theoretical foundation for research into the molecular mechanisms, clinical diagnosis, and treatment of this disease.
Topics: Humans; Stomach Neoplasms; Ferroptosis; Precancerous Conditions; Biomarkers
PubMed: 37752199
DOI: 10.1038/s41598-023-43198-4 -
Causal association between dietary factors and esophageal diseases: A Mendelian randomization study.PloS One 2023Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between dietary factors and gastroesophageal reflux...
BACKGROUND
Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between dietary factors and gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), or esophageal cancer (EC).
METHODS
Genome-wide association study (GWAS) data for eighteen types of dietary intake were obtained from the UK Biobank. GWAS data for GERD, BE, and EC were sourced from the FinnGen consortium. We performed univariable and multivariable MR analysis to assess the cause effect between dietary factors and esophageal diseases. MR results were expressed as odds ratios (OR) with 95% confidence intervals (CI).
RESULTS
Raw vegetable intake was associated with a lower risk of GERD (OR = 0.478; P = 0.011). On the contrary, cooked vegetable intake increased the risk of GERD (OR = 1.911; P = 0.024). Bread intake was associated with increased odds of BE (OR = 6.754; P = 0.007), while processed meat intake was associated with reduced risk of BE (OR = 0.210; P = 0.035). We also observed evidence that increased consumption of dried fruit (OR = 0.087; P = 0.022) and salt added to food (OR = 0.346; P = 0.045) could prevent EC. The results of multivariable MR showed that the protective effect of consumption of salt added to food on EC was no longer significant after adjusting for the consumption of dried fruit.
CONCLUSION
Vegetable consumption was associated with GERD, whereas consumption of bread and processed meat was associated with BE. Dried fruit intake was associated with a lower risk of EC, and the protective effect of consumption of salt added food on EC may also be mediated by consumption of dried fruit. Future research should be performed to investigate the mechanisms behind these cause-and-effect relationships to reduce the burden of disease caused by dietary habits.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Barrett Esophagus; Esophageal Neoplasms; Gastroesophageal Reflux; Fruit; Vegetables
PubMed: 38019753
DOI: 10.1371/journal.pone.0292113 -
The Journal of Clinical Investigation Aug 2023Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined...
Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell-rich and T cell-sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC-mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A-positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1-positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.
Topics: Animals; Mice; Humans; Multiple Myeloma; T-Lymphocytes; Precancerous Conditions; Immunotherapy; Antigen Presentation; Dendritic Cells
PubMed: 37526080
DOI: 10.1172/JCI167629