Sujet(s)
Porocarcinome eccrine , Analyse de profil d'expression de gènes , Tumeurs des glandes sudoripares , Humains , Porocarcinome eccrine/génétique , Porocarcinome eccrine/anatomopathologie , Tumeurs des glandes sudoripares/génétique , Tumeurs des glandes sudoripares/anatomopathologie , Transcriptome/génétique , États précancéreux/génétique , États précancéreux/anatomopathologie , Femelle , Transformation cellulaire néoplasique/génétique , Transformation cellulaire néoplasique/anatomopathologie , Mâle , Régulation de l'expression des gènes tumoraux , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking. METHODS: To characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell line-derived tumours were used to investigate the tumour-promoting role of genes. RESULTS: Spatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4 A (SEMA4A) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival. CONCLUSION: Gallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.
Sujet(s)
Adénocarcinome , Évolution de la maladie , Tumeurs de la vésicule biliaire , Analyse de profil d'expression de gènes , Humains , Tumeurs de la vésicule biliaire/génétique , Tumeurs de la vésicule biliaire/anatomopathologie , Adénocarcinome/génétique , Adénocarcinome/anatomopathologie , Transcriptome , Mâle , Régulation de l'expression des gènes tumoraux , États précancéreux/génétique , États précancéreux/anatomopathologie , Femelle , Lignée cellulaire tumorale , Organoïdes/anatomopathologie , Vésicule biliaire/anatomopathologie , Sujet âgé , Adulte d'âge moyenRÉSUMÉ
To assess the diagnostic efficacy of SEPT9 along with PAX5 gene methylation detection in gastrointestinal cancer and precancerous lesions, the peripheral blood of 62 patients with gastric cancer (GC) and 60 patients with no evidence of disease (as the control group) were retrospectively collected. The methylation rates of PAX5 and SEPT9 gene promoters in blood samples of GC group were detected by PCR. At the same time, the differences in methylation rates of genes in the two groups were compared, and the predictive value of plasma methylation PAX5 and SEPT9 in GC was evaluated by receiver operating characteristic (ROC) curve. We found that there were 41 cases of methylated PAX5 gene promoter region and 39 cases of methylated SEPT9 gene promoter region in GC group. The control group contained 14 cases of PAX5 gene promoter methylation and 12 cases of RNF¹80 gene promoter methylation. The occurrence of PAX5 promoter methylation was correlated with age of GC patients. There were statistically significant differences in mSEPT9 gene in patients with different TNM stages. Kaplan-Meier survival curve analysis revealed that the three-year overall survival rate of GC patients with PAX5 methylation was lower than that of GC patients without PAX5 methylation. No significant difference was discovered in 3-year overall survival rate between GC patients with SEPT9 methylation and those without SEPT9 methylation. Combined detection could not improve the diagnostic value of GC, but could promote diagnosis sensitivity. In summary, the risk of PAX5 and SEPT9 gene methylation in GC patients presents higher when compared with healthy people. PAX5 gene methylation is closely related to age, while SEPT9 is closely related to tumor TNM stage, and PAX5 gene methylation can decrease the survival rate of GC patients. Detection of PAX5 gene methylation level can assist in evaluating the prognosis of GC patients.
Sujet(s)
Méthylation de l'ADN , Protéine activatrice spécifique des lymphocytes B , États précancéreux , Régions promotrices (génétique) , Septines , Humains , Septines/génétique , Méthylation de l'ADN/génétique , Protéine activatrice spécifique des lymphocytes B/génétique , Protéine activatrice spécifique des lymphocytes B/métabolisme , Femelle , Mâle , Adulte d'âge moyen , Régions promotrices (génétique)/génétique , Sujet âgé , États précancéreux/génétique , États précancéreux/diagnostic , États précancéreux/anatomopathologie , Tumeurs gastro-intestinales/génétique , Tumeurs gastro-intestinales/diagnostic , Tumeurs gastro-intestinales/anatomopathologie , Courbe ROC , Estimation de Kaplan-Meier , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/diagnostic , Tumeurs de l'estomac/anatomopathologie , Adulte , Marqueurs biologiques tumoraux/génétique , Études rétrospectives , Stadification tumoraleRÉSUMÉ
It takes more than 20 years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here, we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into six modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.
Sujet(s)
Adénomes , Marqueurs biologiques tumoraux , Tumeurs colorectales , Vésicules extracellulaires , Humains , Tumeurs colorectales/génétique , Tumeurs colorectales/sang , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/diagnostic , Vésicules extracellulaires/génétique , Vésicules extracellulaires/métabolisme , Adénomes/génétique , Adénomes/sang , Adénomes/anatomopathologie , Marqueurs biologiques tumoraux/sang , Marqueurs biologiques tumoraux/génétique , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Biopsie liquide/méthodes , États précancéreux/génétique , États précancéreux/sang , États précancéreux/anatomopathologie , Stadification tumoraleRÉSUMÉ
Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.
Sujet(s)
Microbiote , Infections à papillomavirus , États précancéreux , Telomerase , Télomère , Tumeurs du col de l'utérus , Vagin , Humains , Femelle , Telomerase/métabolisme , Telomerase/génétique , Vagin/microbiologie , Vagin/virologie , Microbiote/génétique , Infections à papillomavirus/virologie , Infections à papillomavirus/complications , Infections à papillomavirus/génétique , Adulte , Télomère/métabolisme , Télomère/génétique , Adulte d'âge moyen , États précancéreux/virologie , États précancéreux/microbiologie , États précancéreux/génétique , États précancéreux/anatomopathologie , Tumeurs du col de l'utérus/virologie , Tumeurs du col de l'utérus/microbiologie , Tumeurs du col de l'utérus/génétique , Tumeurs du col de l'utérus/anatomopathologie , Homéostasie des télomères , Papillomaviridae/génétiqueRÉSUMÉ
Squamous cell lung cancer (SCLC) occurs as a result of dysregenerative changes in the bronchial epithelium: basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia. We previously suggested that combinations of precancerous changes detected in the small bronchi of patients with SCLC may reflect various "scenarios" of the precancerous process: isolated BCHâstopping at the stage of hyperplasia, BCH+SMâprogression of hyperplasia into metaplasia, SM+dysplasiaâprogression of metaplasia into dysplasia. In this study, DNA methylome of various forms of precancerous changes in the bronchial epithelium of SCLC patients was analyzed using the genome-wide bisulfite sequencing. In BCH combined with SM, in contrast to isolated BCH, differentially methylated regions were identified in genes of the pathogenetically significant MET signaling pathway (RNMT, HPN). Differentially methylated regions affecting genes involved in inflammation regulation (IL-23, IL-23R, IL12B, IL12RB1, and FIS1) were detected in SM combined with dysplasia in comparison with SM combined with BCH. The revealed changes in DNA methylation may underlie various "scenarios" of the precancerous process in the bronchial epithelium.
Sujet(s)
Bronches , Méthylation de l'ADN , Hyperplasie , Tumeurs du poumon , Métaplasie , États précancéreux , Humains , Hyperplasie/anatomopathologie , Hyperplasie/génétique , Métaplasie/génétique , Métaplasie/anatomopathologie , Métaplasie/métabolisme , Bronches/anatomopathologie , Bronches/métabolisme , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , États précancéreux/génétique , États précancéreux/anatomopathologie , États précancéreux/métabolisme , Mâle , Femelle , Adulte d'âge moyen , Épigénome/génétique , Muqueuse respiratoire/anatomopathologie , Muqueuse respiratoire/métabolisme , Sujet âgé , Carcinome pulmonaire à petites cellules/génétique , Carcinome pulmonaire à petites cellules/anatomopathologie , Carcinome pulmonaire à petites cellules/métabolisme , Carcinome épidermoïde/génétique , Carcinome épidermoïde/anatomopathologie , Carcinome épidermoïde/métabolismeRÉSUMÉ
Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence suggests that pancreatic intraepithelial neoplasia (PanIN), a microscopic precursor lesion that gives rise to pancreatic cancer, is larger and more prevalent than previously believed. Better understanding of the growth-law dynamics of PanINs may improve our ability to understand how a miniscule fraction makes the transition to invasive cancer. Here, using three-dimensional tissue mapping, we analyzed >1000 PanINs and found that lesion size is distributed according to a power law. Our data suggest that in bulk, PanIN size can be predicted by general growth behavior without consideration for the heterogeneity of the pancreatic microenvironment or an individual's age, history, or lifestyle. Our models suggest that intraductal spread and fusing of lesions drive our observed size distribution. This analysis lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, and molecular features to understand tumorigenesis and demonstrates the utility of combining experimental measurement with dynamic modeling in understanding tumorigenesis.
Sujet(s)
Tumeurs du pancréas , États précancéreux , Humains , Tumeurs du pancréas/génétique , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/épidémiologie , États précancéreux/génétique , États précancéreux/anatomopathologie , Incidence , Génomique/méthodes , Épithélioma in situ/génétique , Épithélioma in situ/anatomopathologie , Épithélioma in situ/épidémiologie , Carcinome du canal pancréatique/génétique , Carcinome du canal pancréatique/anatomopathologie , Modèles théoriquesRÉSUMÉ
BACKGROUND AND AIM: Colorectal cancer (CRC) is considered one of the most common cancers in the world. Serrated polyps were found to be precursor lesions for CRC. BRAF mutation (V600E) has been strongly linked to the development of these lesions. No previous study concerning BRAF immunohistochemical expression in serrated polyps- was done in Oman. The primary objective of our study was to assess the prevalence of BRAF (V600E) mutation in serrated colorectal polyps in the Omani population. The secondary objectives were to assess the prevalence of serrated polyps and their characteristic features: type, site and size as well as the relationship between BRAF (V600E) mutation and polyp type, site and size. MATERIALS AND METHODS: Ninety-one hyperplastic polyps (HP) (76.5%), 24 sessile serrated lesions (SSL) (20.2%) and 4 cases of tubular adenomas with low grade dysplasia (3.4%) were studied for BRAF (V600E) immunohistochemical expression. No case of traditional serrated adenoma (TSA) was present. Control cases of craniopharyngioma and papillary thyroid carcinoma were included. RESULTS: BRAF (V600E) IHC was positive in 63 of the HP polyps (69.2%), 13 SSLs (54.2%) and none of the adenomatous polyps. The majority of positive polyps (75.0%) were ≤5 mm in size, 17.9% were 5-10 mm and 7.1% were ≥10 mm in size. The majority of BRAF (V600E) positive polyps (68.1 %) were in the distal colon and 31.9 % were in the proximal colon. The majority of positive cases for BRAF (V600E) were showing multiple polyps (61.8 %). None of the tubular adenomas showed any BRAF (V600E) positivity. CONCLUSION: Serrated polyps are now well known for their potential to develop CRC. Immunohistochemistry is an easy and reproducible way to detect BRAF (V600E) mutation. Our study showed there is high prevalence (64.3%) of BRAF mutation in serrated polyps in the Omani population. The majority of these polyps- were HP and SSL; and ≤5 mm in size and located in the distal colon.
Sujet(s)
Adénomes , Polypes coliques , Tumeurs colorectales , Mutation , Protéines proto-oncogènes B-raf , Humains , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/métabolisme , Femelle , Mâle , Oman , Polypes coliques/génétique , Polypes coliques/anatomopathologie , Polypes coliques/métabolisme , Adulte d'âge moyen , Tumeurs colorectales/génétique , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Adulte , Adénomes/génétique , Adénomes/anatomopathologie , Adénomes/métabolisme , Centres de soins tertiaires , Pronostic , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Sujet âgé , Études de suivi , Études cas-témoins , Cancer papillaire de la thyroïde/génétique , Cancer papillaire de la thyroïde/anatomopathologie , Cancer papillaire de la thyroïde/métabolisme , États précancéreux/génétique , États précancéreux/anatomopathologie , États précancéreux/métabolisme , Jeune adulte , Tumeurs de la thyroïde/génétique , Tumeurs de la thyroïde/anatomopathologie , Tumeurs de la thyroïde/métabolisme , Techniques immunoenzymatiques , Hyperplasie/génétique , Hyperplasie/anatomopathologie , Hyperplasie/métabolisme , Carcinome papillaire/génétique , Carcinome papillaire/anatomopathologie , Carcinome papillaire/métabolismeSujet(s)
Tumeurs colorectales , ADN tumoral , Dépistage précoce du cancer , Fèces , Humains , Tumeurs colorectales/sang , Tumeurs colorectales/diagnostic , Tumeurs colorectales/génétique , ADN tumoral/sang , ADN tumoral/analyse , Dépistage précoce du cancer/méthodes , Fèces/composition chimique , Sang occulte , Séquençage nucléotidique à haut débit , Sensibilité et spécificité , États précancéreux/diagnostic , États précancéreux/génétiqueRÉSUMÉ
BACKGROUND/AIM: Gastric cancer and its precancerous lesions represent a significant public health concern. A subset of gastric cancers exhibits mutations in the TP53 gene, often accompanying distinctive morphologic alterations. This study aimed to assess the diagnostic efficacy of p53 immunostaining in real-world clinical settings. PATIENTS AND METHODS: A retrospective analysis was conducted on 50 cases of gastric tumors and tumor-like lesions, wherein p53 immunostaining played a pivotal diagnostic role. The staining pattern of p53 was examined in conjunction with clinicopathologic parameters. RESULTS: Mutant p53 staining pattern demonstrated a significant association with high-grade nuclear atypia (p<0.001), high-grade dysplasia, and tubular adenocarcinoma (p<0.001), as well as microsatellite instability status (p=0.034). Furthermore, the diagnostic utility of p53 immunostaining was evident in scenarios where: 1) biopsy specimens contained few tumor cells, 2) pathologic evaluation of resection margins was limited by cauterization artifacts, and 3) distinction between low-grade and high-grade gastric dysplasia was challenging. CONCLUSION: P53 immunostaining can be helpful for the diagnosis of gastric tumor and tumor-like lesions, and accurate pathologic margin evaluation, particularly in lesions demonstrating intestinal-type differentiation and some degree of nuclear atypia.
Sujet(s)
Marqueurs biologiques tumoraux , Immunohistochimie , Tumeurs de l'estomac , Protéine p53 suppresseur de tumeur , Humains , Tumeurs de l'estomac/diagnostic , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Protéine p53 suppresseur de tumeur/métabolisme , Protéine p53 suppresseur de tumeur/génétique , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Marqueurs biologiques tumoraux/métabolisme , Adulte , Études rétrospectives , Sujet âgé de 80 ans ou plus , Instabilité des microsatellites , États précancéreux/diagnostic , États précancéreux/génétique , États précancéreux/métabolisme , États précancéreux/anatomopathologie , Grading des tumeurs , MutationRÉSUMÉ
The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC-derived cell lines. We further demonstrated that TRIP12 was required for PDAC-derived cell growth and for the expression of E2F-targeted genes. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of KrasG12D-induced preneoplastic lesions and impaired metastasis formation in the presence of mutated KrasG12D and Trp53R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Sujet(s)
Cellules acineuses , Carcinome du canal pancréatique , Tumeurs du pancréas , Ubiquitin-protein ligases , Animaux , Tumeurs du pancréas/anatomopathologie , Tumeurs du pancréas/génétique , Tumeurs du pancréas/métabolisme , Tumeurs du pancréas/enzymologie , Humains , Cellules acineuses/anatomopathologie , Cellules acineuses/métabolisme , Cellules acineuses/enzymologie , Ubiquitin-protein ligases/métabolisme , Ubiquitin-protein ligases/génétique , Carcinome du canal pancréatique/anatomopathologie , Carcinome du canal pancréatique/génétique , Carcinome du canal pancréatique/métabolisme , Carcinome du canal pancréatique/enzymologie , Métaplasie/anatomopathologie , Métaplasie/métabolisme , Plasticité cellulaire , Carcinogenèse/génétique , Carcinogenèse/métabolisme , Souris , Lignée cellulaire tumorale , Prolifération cellulaire , Souris knockout , Régulation de l'expression des gènes tumoraux , États précancéreux/anatomopathologie , États précancéreux/génétique , États précancéreux/métabolisme , États précancéreux/enzymologie , Transformation cellulaire néoplasique/génétique , Transformation cellulaire néoplasique/anatomopathologie , Transformation cellulaire néoplasique/métabolisme , Protéines de transportRÉSUMÉ
Oral Submucous Fibrosis (OSMF) is a chronic precancerous disorder of the oral mucosa caused by chewing of areca nut and its other variants. Chewing of areca nuts leads to dysregulated expression of specific genes, leading to various premalignant or malignant disorders. This study aimed to determine the differential expression of the diagnostic genes (MYH6, TNNT3, MYL1, and TPM2) in healthy controls and OSMF patients using saliva and tissue samples, determining the histopathological grade of the clinical samples. A total of 20 patients were included in the study and were divided into two groups: Group I consisted of 10 healthy patients (control group) and Group II consisted of 10 OSMF patients. Unstimulated whole saliva samples were collected from both groups, and the tissue samples were divided into two parts: one for RT-qPCR analysis and the other for histopathological assay. The expression profile of genes concerning OSMF saliva and tissue samples was significantly upregulated compared to the healthy control, and all the clinical samples of the study were categorized into histopathological grade 1. The findings of this study concluded that these genes can be referred to as diagnostic genes for OSMF in early and very early clinical samples, and saliva can be used as a promising diagnostic tool for early OSMF studies.
Sujet(s)
Fibrose buccale sous-muqueuse , Salive , Humains , Fibrose buccale sous-muqueuse/génétique , Fibrose buccale sous-muqueuse/anatomopathologie , Mâle , Adulte , Femelle , Transcriptome , Muqueuse de la bouche/anatomopathologie , Adulte d'âge moyen , Analyse de profil d'expression de gènes/méthodes , Areca/effets indésirables , Jeune adulte , États précancéreux/génétique , États précancéreux/anatomopathologieRÉSUMÉ
BACKGROUND: Despite the oral cavity being readily accessible, oral cancer (OC) remains a significant burden. The objective of this study is to develop a DNA ploidy-based cytology test for early detection of high-risk oral lesions. METHODS: This retrospective study was conducted using 569 oral brushing samples collected from 95 normal and 474 clinically abnormal mucosa with biopsy diagnosis of reactive, low-grade or high-grade precancer or cancers. Brushing cells were processed to characterize DNA ploidy. A two-step DNA ploidy-based algorithm, the DNA ploidy oral cytology (DOC) test, was developed using a training set, and verified in test and validation sets to differentiate high-grade lesions (HGLs) from normal. The prognostic value of the test was evaluated by an independent outcome cohort, including progressed and non-progressing normal, reactive and low-grade lesions. Classification performance was assessed by accuracy, sensitivity, and specificity, while the prognostic value was evaluated by using the Cox proportional hazards analysis on 3-year progression-free survival (PFS). RESULTS: The developed DOC test exhibited high accuracy for detecting HGLs in the test and validation sets, with a sensitivity of 0.97 and 0.96, respectively. Its application to the Outcome cohort demonstrated significant prognostic value for 3-year PFS (log rank, p < 0.001). Multivariate analysis showed that high-grade pathology was the only variable explaining positive DOC test, not age, smoking, or lesional site. CONCLUSION: Clinical implementation of the DOC test could provide an effective screening method for detecting HGLs for biopsy and lesions at risk of progression.
Sujet(s)
Évolution de la maladie , Tumeurs de la bouche , Ploïdies , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Humains , Mâle , Adulte d'âge moyen , Algorithmes , Cytodiagnostic/méthodes , Dépistage précoce du cancer , Tumeurs de la bouche/anatomopathologie , Tumeurs de la bouche/génétique , États précancéreux/anatomopathologie , États précancéreux/génétique , Pronostic , Études rétrospectives , Sensibilité et spécificitéRÉSUMÉ
BACKGROUND AND OBJECTIVES: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. METHODS: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. RESULTS: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub-entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise-reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. CONCLUSIONS: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings.
Sujet(s)
Porocarcinome eccrine , Analyse de profil d'expression de gènes , Tumeurs des glandes sudoripares , Humains , Porocarcinome eccrine/génétique , Porocarcinome eccrine/anatomopathologie , Tumeurs des glandes sudoripares/génétique , Tumeurs des glandes sudoripares/anatomopathologie , Tumeurs des glandes sudoripares/métabolisme , États précancéreux/génétique , États précancéreux/anatomopathologie , Femelle , Mâle , Transformation cellulaire néoplasique/génétique , Régulation de l'expression des gènes tumoraux , Sujet âgé , Adulte d'âge moyenRÉSUMÉ
OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.
Sujet(s)
Adénocarcinome pulmonaire , , Tumeurs du poumon , Mutation , Invasion tumorale , Humains , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/anatomopathologie , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Évolution de la maladie , Régulation de l'expression des gènes tumoraux , Transcriptome , Analyse de profil d'expression de gènes , Adénocarcinome in situ/génétique , Adénocarcinome in situ/anatomopathologie , États précancéreux/génétique , États précancéreux/anatomopathologie , Marqueurs biologiques tumoraux/génétiqueRÉSUMÉ
Objectives: To develop and validate predictive models for esophageal squamous cell carcinoma (ESCC) using circulating cell-free DNA (cfDNA) terminal motif analysis. The goal was to improve the non-invasive detection of early-stage ESCC and its precancerous lesions. Methods: Between August 2021 and November 2022, we prospectively collected plasma samples from 448 individuals at the Department of Endoscopy, Cancer Hospital, Chinese Academy of Medical Sciences for cfDNA extraction, library construction, and sequencing. We analyzed 201 cases of ESCC, 46 high-grade intraepithelial neoplasia (HGIN), 46 low-grade intraepithelial neoplasia (LGIN), 176 benign esophageal lesions, and 29 healthy controls. Participants, including ESCC patients and control subjects, were randomly assigned to a training set (n=284) and a validation set (n=122). The training cohort underwent z-score normalization of cfDNA terminal motif matrices and a selection of distinctive features differentiated ESCC cases from controls. The random forest classifier, Motif-1 (M1), was then developed through principal component analysis, ten-fold cross-validation, and recursive feature elimination. M1's efficacy was then validated in the validation and precancerous lesion sets. Subsequently, individuals with precancerous lesions were included in the dataset and participants were randomly allocated to newly formed training (n=243), validation (n=105), and test (n=150) cohorts. Using the same procedure as M1, we trained the Motif-2 (M2) random forest model with the training cohort. The M2 model's accuracy was then confirmed in the validation cohort to establish the optimal threshold and further tested by performing validation in the test cohort. Results: We developed two cfDNA terminal motif-based predictive models for ESCC and associated precancerous conditions. The first model, M1, achieved a sensitivity of 90.0%, a specificity of 77.4%, and an area under the curve (AUC) of 0.884 in the validation cohort. For LGIN, HGIN, and T1aN0 stage ESCC, M1's sensitivities were 76.1%, 80.4%, and 91.2% respectively. Notably, the sensitivity for jointly predicting HGIN and T1aN0 ESCC reached 85.0%. Both the predictive accuracy and sensitivity increased in line with the cancer's progression (Pï¼0.001). The second model, M2, exhibited a sensitivity of 87.5%, a specificity of 77.4%, and an AUC of 0.857 in the test cohort. M2's sensitivities for detecting precancerous lesions and ESCC were 80.0% and 89.7%, respectively, and it showed a combined sensitivity of 89.4% for HGIN and T1aN0 stage ESCC. Conclusions: Two predictive models based on cfDNA terminal motif analysis for ESCC and its precancerous lesions are developed. They both show high sensitivity and specificity in identifying ESCC and its precancerous stages, indicating its potential for early ESCC detection.
Sujet(s)
Acides nucléiques acellulaires , Tumeurs de l'oesophage , Carcinome épidermoïde de l'oesophage , États précancéreux , Humains , Carcinome épidermoïde de l'oesophage/génétique , Carcinome épidermoïde de l'oesophage/sang , Carcinome épidermoïde de l'oesophage/diagnostic , Tumeurs de l'oesophage/génétique , Tumeurs de l'oesophage/sang , Tumeurs de l'oesophage/diagnostic , États précancéreux/sang , États précancéreux/diagnostic , États précancéreux/génétique , Acides nucléiques acellulaires/sang , Dépistage précoce du cancer/méthodes , Marqueurs biologiques tumoraux/sang , Mâle , Femelle , Épithélioma in situ/sang , Épithélioma in situ/diagnostic , Épithélioma in situ/génétique , Épithélioma in situ/anatomopathologieSujet(s)
Carcinome épidermoïde , Altération de l'ADN , Kératinocytes , Tumeurs cutanées , Humains , Tumeurs cutanées/génétique , Tumeurs cutanées/anatomopathologie , Tumeurs cutanées/métabolisme , Carcinome épidermoïde/génétique , Carcinome épidermoïde/anatomopathologie , Carcinome épidermoïde/métabolisme , Kératinocytes/métabolisme , Kératinocytes/anatomopathologie , Régulation de l'expression des gènes tumoraux , États précancéreux/génétique , États précancéreux/anatomopathologie , États précancéreux/métabolismeRÉSUMÉ
Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.
Sujet(s)
Tumeurs gastro-intestinales , Humains , Tumeurs gastro-intestinales/thérapie , Tumeurs gastro-intestinales/diagnostic , Tumeurs gastro-intestinales/génétique , Tumeurs gastro-intestinales/étiologie , États précancéreux/diagnostic , États précancéreux/génétique , États précancéreux/anatomopathologie , États précancéreux/thérapie , Prédisposition génétique à une maladie , Dépistage précoce du cancer , Syndromes néoplasiques héréditaires/diagnostic , Syndromes néoplasiques héréditaires/génétique , Syndromes néoplasiques héréditaires/thérapieRÉSUMÉ
Skin cancers, including melanoma and keratinocyte carcinomas, are responsible for increasing health care burden internationally. Risk stratification and early detection are paramount for prevention and less risky treatment to overall improve patient outcomes and disease morbidity. Here, the authors discuss the key concepts leading to skin cancer initiation and progression. The authors also outline precursor and progression models for melanoma and keratinocyte carcinomas, including discussion of genetic alterations associated with the various stages of progression. Finally, the authors discuss the significance of immunoediting and the drivers behind increased risk of cutaneous malignancy in the state of immune dysregulation.
Sujet(s)
Dépistage précoce du cancer , Génomique , Tumeurs cutanées , Humains , Tumeurs cutanées/génétique , Tumeurs cutanées/diagnostic , Tumeurs cutanées/thérapie , Génomique/méthodes , Mélanome/génétique , Mélanome/diagnostic , Évolution de la maladie , États précancéreux/génétique , États précancéreux/diagnosticRÉSUMÉ
The highest frequency of genetic alterations in the tumor suppressor ARID1A occurs in malignancies of the female reproductive tract. The prevalence of ARID1A alterations in gynecologic precancers and cancers is summarized from the literature, and the putative mechanisms of tumor suppressive action examined both in benign/precursor lesions including endometriosis and atypical hyperplasia and in malignancies of the ovary, uterus, cervix and vagina. ARID1A alterations in gynecologic cancers are usually loss-of-function mutations, resulting in diminished or absent protein expression. ARID1A deficiency results in pleiotropic downstream effects related not only to its role in transcriptional regulation as a SWI/SNF complex subunit, but also related to the functions of ARID1A in DNA replication and repair, immune modulation, cell cycle progression, endoplasmic reticulum (ER) stress and oxidative stress. The most promising actionable signaling pathway interactions and therapeutic vulnerabilities of ARID1A mutated cancers are presented with a critical review of the currently available experimental and clinical evidence. The role of ARID1A in response to chemotherapeutic agents, radiation therapy and immunotherapy is also addressed. In summary, the multi-faceted role of ARID1A mutation in precancer and cancer is examined through a clinical lens focused on development of novel preventive and therapeutic interventions for gynecological cancers.