A mucus production programme promotes classical pancreatic ductal adenocarcinoma.

OBJECTIVE: The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators. DESIGN: We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models. RESULTS: Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA - the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2/IRE1ß that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation. CONCLUSIONS: Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.

Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Oncogenic 'hotspot' mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice ('Kras;Gnas' mice) caused development of cystic lesions recapitulating IPMNs. OBJECTIVE: We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies. DESIGN: We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the 'Kras;Gnas' autochthonous model and tumour-derived cell lines (Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/Cas9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells. RESULTS: Induction of Gnas R201C-and resulting G(s)alpha signalling-leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D;Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction. CONCLUSION: Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.

Immune evasion in HPV- head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss.

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV-) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3+ and CD8+ T cell microenvironments in precancer (mostly CD3+, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV- HNSC after anti-PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype.

OBJECTIVE: Due to the limited number of modifiable risk factors, secondary prevention strategies based on early diagnosis represent the preferred route to improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). Here, we provide a comparative morphogenetic analysis of PDAC precursors aiming at dissecting the process of carcinogenesis and tackling the heterogeneity of preinvasive lesions. DESIGN: Targeted and whole-genome low-coverage sequencing, genome-wide methylation and transcriptome analyses were applied on a final collective of 122 morphologically well-characterised low-grade and high-grade PDAC precursors, including intestinal and gastric intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasias (PanIN). RESULTS: Epigenetic regulation of mucin genes determines the phenotype of PDAC precursors. PanIN and gastric IPMN display a ductal molecular profile and numerous similarly regulated pathways, including the Notch pathway, but can be distinguished by recurrent deletions and differential methylation and, in part, by the expression of mucin-like 3. Intestinal IPMN are clearly distinct lesions at the molecular level with a more instable genotype and are possibly related to a different ductal cell compartment. CONCLUSIONS: PDAC precursors with gastric and intestinal phenotype are heterogeneous in terms of morphology, genetic and epigenetic profile. This heterogeneity is related to a different cell identity and, possibly, to a different aetiology.

The Magic Triangle in Oral Potentially Malignant Disorders: Vitamin D, Vitamin D Receptor, and Malignancy.

OPMDs (oral potentially malignant disorders) are a group of disorders affecting the oral mucosa that are characterized by aberrant cell proliferation and a higher risk of malignant transformation. Vitamin D (VitD) and its receptor (VDR) have been extensively studied for their potential contributions to the prevention and therapeutic management of various diseases and neoplastic conditions, including oral cancer. Observational studies suggest correlations between VitD deficiency and higher cancer risk, worse prognosis, and increased mortality rates. Interestingly, emerging data also suggest a link between VitD insufficiency and the onset or progression of OPMDs. Understanding the role of the VitD-VDR axis not only in established oral tumors but also in OPMDs might thus enable early detection and prevention of malignant transformation. With this article, we want to provide an overview of current knowledge about OPMDs and VitD and investigate their potential association and ramifications for clinical management of OPMDs.

Severity of gastric intestinal metaplasia predicts the risk of gastric cancer: a prospective multicentre cohort study (GCEP).

OBJECTIVE: To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC. METHODS: A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN). RESULTS: There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV. CONCLUSIONS: We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.

Human gastric microbiota transplantation recapitulates premalignant lesions in germ-free mice.

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer-related mortality. Although microbes besides Helicobacter pylori may also contribute to gastric carcinogenesis, wild-type germ-free (GF) mouse models investigating the role of human gastric microbiota in the process are not yet available. We aimed to evaluate the histopathological features of GF mouse stomachs transplanted with gastric microbiota from patients with different gastric disease states and their relationships with the microbiota. DESIGN: Microbiota profiles in corpus and antrum tissues and gastric fluid from 12 patients with gastric dysplasia or GC were analysed. Thereafter, biopsied corpus and antrum tissues and gastric fluid from patients (n=15 and n=12, respectively) with chronic superficial gastritis, intestinal metaplasia or GC were inoculated into 42 GF C57BL/6 mice. The gastric microbiota was analysed by amplicon sequencing. Histopathological features of mouse stomachs were analysed immunohistochemically at 1 month after inoculation. An independent set of an additional 15 GF mice was also analysed at 1 year. RESULTS: The microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation. CONCLUSION: Major histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.

Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness.

BACKGROUND: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives DCIS to invasive breast cancer is unclear. Basal-like invasive breast cancers are aggressive. We have previously shown that NRAS is highly expressed selectively in basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers. METHODS: Wilcoxon rank-sum test was performed to assess expression of NRAS in DCIS compared to invasive breast tumors in patients. NRAS mRNA levels were also determined by fluorescence in situ hybridization in patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and association of NRAS mRNA levels with DCIS and invasive breast cancer was assessed by paired Wilcoxon signed-rank test. Pearson's correlation was calculated between NRAS mRNA levels and basal biomarkers in the TMAs, as well as in patient datasets. RNA-seq data were generated in cell lines, and unsupervised hierarchical clustering was performed after combining with RNA-seq data from a previously published patient cohort. RESULTS: Invasive breast cancers showed higher NRAS mRNA levels compared to DCIS samples. These NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signatures, lower ER, and higher p53 protein and Ki67 levels. We have shown previously that NRAS drives aggressive features in DCIS-like and basal-like SUM102PT cells. Here, we found that NRAS-silencing induced a shift to a luminal gene expression pattern. Conversely, NRAS overexpression in the luminal DCIS SUM225 cells induced a basal-like gene expression pattern, as well as an epithelial-to-mesenchymal transition signature. Furthermore, these cells formed disorganized mammospheres containing cell masses with an apparent reduction in adhesion. CONCLUSIONS: These data suggest that elevated NRAS levels in DCIS are not only a marker but can also control the emergence of basal-like features leading to more aggressive tumor activity, thus supporting the therapeutic hypothesis that targeting NRAS and/or downstream pathways may block disease progression for a subset of DCIS patients with high NRAS.

The upregulation of oncogenic miRNAs in swabbed samples obtained from oral premalignant and malignant lesions.

OBJECTIVES: Oncogenic miRNAs upregulated in OSCC play a range of versatile roles in oral carcinogenesis. Oral potentially malignant disorders (OPMDs) are the antecedent lesions to oral squamous carcinoma (OSCC) and they require a definitive diagnosis and early intervention. This study hypothesizes the presence of aberrant oncogenic miRNA expression in swabbed oral lesions. MATERIALS AND METHODS: The expression of miR-21, miR-31, miR-134, miR-146a, and miR-211 in swabbed samples from 36 dysplastic or hyperplastic OPMDs and 10 OSCCs, relative to respective normal mucosa within the same patient, is analyzed with qRT-PCR to develop a diagnosis. RESULTS: Upregulation of all tested miRNAs in OPMD and OSCC samples comparing to controls is found to have occurred. Receiver operating characteristics curve analysis shows that miR-31 gives the best diagnostic accuracy of 0.91 when differentiating OPMD/OSCC from controls. An analysis of miR-134 and miR-211 expression allows the discrimination of the dysplastic state associated with OPMD, while the use of expression of the combined miRNAs further improves the analytical performances when identifying the dysplastic state. The concordant upregulation of miR-21, miR-31, and miR-146a is found to occur during an early stage of OSCC carcinogenesis. CONCLUSION: This study demonstrates the upregulation of multiple oncogenic miRNAs in swabbed OPMD and OSCC samples. miRNA expression in swabbed collectives enables the differentiation between normal mucosa and OPMD/OSCC, independent of their histopathological severity. CLINICAL RELEVANCE: This conventional and convenient sampling tool, when coupled with an assessment of miR-31 expression, would seem to be an adjuvant approach to the diagnosis of OPMD and OSCC.

Plasma sex hormones and risk of conventional and serrated precursors of colorectal cancer in postmenopausal women.

BACKGROUND: Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown. METHODS: We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses' Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant. RESULTS: During 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24-0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17-1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02-2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99-1.78, P for trend = 0.03, respectively). CONCLUSIONS: The findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis.

Aneuploidy and loss of heterozygosity as risk markers for malignant transformation in oral mucosa.

The ability to predict malignant transformation in oral potentially malignant disorders would inform targeted treatment, provide prognostic information and allow secondary prevention. DNA ploidy and loss of heterozygosity assays are already in clinical use, and loss of heterozygosity has been used in prospective clinical trials. This review appraises published evidence of predictive ability and explores interpretation of heterogeneous studies, with different diagnostic methods, criteria and intention. Both methods have a sound biological foundation and have predictive value independent of dysplasia grading and clinical parameters. The application of these two techniques cannot be directly compared because of differences in expression of results and application to populations of different risk. Predicting malignant transformation accurately on an individual patient basis is not yet possible with either technique. However, they are valuable applications to stratify patients for inclusion in trials, identify the lowest risk patients and exclude risk when biopsy results are indeterminate for dysplasia.

Computational modelling suggests that Barrett's oesophagus may be the precursor of all oesophageal adenocarcinomas.

OBJECTIVE: Barrett's oesophagus (BE) is a known precursor to oesophageal adenocarcinoma (OAC) but current clinical data have not been consolidated to address whether BE is the origin of all incident OAC, which would reinforce evidence for BE screening efforts. We aimed to answer whether all expected prevalent BE, diagnosed and undiagnosed, could account for all incident OACs in the US cancer registry data. DESIGN: We used a multiscale computational model of OAC that includes the evolutionary process from normal oesophagus through BE in individuals from the US population. The model was previously calibrated to fit Surveillance, Epidemiology and End Results cancer incidence curves. Here, we also utilised age-specific and sex-specific US census data for numbers at-risk. The primary outcome for model validation was the expected number of OAC cases for a given calendar year. Secondary outcomes included the comparisons of resulting model-predicted prevalence of BE and BE-to-OAC progression to the observed prevalence and progression rates. RESULTS: The model estimated the total number of OAC cases from BE in 2010 was 9970 (95% CI: 9140 to 11 980), which recapitulates nearly all OAC cases from population data. The model simultaneously predicted 8%-9% BE prevalence in high-risk males age 45-55, and 0.1%-0.2% non-dysplastic BE-to-OAC annual progression in males, consistent with clinical studies. CONCLUSION: There are likely few additional OAC cases arising in the US population outside those expected from individuals with BE. Effective screening of high-risk patients could capture the majority of population destined for OAC progression and potentially decrease mortality through early detection and curative removal of small (pre)cancers during surveillance.

Evaluation of pre-malignant cervical lesions in females presenting with abnormal pelvic complaints.

OBJECTIVE: To evaluate premalignant cervical lesions by using Papanicolaou smears in females presenting with abnormal pelvic complaints. METHODS: The descriptive cross-sectional study was conducted from June to November 2013 at the Department of Histopathology, Mayo Hospital, Lahore, and comprised female patients aged 25-70 years presenting with abnormal pelvic complaints with no cause in the uterus checked through ultrasonography who were undergoing cervical Papanicolaou smear. The smears were spray-fixed and placed in 95% reagent alcohol and was then stained with haematoxylin and eosin stain. The cytological examination was carried out under light microscope. SPSS 16 was used for data analysis. RESULTS: There were 210 women with a mean age of 39.51±8.32 years. Vaginal discharge was present in 89(42.4%) women; postcoital bleeding in 12(5.7%), and intermenstrual bleeding was present in 21(10%) women. Dyspareunia was present in 33(15.7%) women, and pelvic pain in 60(28.6%). Overall, premalignant cervical cancer was noted in 17(8.1%) patients. Atypical squamous cells of unknown significance was present in 5(2.4%) women, low-grade squamous intraepithelial lesion (LSIL) in 8(3.8%), and high-grade squamous intraepithelial lesion in 4(1.9%) patients of cervical cancer. CONCLUSIONS: The frequency of premalignant cervical lesions in symptomatic patients was high enough to highlight the importance of early detection of cervical cancer.

Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients.

OBJECTIVE: Operative link on gastritis assessment (OLGA) staging for gastritis ranks the risk for gastric cancer (GC) in progressive stages (0-IV). This prospective study aimed at quantifying the cancer risk associated with each gastritis stage. DESIGN: A cohort of 1755 consecutive patients with dyspepsia underwent initial (T-0) oesophagogastroduodenoscopy with mapped gastric biopsies, OLGA staging and assessment of Helicobacter pylori infection. Patients were followed for 55 months (median); patients with stages II III and IV underwent a second endoscopy/restaging (T-1), and those with stages 0 and I were followed clinically and through in-depth clinical and record checking. Endpoints were OLGA stage at T-1 and development of gastric epithelial neoplasia. RESULTS: At T-0, 77.6% of patients had stage 0, 14.4% stage I, 5.1% stage II, 2.1% stage III and 0.85% stage IV. H. pylori infection was detected in 603 patients at T-0 and successfully eradicated in 602 of them; 220 had a documented history of H. pylori eradication; and 932 were H. pylori naïve-negative. Incident neoplastic lesions (prevalence=0.4%; low-grade intraepithelial neoplasia (IEN)=4; high-grade IEN=1; GC=2) developed exclusively in patients with stages III-IV. The risk for epithelial neoplasia was null in patients at stages 0, I and II (95% CI 0 to 0.4), 36.5 per 1000 person-years in patients at stage III (95% CI 13.7 to 97.4) and 63.1 per 1000 person-years in patients at stage IV (95% CI 20.3 to 195.6). CONCLUSIONS: This prospective study confirms that OLGA staging reliably predicts the risk for development of gastric epithelial neoplasia. Although no neoplastic lesions arose in H. pylori-naïve patients, the H. pylori eradication in subjects with advanced stages (III-IV) did not abolish the risk for neoplastic progression.

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1.

BACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

The association between fecal hemoglobin concentration and oral potentially malignant disorders.

OBJECTIVES: The present study was to investigate the association between fecal hemoglobin (f-Hb) concentration and oral cancer and its precursor, oral potentially malignant disorders (OPMD). METHODS: We used a population-based longitudinal cohort study data based on both Taiwanese nationwide oral and colorectal cancer screening programs implemented between 2004 and 2009. The total of 235,234 smokers and/or betel-quid chewers aged 50 to 69 years free of oral cancer and OPMD at entry were followed up over time to quantify the association between baseline f-Hb concentration on newly diagnosed oral cancer and OPMD. RESULTS: The risk of OPMD increased with baseline f-Hb in a dose manner, yielding a statistically significant elevated risk of developing OPMD in parallel with the incremental concentration of f-Hb (adjusted hazard ratios = 0.99, 1,11, 1,07, 1,57, and 1,63 for f-Hb categories of 1-9, 10-19, 20-49, 50-89, and ≥90 µg Hb/g, respectively, as compared with the reference group (low and undetectable f-Hb concentrations)) However, there was lacking of a statistical significance for the corresponding association regarding the risk of oral cancer, which is possibly due to sparse cases given a shorter follow-up time. CONCLUSION: We discovered that f-Hb concentration was positively related to the risk of OPMD. f-Hb can be used as a biomarker for early detection of OPMD.

Leveraging premalignant biology for immune-based cancer prevention.

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.

Are There Any Predictors of Endometrial Premalignancy/Malignancy within Endometrial Polyps in Infertile Patients?

BACKGROUND: In the literature, there is no detailed analysis on the prediction factors for premalignancy/malignancy within endometrial polyps (EPs) in infertile patients. In this study, we aimed to determine the frequency of endometrial premalignancy/malignancy within EPs in infertile patients undergoing office hysteroscopic polypectomy and identify the factors that can potentially predict an endometrial premalignancy/malignancy within EPs. METHOD: A total of 957 infertile patients undergoing office hysteroscopy were diagnosed with EPs between February 2011 and August 2018. Patients were divided into 2 groups according to the pathological examination of EPs as benign (Group 1; n = 939) and premalignant/malignant (Group 2; n = 18). The medical records of all patients included in the study were reviewed retrospectively. RESULTS: In this cohort, prevalence of endometrial premalignancy/malignancy within EPs was 18/957 (1.88%). On univariate analysis, age, polyp size, diabetes, hypertension, and causes of infertility did not differ between the 2 groups. On multivariate analysis, diffuse polypoid appearance of the endometrial cavity on office hysteroscopy (hazard ratio [HR] 4.1; 95% CI 1.576-10.785), duration of infertility, (HR 4; 95% CI 1.279-12.562), and body mass index (HR 7.9; 95% CI 2.591-24.258) were found to be independent predictors of endometrial premalignancy/malignancy within polyps in infertile patients. CONCLUSION: When diffuse polypoid appearance of the endometrial cavity is detected in an infertile patient during office hysteroscopy, hysteroscopy-guided resection and endometrial curettage should be performed. The pathological specimen should be sent for histopathological evaluation to diagnose possible endometrial premalignancy/malignancy within polyps.

Modeling Human Ductal Carcinoma In Situ in the Mouse.

Breast cancer development is a multi-step process in which genetic and molecular heterogeneity occurs at multiple stages. Ductal carcinoma arises from pre-invasive lesions such as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), which progress to invasive and metastatic cancer. The feasibility of obtaining tissue samples from all stages of progression from the same patient is low, and thus molecular studies dissecting the mechanisms that mediate the transition from pre-invasive DCIS to invasive carcinoma have been hampered. In the past 25 years, numerous mouse models have been developed that partly recapitulate the histological and biological properties of early stage lesions. In this review, we discuss in vivo model systems of breast cancer progression from syngeneic mouse models to human xenografts, with particular focus on how accurately these models mimic human disease.