BACKGROUND:Pancreatic cancer (PC) presents a significant challenge in oncology because of its late-stage diagnosis and limited treatment options. The inadequacy of current screening methods has prompted investigations into stool-based assays and microbial classifiers as potential early detection markers. The gut microbiota composition of PC patients may be influenced by population differences, thereby impacting the accuracy of disease prediction. However, comprehensive profiling of the PC gut microbiota and analysis of these cofactors remain limited. Therefore, we analyzed the stool microbiota of 33 Finnish and 50 Iranian PC patients along with 35 Finnish and 34 Iranian healthy controls using 16S rRNA gene sequencing. We assessed similarities and differences of PC gut microbiota in both populations while considering sociocultural impacts and generated a statistical model for disease prediction based on microbial classifiers. Our aim was to expand the current understanding of the PC gut microbiota, discuss the impact of population differences, and contribute to the development of early PC diagnosis through microbial biomarkers. RESULTS:Compared with healthy controls, PC patients presented reduced microbial diversity, with discernible microbial profiles influenced by factors such as ethnicity, demographics, and lifestyle. PC was marked by significantly higher abundances of facultative pathogens including Enterobacteriaceae, Enterococcaceae, and Fusobacteriaceae, and significantly lower abundances of beneficial bacteria. In particular, bacteria belonging to the Clostridia class, such as butyrate-producing Lachnospiraceae, Butyricicoccaceae, and Ruminococcaceae, were depleted. A microbial classifier for the prediction of pancreatic ductal adenocarcinoma (PDAC) was developed in the Iranian cohort and evaluated in the Finnish cohort, where it yielded a respectable AUC of 0.88 (95% CI 0.78, 0.97). CONCLUSIONS:This study highlights the potential of gut microbes as biomarkers for noninvasive PC screening and the development of targeted therapies, emphasizing the need for further research to validate these findings in diverse populations. A comprehensive understanding of the role of the gut microbiome in PC could significantly enhance early detection efforts and improve patient outcomes.

Background: Stools from colorectal cancer patients are noninvasive samples that could be used to compare the frequency of hotspot mutations between two different ethnic cohorts. Materials and Methods: We collected stool samples from the Iranian cohort (52 patients and 49 controls) and the Finnish cohort (40 patients and 14 controls). Following stool DNA extraction, we used the AmpliSeq Colon and Lung Cancer panel to prepare DNA libraries before sequencing. Results: The Iranian cohort exhibited 35 hotspot mutations in the BRAF, ERBB4, FBXW7, FGFR1, FGFR3, KRAS, MAP2K, MET, NRAS, PIK3C, SMAD4, and TP53 genes. In the Finnish cohort, 13 hotspot mutations were found in the AKT1, APC, KIT, KRAS, SMO, STK11, and TP53 genes. Mutations in NRAS and FGFR3 were observed only in the Iranian cohort, while APC mutations were exclusive for the Finnish cohort. Conclusion: Genes involved in MAPK and PI3K-MAPK pathways showed a higher frequency of mutations in Iranian patients which may have therapeutic implications.

PDF file - KB, Supplementary Table S1. Taqman information for expression analysis of microRNAs. Supplementary Table S2. List of the 11 microRNAs used in the classifier model. Supplementary Table S3. List of the genes with a fc<0.77 (Down-regulated) or fc>1.3 (Up-regulated) and a pvalue≤0.05 identified in the expression array.

Increasing evidence suggests that the SYT-SSX fusion gene plays an important role in synovial sarcoma development and progression. However, very little is known about the downstream targets of SYT-SSX. In this study, we used antisense oligonucleotides to block the expression of the SYT-SSX fusion gene in synovial sarcoma cells. By comparing SYT-SSX inhibited cells with noninhibited cells, the gene expression profile was analysed using cDNA microarray and established by real-time PCR. Herewith, using a filter containing 1176 cancer-relevant genes, we found that the DNA repair gene XRCC4 and the DNA mismatch repair gene MSH2 were downregulated, whereas the gene encoding for the serine/threonine protein kinase PRK (also known as CNK), and the macrophage inhibitory cytokine MICI (also known as PLAB) were upregulated after the inhibition of SYT-SSX. In comparison, expression of the XRCC4 gene was undergoing the strongest alteration. Consistently, the protein expression of XRCC4 was found to be decreased after SYT-SSX inhibition, whereas there were no detectable changes for the other gene products. Our study provides some clues to elucidate the signaling pathways of the SYT-SSX fusion gene, as well as it demonstrates a valuable model system for search for other SYT-SSX targets.

Supplementary Table 6 from Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category

PDF file - 64KB, Regression analysis of the log transformed hsa-miR-31-3p and gene expression levels plotted on x-axis and y-axis, respectively. The name of the gene and correlation p-values between expression values are indicated in the main title. Intervals specify computation of confidence (in red) or prediction (tolerance, in blue) intervals at 0.95 levels.

PDF file - 62KB, Kaplan-Meier curve for PFS according to the classification in high risk and low risk patients by the level of expression of 11 microRNAs.

Supplementary Data from Genomic Profiling of Chondrosarcoma: Chromosomal Patterns in Central and Peripheral Tumors

PDF file - 60KB, The red spot indicates the area under the curve superior to 0.7 for predicting the PFS at different endpoints, blue spot indicates the area under the curve superior to 0.64 which corresponds to the mean of the area under the curve for predicting the PFS at different endpoints.

Supplementary Table 5 from Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category

Supplementary Table 4 from Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category

PDF file - 62KB, Kaplan-Meier PFS according to level of expression of hsa-miR-31-3p in the whole series of 132 patients. For the 102 patients who were NRAS wild-type based on Sanger sequencing of exon 2 and 3, the hazard ratio was 2.51 CI95 percent (1.6-4) and the median progression free survival was 10.14 and 35.71 weeks respectively for the high and low risk groups.

PDF file - 64KB, Kaplan-Meier PFS according to level of expression of hsa-miR-31-3p in training set 1.

Supplementary Data and Figure Legends from Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer

Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient and cost-effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers.

Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.

Colorectal cancer (CRC) rated among the three most diagnosed cancers and the fourth main cause of death worldwide. CRC is a curable cancer provided to be diagnosed at its early-stage. Colonoscopy, stool and blood-based tests are in use for CRC diagnosis/screening. Due to low patient compliance, low specificity and high rate of false results, more reliable methods with desired level of detection accuracy and high patients’ compliance are highly demanded. Detecting hotspot mutations in stool DNA emerged as a robust noninvasive alternative, but due to the different genetic background of various populations and hence varied mutation spectrum/prevalence, prior assessment of CRC mutations in the population is essential. Here, we have evaluated stool DNAs from CRC patients and controls using a NGS based 22 genes panel. Hotspot mutations in NRAS , FGFR3, SMAD4 and TP53 genes had higher prevalence among the CRC patients compare to normal controls. Patients were followed up in their post-surgical period. Six of them (12%) with TP53 mutations (2 patients had NRAS mutation as well) were died of cancer. Those harboring mutations in TP53 and/or NRAS would be regarded as high risk and should be provided with special care.

Background Gastric adenocarcinoma is associated with H. pylori infection and inflammation that can result in the dysbiosis of gastric microbiota. The association of intestinal microbiota with gastric adenocarcinoma subtypes or with gastric gastrointestinal stromal tumors (GIST) is however not well known. Therefore, we performed 16S rRNA gene sequencing on DNA isolated from stool samples of Finnish patients and controls to study differences in microbiota among different histological subtypes of gastric adenocarcinoma, gastric GIST and healthy controls. Results We found that gut microbiota alpha diversity was lowest in diffuse adenocarcinoma patients, followed by intestinal type and GIST patients, although the differences were not significant compared to controls. Beta-diversity analysis however showed significant differences in microbiota composition for all subtypes compared to controls. Significantly higher abundance of Enterobacteriaceae was observed in both adenocarcinoma subtypes, whereas lower abundance of Bifidobacteriaceae was seen only in diffuse adenocarcinoma and of Oscillibacter in intestinal adenocarcinoma. Both GIST and adenocarcinoma patients had higher abundance of Enterobacteriaceae and lower abundance of Lactobacillaceae and Oscillibacter while lower abundance of Lachnoclostridium, Bifidobacterium, Parabacteroides and Barnesiella was seen only in the adenocarcinoma patients. Conclusions Our analysis shows association of higher Enterobacteriaceae abundance with all types of gastric tumors. Therefore it could be potentially useful as a marker of gastric malignancies. Lower gut microbiota diversity might be indicative of poorly differentiated, invasive, advanced or aggressive tumors and could possibly be a prognostic marker for gastric tumors.