scholarly journals Genomic, Microbial and Immunological Microenvironment of Colorectal Polyps

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3382
Author(s):  
Benita C. Y. Tse ◽  
Zoe Welham ◽  
Alexander F. Engel ◽  
Mark P. Molloy
Keyword(s):  
Control Strategies ◽  
Prognostic Significance ◽  
Cancer Control ◽  
Colorectal Polyps ◽  
Driver Mutations ◽  
Tumour Suppressor Genes ◽  
Potential Contribution ◽  
Colonoscopic Surveillance ◽  
Sequencing Technologies ◽  
Molecular Landscape

Colorectal cancer (CRC) develops from pre-cancerous cellular lesions in the gut epithelium, known as polyps. Polyps themselves arise through the accumulation of mutations that disrupt the function of key tumour suppressor genes, activate proto-oncogenes and allow proliferation in an environment where immune control has been compromised. Consequently, colonoscopic surveillance and polypectomy are central pillars of cancer control strategies. Recent advances in genomic sequencing technologies have enhanced our knowledge of key driver mutations in polyp lesions that likely contribute to CRC. In accordance with the prognostic significance of Immunoscores for CRC survival, there is also a likely role for early immunological changes in polyps, including an increase in regulatory T cells and a decrease in mature dendritic cell numbers. Gut microbiotas are under increasing research interest for their potential contribution to CRC evolution, and changes in the gut microbiome have been reported from analyses of adenomas. Given that early changes to molecular components of bowel polyps may have a direct impact on cancer development and/or act as indicators of early disease, we review the molecular landscape of colorectal polyps, with an emphasis on immunological and microbial alterations occurring in the gut and propose the potential clinical utility of these data.

scholarly journals Low Back Pain: The Potential Contribution of Supraspinal Motor Control and Proprioception

2018 ◽  
Vol 25 (6) ◽  
pp. 583-596 ◽  
Author(s):  
Michael Lukas Meier ◽  
Andrea Vrana ◽  
Petra Schweinhardt
Keyword(s):  
Low Back Pain ◽  
Motor Control ◽  
Back Pain ◽  
Control Strategies ◽  
Intervertebral Discs ◽  
Cortical Reorganization ◽  
Potential Contribution ◽  
Low Back ◽  
Output Side

Motor control, which relies on constant communication between motor and sensory systems, is crucial for spine posture, stability and movement. Adaptions of motor control occur in low back pain (LBP) while different motor adaption strategies exist across individuals, probably to reduce LBP and risk of injury. However, in some individuals with LBP, adapted motor control strategies might have long-term consequences, such as increased spinal loading that has been linked with degeneration of intervertebral discs and other tissues, potentially maintaining recurrent or chronic LBP. Factors contributing to motor control adaptations in LBP have been extensively studied on the motor output side, but less attention has been paid to changes in sensory input, specifically proprioception. Furthermore, motor cortex reorganization has been linked with chronic and recurrent LBP, but underlying factors are poorly understood. Here, we review current research on behavioral and neural effects of motor control adaptions in LBP. We conclude that back pain-induced disrupted or reduced proprioceptive signaling likely plays a pivotal role in driving long-term changes in the top-down control of the motor system via motor and sensory cortical reorganization. In the outlook of this review, we explore whether motor control adaptations are also important for other (musculoskeletal) pain conditions.

scholarly journals The state of cancer in Meru, Kenya: a retrospective study

2019 ◽  
Vol 2 ◽  
pp. 167
Author(s):  
Francis Kobia ◽  
Jesse Gitaka ◽  
Francis Makokha ◽  
Moses Kamita ◽  
Joshua Kibera ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Stomach Cancer ◽  
Control Strategies ◽  
Cancer Control ◽  
Cancer Registries ◽  
The State ◽  
Cancer Type ◽  
African Countries ◽  
Low Middle Income Countries ◽  
Cancer Rates

Background: It is projected that by 2030, 70% of all cancer related deaths will occur in low-middle income countries. However, data on the state of cancer in most African countries is scanty. Cancer estimates for Kenya are based on the Nairobi and Eldoret cancer registries, leaving most parts of the country unrepresented. Lacking national coverage, these data do not accurately reflect Kenya’s cancer burden. The paucity of reliable data impedes formulation of effective cancer control strategies and cancer research prioritization. Here, we report the findings of a retrospective study of the cancer state in Meru County, Kenya. Methods: A retrospective analysis of patient files at Meru hospice was carried out. 2349 cancer cases seen at the Meru hospice between 2003 and 2018 were analyzed. Data abstracted from the records included patient age, gender and cancer type. The abstracted data was analyzed by descriptive statistics. Results: Our results indicate that cancer is almost evenly distributed across genders, with men accounting for 49% and women 51%. Stomach cancer rates are strikingly elevated and equal to those in countries with the highest stomach cancer rates globally – making it the commonest cancer in this region (14%). Among men, the most common cancers affect the prostate (18%), stomach (17%), esophagus (14%), head & neck (12%), liver (8%) and colorectum (5%). Among women, the commonest are cancers of the breast (22%), cervix (20%), stomach (11%), esophagus (8%), head & neck (6%) and liver (5%). Breast cancer occurs at a notably early age, with 20% of those affected aged below 40. Lung cancer rates are notably low in this region (1.3%) relative to world estimates. Conclusion: Cancer distribution in Meru is nearly even between sexes. Our analysis suggests that the Meru region is a stomach cancer hotspot and that it also experiences elevated esophageal cancer levels.

scholarly journals Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

2020 ◽  
Vol 21 (22) ◽  
pp. 8757
Author(s):  
Iris B. A. W. te Paske ◽  
Marjolijn J. L. Ligtenberg ◽  
Nicoline Hoogerbrugge ◽  
Richarda M. de Voer
Keyword(s):  
Colorectal Cancer ◽  
Candidate Gene ◽  
Gene Discovery ◽  
Hereditary Colorectal Cancer ◽  
Potential Contribution ◽  
Risk Genes ◽  
Gene Search ◽  
Whole Exome ◽  
Polyposis Syndromes ◽  
Molecular Landscape

To discover novel high-penetrant risk loci for hereditary colorectal cancer (hCRC) and polyposis syndromes many whole-exome and whole-genome sequencing (WES/WGS) studies have been performed. Remarkably, these studies resulted in only a few novel high-penetrant risk genes. Given this observation, the possibility and strategy to identify high-penetrant risk genes for hCRC and polyposis needs reconsideration. Therefore, we reviewed the study design of WES/WGS-based hCRC and polyposis gene discovery studies (n = 37) and provide recommendations to optimize discovery and validation strategies. The group of genetically unresolved patients is phenotypically heterogeneous, and likely composed of distinct molecular subtypes. This knowledge advocates for the screening of a homogeneous, stringently preselected discovery cohort and obtaining multi-level evidence for variant pathogenicity. This evidence can be collected by characterizing the molecular landscape of tumors from individuals with the same affected gene or by functional validation in cell-based models. Together, the combined approach of a phenotype-driven, tumor-based candidate gene search might elucidate the potential contribution of novel genetic predispositions in genetically unresolved hCRC and polyposis.

scholarly journals Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations

2020 ◽  
Author(s):  
Birgit Assmus ◽  
Sebastian Cremer ◽  
Klara Kirschbaum ◽  
David Culmann ◽  
Katharina Kiefer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Amplicon Sequencing ◽  
Driver Mutations ◽  
Driver Gene ◽  
Roc Curve Analysis ◽  
Driver Genes ◽  
Clone Size

Abstract Aims Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF. Methods and results We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF < 0.5%), 29% with only one DNMT3A- or TET2-CH-driver mutations above the respective cut-off level and 42% in patients harbouring both DNMT3A- and TET2-CH-driver mutations above the respective cut-off levels. In carriers of a DNMT3A mutation with VAF ≥ 1.15%, 5-year mortality was 31%, compared with 18% mortality in those with VAF < 1.15% (P = 0.048). Likewise, in patients with TET2 mutations, 5-year mortality was 32% with VAF ≥ 0.73%, compared with 19% mortality with VAF < 0.73% (P = 0.029). Conclusion The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

scholarly journals Genetics of MDS

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1049-1059 ◽  
Author(s):  
Seishi Ogawa
Keyword(s):  
Rna Splicing ◽  
Myeloid Leukemia ◽  
Chromatin Modification ◽  
Driver Mutations ◽  
Subsequent Transformation ◽  
The Past ◽  
Sequencing Technologies ◽  
Age Related ◽  
Clonal Origin ◽  
Dna Methylations

Abstract Our knowledge about the genetics of myelodysplastic syndromes (MDS) and related myeloid disorders has been dramatically improved during the past decade, in which revolutionized sequencing technologies have played a major role. Through intensive efforts of sequencing of a large number of MDS genomes, a comprehensive registry of driver mutations recurrently found in a recognizable fraction of MDS patients has been revealed, and ongoing efforts are being made to clarify their impacts on clinical phenotype and prognosis, as well as their role in the pathogenesis of MDS. Among major mutational targets in MDS are the molecules involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. Showing substantial overlaps with driver mutations seen in acute myeloid leukemia (AML), as well as age-related clonal hematopoiesis in healthy individuals, these mutations are presumed to have a common clonal origin. Mutations are thought to be acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis, ultimately giving rise to MDS and subsequent transformation to AML in many patients. Significant correlations between mutations suggest the presence of functional interactions between mutations, which dictate disease progression. Mutations are frequently associated with specific disease phenotype, drug response, and clinical outcomes, and thus, it is essential to be familiar with MDS genetics for better management of patients. This review aims to provide a brief overview of the recent progresses in MDS genetics.

scholarly journals P061 The molecular landscape of perianal fistula in Crohn’s disease: opportunities for new therapeutic approaches

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S165-S165
Author(s):  
G Bislenghi ◽  
B Verstockt ◽  
J Sabino ◽  
C Caenepeel ◽  
S Verstockt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Differential Gene Expression ◽  
Perianal Fistula ◽  
Rectal Mucosa ◽  
Fistula Tract ◽  
Potential Contribution ◽  
Differential Gene ◽  
Molecular Landscape

Abstract Background Perianal Crohn’s disease (CD) is a debilitating condition, often refractory to medical therapy and requiring repetitive surgical interventions. Nonetheless, its pathophysiology is very poorly understood. Hence, we molecularly characterised the fistula tract and compared it to the molecular landscape of its inner rectal orifice. Methods We collected paired surgical biopsies from the fistula tract and the inner rectal fistula orifice in 29 CD patients with draining perianal fistula, requiring surgical examination under anaesthesia. RNA was extracted and single-end RNA sequencing performed using Illumina HiSeq4000. Sequencing data were analysed through differential gene expression (DESeq2) and corrected for the presence of proctitis. A false discovery rate of 0.001 was considered significant. In addition, cellular deconvolution methods (CIBERSORT) were applied to study the cellular composition of the fistula tract. Results Differential gene expression revealed 2701 transcripts being differentially expressed (1727 up, 974 down in fistula) between the fistula tract and the paired rectal mucosa. The top upregulated gene, LBP (fold change [FC]=2858.8, p = 3.6E−13), highlights the potential contribution of the microbiome. LBP has a central role in the innate immune system by binding to bacterial lipopolysaccharides (LPS) and facilitating the affinity between LPS and CD14, with the subsequent release of various cytokines. Several extracellular matrix proteins could be identified within the top 25 of upregulated genes, including MMP13 (FC = 358.8, p = 1.3E−11), ADAM12 (FC = 175.6, p = 1.4E−12), COL1A1 (FC = 77.1, p = 2.7E−10) and COL5A3 (FC = 32.1, p = 1.7E−12), emphasising the intense tissue remodelling going on in the fistula tract. Despite correcting for the confounding effect of proctitis, the fistula tract expressed higher levels of IL6 (FC = 133.1, p = 3.7E−9), TNF(FC = 14.2, p = 4.8E−5), OSM (FC = 24.3, p = 8.9E−5), IL12p40 (FC = 10.0, p = 8.1E−3), integrin α 4 (FC = 4.5, p = 9.3E−3), integrin β 7(FC = 3.8, p = 4.1E−3) but not IL23p19 (FC = 1.2, p = 0.9). Top downregulated genes were linked to the intestinal epithelium, including KRT19 (FC = −489.1, p = 5.5E−17), KRT8 (FC = −324.0, p = 1.1E−16), CEACAM6 (FC=−515.1, p = 4.5E−16) and MUC2 (FC=−795.4, p = 3.0E−15). Cellular deconvolution identified CD4 memory resting T cells (18.5%), M0 macrophages (17%), M2 macrophages (15.2%), neutrophils (9.2%) and plasma cells (7.5%) as the most abundant cells within the fistula tract. Conclusion We molecularly characterised the fistula tract in perianal CD and identified clear biological differences in comparison to the luminal tract, highlighting the potential of new therapeutic targets and cell types driving this debilitating condition.

scholarly journals NTRK2 Fusion Driven Pediatric Glioblastoma: Identification of key molecular drivers by personalized oncology

2019 ◽  
Vol 46 (s2) ◽  
pp. S64
Author(s):  
Levine ◽  
Y Shen ◽  
K Mungall ◽  
J Serrano ◽  
M Snuderl ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Braf V600e ◽  
Current Status ◽  
Driver Mutations ◽  
List Type ◽  
Idh1 R132h ◽  
Tyrosine Kinase 2 ◽  
Cerebellar Glioblastoma ◽  
Molecular Landscape

We describe the case of an 11-month-old girl with a rare cerebellar glioblastoma driven by a NACC2-NTRK2 (Nucleus Accumbens Associated Protein 2-Neurotrophic Receptor Tyrosine Kinase 2) fusion. Initial workup of our case demonstrated homozygous CDKN2A deletion, but immunohistochemistry for other driver mutations, including IDH1 R132H, BRAF V600E, and H3F3A K27M were negative, and ATRX was retained. Tissue was subsequently submitted for personalized oncogenomic analysis, including whole genome and whole transcriptome sequencing, which demonstrated an activating NTRK2 fusion, as well as high PD-L1 expression, which was subsequently confirmed by immunohistochemistry. Furthermore, H3 and IDH demonstrated wildtype status. These findings suggested the possibility of treatment with either NTRK- or immune checkpoint- inhibitors through active clinical trials. Ultimately, the family pursued standard treatment that involved Head Start III chemotherapy and proton radiotherapy. Notably, at most recent follow upapproximately two years from initial diagnosis, the patient is in disease remission and thriving, suggesting favorable biology despite histologic malignancy. This case illustrates the value of personalized oncogenomics, as the molecular profiling revealed two actionable changes that would not have been apparent through routine diagnostics. NTRK fusions are known oncogenic drivers in a range of cancer types, but this is the first report of a NACC2-NTRK2 fusion in a glioblastoma.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Explore the current molecular landscape of pediatric high grade gliomas2.Recognize the value of personalized oncogenomic analysis, particularly in rare and/or aggressive tumors3.Discuss the current status of NTRK inhibitor clinical trials

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