scholarly journals Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates

Gut ◽  
2016 ◽  
Vol 66 (12) ◽  
pp. 2132-2140 ◽  
Author(s):  
Chelsie K Sievers ◽  
Luli S Zou ◽  
Perry J Pickhardt ◽  
Kristina A Matkowskyj ◽  
Dawn M Albrecht ◽  
...  
Keyword(s):  
Computer Modelling ◽  
Clonal Evolution ◽  
Colorectal Polyps ◽  
Colon Polyps ◽  
Growth Behaviour ◽  
Differential Growth ◽  
Polyp Size ◽  
Driver Genes ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Mutations

Objective and designThe goal of the study was to determine whether the mutational profile of early colorectal polyps correlated with growth behaviour. The growth of small polyps (6–9 mm) that were first identified during routine screening of patients was monitored over time by interval imaging with CT colonography. Mutations in these lesions with known growth rates were identified by targeted next-generation sequencing. The timing of mutational events was estimated using computer modelling and statistical inference considering several parameters including allele frequency and fitness.ResultsThe mutational landscape of small polyps is varied both within individual polyps and among the group as a whole but no single alteration was correlated with growth behaviour. Polyps carried 0–3 pathogenic mutations with the most frequent being inAPC,KRAS/NRAS,BRAF,FBXW7andTP53. In polyps with two or more pathogenic mutations, allele frequencies were often variable, indicating the presence of multiple populations within a single tumour. Based on computer modelling, detectable mutations occurred at a mean polyp size of 30±35 crypts, well before the tumour is of a clinically detectable size.ConclusionsThese data indicate that small colon polyps can have multiple pathogenic mutations in crucial driver genes that arise early in the existence of a tumour. Understanding the molecular pathway of tumourigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps are more likely to progress into adenocarcinomas and which patients are at greater risk of developing advanced disease.

scholarly journals Prognostic Significance of DR-70 Levels in Dysplastic Colorectal Polyps

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Atakan Yesil ◽  
Gul Babacan Abanonu ◽  
Yasar Colak ◽  
Nurcan Paker ◽  
Can Gonen
Keyword(s):  
Prognostic Significance ◽  
Serum Levels ◽  
Colorectal Polyps ◽  
Adenomatous Polyps ◽  
Control Group ◽  
Low Grade ◽  
Colon Polyps ◽  
High Grade ◽  
Polyp Size ◽  
Potential Marker

Background. To investigate the relationship between DR-70 serum levels and dysplastic colon polyps.Materials and Methods. A total of 130 patients with adenomatous polyps detected by colonoscopy and divided into two groups including low versus high grade polyp, along with 50 healthy blood donors were included in the study. Blood samples from each participant were analyzed for serum CEA and DR-70 levels.Results. No statistically significant differences were observed between the two groups in terms of age or gender. The median DR-70 level was 0.5 μg/mL in the healthy control group and 1.1 μg/mL in group 1b (i.e., the high grade polyp) (P<0.001). DR-70 was higher in group 1b as compared to group 1a (P<0.001). However, the median DR-70 values for the low grade polyp group (i.e., group 1a) and the control group were similar (P=0.067). In order to determine independent predictors of high grade dysplasia, CEA, DR-70, polyp size, and age parameters were subjected to multiple logistical regression analyses via the Enter method; the model was statistically significant (P<0.001).Conclusions. DR-70, a marker used to measure FDP, which is generated by all major cancers, is a potential marker to identify patients with advanced adenomatous polyps, that is, precursors of colorectal cancer.

The Rate of Adenocarcinoma in Endoscopically Removed Colorectal Polyps

2005 ◽  
Vol 71 (12) ◽  
pp. 1024-1026 ◽  
Author(s):  
Stephen R. Odom ◽  
Stephen D. Duffy ◽  
James E. Barone ◽  
Vishal Ghevariya ◽  
Steven J. McClane
Keyword(s):  
Adverse Outcome ◽  
Colorectal Polyps ◽  
Colon Polyps ◽  
Polyp Size ◽  
Rectal Polyps ◽  
Accepted Standard ◽  
Pathology Reports ◽  
Villous Adenomas

The purpose of this study was to determine the rate of cancer in a modern series of colorectal polyps. All pathology reports from colon and rectal polyps from 1999 to 2002 were reviewed. Reports of bowel resections, cancer-free polyps, and polyp-free mucosal biopsies were excluded. Polyps were grouped by size, and the rate of adenocarcinoma was determined. χ2 was used for analysis. A total of 4,443 polyps were found, of which 3,225 were adenomatous [2,883 (89.4%) tubular adenomas, 399 (9.3%) tubulo-villous adenomas, 32 (1.0%) villous adenomas, and 11 (0.3%) carcinomas]. The rate of adenocarcinoma by size was 0.07 per cent for polyps <1 cm, 2.41 per cent for polyps 1-2 cm, and 19.35 per cent for polyps >2 cm, representing significantly fewer cancers for each category of polyp size than the accepted standard. The rate of carcinoma in colon polyps is much lower than previously thought and currently stated in many texts. These data do not alter the recommendations for polyp removal, however, failure to retrieve a specimen in a polyp <1 cm in size is unlikely to have an adverse outcome because the chances of malignancy are very low.

scholarly journals Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shumaila Sayyab ◽  
Anders Lundmark ◽  
Malin Larsson ◽  
Markus Ringnér ◽  
Sara Nystedt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Driver Genes ◽  
Protein Coding ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

scholarly journals Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 731
Author(s):  
Renáta Váraljai ◽  
Susanne Horn ◽  
Antje Sucker ◽  
Daniela Piercianek ◽  
Verena Schmitt ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Genetic Variants ◽  
Genetic Alterations ◽  
Metastasis Formation ◽  
Driver Genes ◽  
Targeted Next Generation Sequencing ◽  
Paired Samples ◽  
Melanoma Metastases ◽  
Frequent Event ◽  
Genetic Landscape

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

scholarly journals Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 815 ◽  
Author(s):  
Egle Rebane-Klemm ◽  
Laura Truu ◽  
Leenu Reinsalu ◽  
Marju Puurand ◽  
Igor Shevchuk ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Atp Synthesis ◽  
Colorectal Polyps ◽  
Metabolic Phenotype ◽  
Mitochondrial Outer Membrane ◽  
Control Group ◽  
Colon Polyps ◽  
Wild Type ◽  
Tissue Samples ◽  
Potential Component

This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue (control) were collected. Patients with polyps and CRC were divided into three molecular groups: KRAS mutated, BRAF mutated and KRAS/BRAF wild-type. Mitochondrial respiration in permeabilized tissue samples was observed using high resolution respirometry. ADP-activated respiration rate (Vmax) and an apparent affinity of mitochondria to ADP, which is related to mitochondrial outer membrane (MOM) permeability, were determined. Clear differences were present between molecular groups. KRAS mutated CRC group had lower Vmax values compared to wild-type; however, the Vmax value was higher than in the control group, while MOM permeability did not change. This suggests that KRAS mutation status might be involved in acquiring oxidative phenotype. KRAS mutated polyps had higher Vmax values and elevated MOM permeability as compared to the control. BRAF mutated CRC and polyps had reduced respiration and altered MOM permeability, indicating a glycolytic phenotype. To conclude, prognostic biomarkers KRAS and BRAF are likely related to the metabolic phenotype in CRC and polyps. Assessment of the tumor mitochondrial ATP synthesis could be a potential component of patient risk stratification.

scholarly journals A118 POLYP SIZE CUT-OFF LEVEL TO IMPLEMENT OPTICAL POLYP DIAGNOSIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 98-99
Author(s):  
M Taghiakbari ◽  
R Djinbachian ◽  
D von Renteln
Keyword(s):  
Colorectal Polyps ◽  
Optical Diagnosis ◽  
Clinical Implementation ◽  
Polyp Size ◽  
Funding Agencies ◽  
Size Groups ◽  
Surveillance Interval ◽  
High Reduction ◽  
Advanced Adenomas ◽  
Post Hoc

Abstract Background Optical polyp diagnosis can be used for real-time pathology prediction of colorectal polyps ≤10 mm. However, the risk of misdiagnosing a polyp with advanced pathology potentially increases with increasing polyp size. Aims This study aimed to evaluate different size cut-offs for using optical polyp diagnosis and the associated risk of patients undergoing inadequate follow-up or surveillance. Methods In a post-hoc analysis of two prospective studies, the performance of optical diagnosis was evaluated in three polyp size groups: 1–3 mm, 1–5 mm, and 1–10 mm. The primary outcome was the proportion of patients with advanced adenomas and delayed or inappropriate surveillance. Secondary outcomes included percentage of polyps with advanced pathology, agreement between surveillance intervals based on high-confidence optical diagnosis and pathology outcomes, reduction in histopathological examinations, and proportion of patients who could receive an immediate surveillance interval recommendation. Results We included 1525 patients with complete colonoscopies (mean age 62.9 years, 50.2% male). The percentage of patients with advanced adenomas and delayed or inappropriate surveillance was 0.7%, 1.7%, and 1.8% when using optical diagnosis for patients with polyps of 1–3, 1–5, and 1–10 mm, respectively. The percentage of polyps with advanced pathology was 0.5%, 1.4%, and 1.9%, respectively. Surveillance interval agreement between pathology and optical diagnosis was 99%, 98%, and 97.8%, respectively. Total reduction in pathology examinations was 33.9%, 53.5%, and 69.0%, respectively. Conclusions A 3-mm cut-off for clinical implementation of optical polyp diagnosis yielded high surveillance interval agreement with pathology and a high reduction in pathology examinations while minimizing the risk of inappropriate management for polyps with advanced pathology. Funding Agencies None

NIMG-52. RADIOGENOMICS SIGNATURES IN KEY DRIVER GENES IN GLIOBLASTOMA EVALUATED WITH AND WITHOUT THE PRESENCE OF CO-OCCURRING MUTATIONS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi141-vi141
Author(s):  
Anahita Fathi Kazerooni ◽  
Hamed Akbari ◽  
Spyridon Bakas ◽  
Erik Toorens ◽  
Chiharu Sako ◽  
...  
Keyword(s):  
Gabor Wavelet ◽  
Egfr Mutations ◽  
Driver Gene ◽  
Significant Heterogeneity ◽  
Driver Genes ◽  
Targeted Next Generation Sequencing ◽  
Promising Tool ◽  
Key Driver ◽  
In Vivo Characterization

Abstract PURPOSE Glioblastomas display significant heterogeneity on the molecular level, typically harboring several co-occurring mutations, which likely contributes to failure of molecularly targeted therapeutic approaches. Radiogenomics has emerged as a promising tool for in vivo characterization of this heterogeneity. We derive radiogenomic signatures of four mutations via machine learning (ML) analysis of multiparametric MRI (mpMRI) and evaluate them in the presence and absence of other co-occurring mutations. METHODS We identified a retrospective cohort of 359 IDH-wildtype glioblastoma patients, with available pre-operative mpMRI (T1, T1Gd, T2, T2-FLAIR) scans and targeted next generation sequencing (NGS) data. Radiomic features, including morphologic, histogram, texture, and Gabor wavelet descriptors, were extracted from the mpMRI. Multivariate predictive models were trained using cross-validated SVM with LASSO feature selection to predict mutation status in key driver genes, EGFR, PTEN, TP53, and NF1. ML models and spatial population atlases of genetic mutations were generated for stratification of the tumors (1) with co-occurring mutations versus wildtypes, (2) with exclusive mutations in each driver gene versus the tumors without any mutations in the pathways associated with these genes. RESULTS ML models yielded AUCs of 0.75 (95%CI:0.62-0.88) / 0.87 (95%CI:0.70-1) for co-occurring / exclusive EGFR mutations, 0.69 (95%CI:0.58-0.80) / 0.80 (95%CI:0.61-0.99) for co-occurring / exclusive PTEN mutations, and 0.77 (95%CI:0.65-0.88) / 0.86 (95%CI:0.69-1) for co-occurring / exclusive TP53 cases. Spatial atlases revealed a predisposition of left temporal lobe for NF1 and right frontotemporal region for TP53 in mutually exclusive tumors, which was not observed in the co-occurring mutation atlases. CONCLUSION Our results suggest the presence of distinct radiogenomic signatures of several glioblastoma mutations, which become even more pronounced when respective mutations do not co-occur with other mutations. These in vivo signatures can contribute to pre-operative stratification of patients for molecular targeted therapies, and potentially longitudinal monitoring of mutational changes during treatment.

scholarly journals Influence of patient age and colorectal polyp size on histopathology findings

2014 ◽  
Vol 27 (2) ◽  
pp. 109-113 ◽  
Author(s):  
Silvana Marques e SILVA ◽  
Viviane Fernandes ROSA ◽  
Antônio Carlos Nóbrega dos SANTOS ◽  
Romulo Medeiros de ALMEIDA ◽  
Paulo Gonçalves de OLIVEIRA ◽  
...  
Keyword(s):  
Demographic Data ◽  
Colorectal Polyp ◽  
Proximal Colon ◽  
Colorectal Polyps ◽  
University Hospital ◽  
Consecutive Series ◽  
Polyp Size ◽  
Patient Age ◽  
Cross Sectional ◽  
Patient Âgé

BACKGROUND: Colorectal cancer is a major cause of morbidity and mortality and can arise through the adenoma-carcinoma sequence. Colonoscopy is considered the method of choice for population-wide cancer screening. AIM: To assess the characteristics of endoscopically resected polyps in a consecutive series of patients who underwent colonoscopy at a university hospital and compare histopathology findings according to patient age and polyp size. METHODS: Retrospective, cross-sectional of 1950 colonoscopy reports from consecutively examined patients. The sample was restricted to reports that mentioned colorectal polyps. A chart review was carried out for collection of demographic data and histopathology results. Data were compared for polyps sized ≤0.5 cm and ≥0.6 cm and then for polyps sized ≤1.0 cm and ≥1.1 cm. Finally, all polyps resected from patients aged 49 years or younger were compared with those resected from patients aged 50 years or older. RESULTS: A total of 272 colorectal polyps were resected in 224 of the 1950 colonoscopies included in the sample (11.5%). Polyps >1 cm tended to be pedunculated (p=0.000) and were more likely to exhibit an adenomatous component (p=0.001), a villous component (p=0.000), and dysplasia (p=0.003). These findings held true when the size cutoff was set at 0.5 cm. Patients aged 50 years or older were more likely to have sessile polyps (p=0.023) and polyps located in the proximal colon (p=0.009). There were no significant differences between groups in histopathology or presence of dysplasia. CONCLUSION: Polyp size is associated with presence of adenomas, a villous component, and dysplasia, whereas patient age is more frequently associated with sessile polyps in the proximal colon.

scholarly journals Endoscopic resection outcomes and predictors of failed en bloc endoscopic mucosal resection of colorectal polyps ≤ 20 mm among advanced endoscopy trainees

2021 ◽  
Vol 09 (11) ◽  
pp. E1820-E1826
Author(s):  
William W. King ◽  
Peter V. Draganov ◽  
Andrew Y. Wang ◽  
Dushant Uppal ◽  
Amir Rumman ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Endoscopic Mucosal Resection ◽  
En Bloc Resection ◽  
Lesion Size ◽  
Bloc Resection ◽  
Colorectal Polyps ◽  
Polyp Size ◽  
En Bloc ◽  
Mucosal Resection ◽  
Piecemeal Resection

Abstract Background and study aims En bloc endoscopic mucosal resection (EMR) is preferred over piecemeal resection for polyps ≤ 20 mm. Data on colorectal EMR training are limited. We aimed to evaluate the en bloc EMR rate of polyps ≤ 20 mm among advanced endoscopy trainees and to identify predictors of failed en bloc EMR. Methods This was a multicenter prospective study evaluating trainee performance in EMR during advanced endoscopy fellowship. A logistic regression model was used to identify the number of procedures and lesion cut-off size associated with an en bloc EMR rate of ≥ 80 %. Multivariate analysis was performed to identify predictors of failed en bloc EMR. Results Six trainees from six centers performed 189 colorectal EMRs, of which 104 (55 %) were for polyps ≤ 20 mm. Of these, 57.7 % (60/104) were resected en bloc. Trainees with ≥ 30 EMRs (OR 6.80; 95 % CI: 2.80–16.50; P = 0.00001) and lesions ≤ 17 mm (OR 4.56;95 CI:1.23–16.88; P = 0.02) were more likely to be associated with an en bloc EMR rate of ≥ 80 %. Independent predictors of failed en bloc EMR on multivariate analysis included: larger polyp size (OR:6.83;95 % CI:2.55–18.4; P = 0.0001), right colon location (OR:7.15; 95 % CI:1.31–38.9; P = 0.02), increased procedural difficulty (OR 2.99; 95 % CI:1.13–7.91; P = 0.03), and having performed < 30 EMRs (OR: 4.87; 95 %CI: 1.05–22.61; P = 0.04). Conclusions In this pilot study, we demonstrated that a relatively low proportion of trainees achieved en bloc EMR for polyps ≤ 20 mm and identified procedure volume and lesion size thresholds for successful en bloc EMR and independent predictors for failed en bloc resection. These preliminary results support the need for future efforts to define EMR procedure competence thresholds during training.

Utility of Mesalazine in Familial Adenomatous Polyposis: Clinical Report of Reduction of Polyp Size in Patients with Ulcerative Colitis, and Safety Examination in Familial Adenomatous Polyposis Patients

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 51-56 ◽  
Author(s):  
Hideki Ishikawa ◽  
Michihiro Mutoh ◽  
Takashi Abe ◽  
Takeshi Nakajima ◽  
Yoji Takeuchi ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Familial Adenomatous Polyposis ◽  
High Dose ◽  
Clinical Report ◽  
Colon Polyps ◽  
Adenomatous Polyposis ◽  
Polyp Size ◽  
Double Blind ◽  
Standard Drug ◽  
Intestinal Polyp

Mesalazine is the gold standard drug for treatment of ulcerative colitis (UC). Here, we describe 4 cases of familial adenomatous polyposis (FAP) patients with UC that showed reduction of intestinal polyp diameter by mesalazine treatment. Of note, the effects of mesalazine on the development of intestinal polyps in FAP patients have not been reported, and we further investigated whether the short-term use of high-dose mesalazine (4 g/day) has harmful effects on FAP patients or not. The authors found that the treatment showed slightly adverse events in FAP patients. However, mesalazine tended to reduce the number of colon polyps in male subjects with FAP. This report provides basic information for planning a double-blind, randomized, clinical trial that aims to show mesalazine’s potential to suppress intestinal polyp development in FAP.

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