Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.

The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

Impact of Direct-Acting Antiviral Therapy on Liver Fibrosis Regression among People with Chronic HCV Infection: Results from a Real-Life Cohort in Patients Who Achieved Sustained Virological Response.

Background and Objectives: The global prevalence of chronic hepatitis C virus (HCV) infection is 0.8%, affecting around 58 million people worldwide. Treatment with DAAs reduces all-cause HCV mortality by 49-68%. This work aims to determine whether there is liver fibrosis regression (LFR) in patients who achieved Sustained Virological Response (SVR) after treatment with DAAs. Materials and Methods: An analytical, observational, single-center, and cohort study was carried out. The final sample consisted of 248 HCV-infected patients. All started treatment with DAAs between January 2015 and December 2017. Five measurements were performed to determine the fibrotic stage in patients (measured in kilopascals (kPa)) using transient elastography (FibroScan®, Echosens, The Netherlands). Results: Taking the baseline fibrotic stage as a reference, the distribution in subgroups was as follows: 77 F4 patients (31.0%); 55 F3 patients (22.2%); 53 F2 patients (21.4%); and 63 F0/F1 patients (25.4%). There were 40 patients (16.1%) with at least one HCV complication and 13 (5.2%) who developed hepatocellular carcinoma. The overall LFR rate was 77.8% (144 of 185 F2/F3/F4 patients, p = 0.01) at the end of the follow-up period. The highest mean FibroScan® values were observed in patients with: "male gender"; "metabolic syndrome"; "subtype 1a"; "NRP DAA"; "at least one HCV complication"; "death from HCV complications"; and "liver transplantation requirement". Conclusions: Treatment with DAAs achieved high rates of LFR and a decrease in mean FibroScan® values in all subgroups.

Global Methylome Scores Correlate with Histological Subtypes of Colorectal Carcinoma and Show Different Associations with Common Clinical and Molecular Features.

BACKGROUND: The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina's 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. RESULTS: SAC has an intermediate methylation pattern between CC and hmMSI-H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). CONCLUSION: These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.

Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor.

Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment. This review revises the current evidence, aiming to propose potential molecular targets and specific treatments for this aggressive tumor.

Elastografía asociada a la ecografía endobronquial en el estudio de adenopatías hiliares y mediastínicas / Endobronchial ultrasound elastography for diagnosing mediastinal and hilar lymph nodes

INTRODUCCIÓN: El objetivo principal es analizar la variabilidad técnica de la EBUS-elastografía para diferenciar entre adenopatías hiliares y mediastínicas benignas y malignas. Como objetivo secundario, se analizan los resultados de la EBUS-elastografía en dicha diferenciación, comparándolos con los resultados anatomopatológicos. MATERIAL Y MÉTODOS: Estudio analítico prospectivo de adenopatías consecutivas en las que se realizó EBUS-elastografía. Se analizan las variables elastográficas y la variabilidad técnica de la EBUS-elastografía. RESULTADOS: Muestra de 24 pacientes, 38 adenopatías. El 60,5% presentaban antecedentes de neoplasia. El 71% tenían intención diagnóstica, el 53% para estadificación mediastínica de una neoplasia conocida; el 25% de los casos con doble intención. Se clasificaron las adenopatías en patrones de color elastográficos, siendo el rojo propio de tejidos elásticos y el azul de rígidos. Las adenopatías con patrón de color predominantemente azul se asociaron con resultado anatomopatológico de malignidad (86% vs. 14%, OR 20,4 (3,1-245,1) p = 0,00015). Se evidenció menor dispersión del color en los histogramas de frecuencias y mayor ratio de píxeles azules y strain ratio en adenopatías con resultado AP de malignidad frente a benignas. Dichas variables presentaron respectivamente 8,7, 9,9 y 31,6% de variabilidad en las repeticiones dentro de la misma adenopatía. Se obtuvo un 66% de consistencia en el caso de los patrones de colores (p = 0,000). CONCLUSIONES: EBUS-elastografía es una herramienta diagnóstica de estudio tisular factible durante la realización de EBUS, capaz de predecir la presencia de infiltración maligna ganglionar. Los datos cuantitativos elastográficos muestran escasa variabilidad en repeticiones dentro de la misma adenopatía, siendo el strain ratio el parámetro elastográfico más variable

INTRODUCTION: The main objective was to analyze the technical variability of EBUS-elastography in the differentiation of benign and malignant hilar and mediastinal lymph nodes. As a secondary objective, the results of the EBUS-elastography in said differentiation were analyzed, comparing them with the anatomopathological results. MATERIAL AND METHODS: Prospective and analytical study of lymph nodes in which EBUS-elastography was performed. Elastographic variables and their variability were analyzed. RESULTS: 24 patients and 38 lymph nodes were evaluated. Of these, 60.5% had a history of neoplasia, 71% of them were EBUS-elastography with diagnostic intention, 53% were mediastinal staging of lung cancer. Both procedures were performed in 25% of the patients. Lymph nodes were classified into elastographic colour patterns, red being characteristic of elastic tissues and blue of rigid tissues. The lymphadenopathies with apredominantly blue pattern were associated with an anatomopathological result of malignancy (86% vs. 14%, OR 20.4 (3.1 -245.1) p-value = .00015). Malignant lymph nodes presented less colour dispersion in the frequency histograms and a higher ratio of blue pixels and higher strain ratio. These variables showed a variability of 8.7, 9.9 and 31.6% respectively in repetitions in the same adenopathy. Finally, a 66% of consistency was obtained in the event of colour pattern variability (p .0000). CONCLUSIONS: EBUS-elastography is feasible during EBUS and may be helpful in predicting malignant lymph node infiltration. The quantitative elastographic data show low variability in repetitions in the same adenopathy. The strain ratio is the most variable elastographic parameter

Endobronchial ultrasound elastography for diagnosing mediastinal and hilar lymph nodes. / Elastografía asociada a la ecografía endobronquial en el estudio de adenopatías hiliares y mediastínicas.

INTRODUCTION: The main objective was to analyze the technical variability of EBUS-elastography in the differentiation of benign and malignant hilar and mediastinal lymph nodes. As a secondary objective, the results of the EBUS-elastography in said differentiation were analyzed, comparing them with the anatomopathological results. MATERIAL AND METHODS: Prospective and analytical study of lymph nodes in which EBUS-elastography was performed. Elastographic variables and their variability were analyzed. RESULTS: 24 patients and 38 lymph nodes were evaluated. Of these, 60.5% had a history of neoplasia, 71% of them were EBUS-elastography with diagnostic intention, 53% were mediastinal staging of lung cancer. Both procedures were performed in 25% of the patients. Lymph nodes were classified into elastographic colour patterns, red being characteristic of elastic tissues and blue of rigid tissues. The lymphadenopathies with apredominantly blue pattern were associated with an anatomopathological result of malignancy (86% vs. 14%, OR 20.4 (3.1 -245.1) p-value = .00015). Malignant lymph nodes presented less colour dispersion in the frequency histograms and a higher ratio of blue pixels and higher strain ratio. These variables showed a variability of 8.7, 9.9 and 31.6% respectively in repetitions in the same adenopathy. Finally, a 66% of consistency was obtained in the event of colour pattern variability (p .0000). CONCLUSIONS: EBUS-elastography is feasible during EBUS and may be helpful in predicting malignant lymph node infiltration. The quantitative elastographic data show low variability in repetitions in the same adenopathy. The strain ratio is the most variable elastographic parameter.

miR-181a-2* expression is different amongst carcinomas from the colorectal serrated route.

Serrated adenocarcinoma (SAC) and colorectal carcinomas showing histological and molecular features of high-level of microsatellite instability (hmMSI-H) are both end points of the serrated pathway of colorectal carcinogenesis. Despite common features (right-sided location, CpG island methylation phenotype and BRAF mutation) there are no studies comparing the microRNA (miRNA) expression profiles in SACs and hmMSI-H. The microtranscriptome from 12 SACs and 8 hmMSI-H were analysed using Affymetrix GeneChip miRNA 3.0 arrays and differentially enriched functions involving immune response were observed from this comparison. miR-181a-2* was found significantly more expressed in hmMSI-H than in SAC and higher expression of this miRNA in microsatellite unstable colorectal cancer were corroborated by Real-Time PCR in an extended series (61 SAC, 21 hmMSI-H). An analysis of genes possibly regulated by miR-181a-2* was carried out and, amongst these, an inverse correlation of NAMPT with miR-181a-2* expression was observed, whereas, for TRAF1 and SALL1, additional regulation mechanisms involving CpG island methylation were observed. miR-181a-2* is associated with particular histological and molecular features of colorectal carcinomas within the serrated pathological pathway and might play a role in the immune responses of microsatellite instability carcinomas.

ColPortal, an integrative multiomic platform for analysing epigenetic interactions in colorectal cancer.

Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide. Different pathological pathways and molecular drivers have been described and some of the associated markers are used to select effective anti-neoplastic therapy. More recent evidence points to a causal role of microbiota and altered microRNA expression in CRC carcinogenesis, but their relationship with pathological drivers or molecular phenotypes is not clearly established. Joint analysis of clinical and omics data can help clarify such relations. We present ColPortal, a platform that integrates transcriptomic, microtranscriptomic, methylomic and microbiota data of patients with colorectal cancer. ColPortal also includes detailed information of histological features and digital histological slides from the study cases, since histology is a morphological manifestation of a complex molecular change. The current cohort consists of Caucasian patients from Europe. For each patient, demographic information, location, histology, tumor staging, tissue prognostic factors, molecular biomarker status and clinical outcomes are integrated with omics data. ColPortal allows one to perform multiomics analyses for groups of patients selected by their clinical data.

Relationship between the polyp detection rate and the post-colonoscopy colorectal cancer rate

Aim: the adenoma detection rate is the quality indicator of colonoscopy that is most closely related to the development of interval colorectal cancer or post-colonoscopy colorectal cancer. However, the recording of this indicator in different units of gastrointestinal endoscopy is obstructed due to the large consumption of resources required for its calculation. Several alternatives have been proposed, such as the polyp detection rate. The objective of this study was to evaluate the relationship between the polyp detection rate and its influence on post-colonoscopy colorectal cancer rate. Patients and methods: in this study, 12,482 colonoscopies conducted by 14 endoscopists were analyzed. The polyp detection rate was calculated for each endoscopist. Endoscopists were grouped into quartiles (Q1, Q2, Q3, and Q4), from lowest to highest polyp detection rate, in order to evaluate whether there were any differences in the development of post-colonoscopy colorectal cancer. Results: the lowest polyp detection rate was 20.66% and the highest was 52.16%, with a median of 32.78 and a standard deviation of +/- 8.54. A strong and positive association between polyp endoscopy diagnosis and adenoma histopathology result was observed and a linear regression was performed. A significantly higher post-colonoscopy colorectal cancer rate was observed in the group of endoscopists with a lower polyp detection rate (p < 0.02). Conclusion: polyp detection rate is a valuable quality indicator of colonoscopy and its calculation is much simpler than that of the adenoma detection rate. In our study, the prevalence of post-colonoscopy colorectal cancer was inversely and significantly related to the endoscopists' polyp detection rate

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Relationship between the polyp detection rate and the post-colonoscopy colorectal cancer rate.

AIM: the adenoma detection rate is the quality indicator of colonoscopy that is most closely related to the development of interval colorectal cancer or post-colonoscopy colorectal cancer. However, the recording of this indicator in different units of gastrointestinal endoscopy is obstructed due to the large consumption of resources required for its calculation. Several alternatives have been proposed, such as the polyp detection rate. The objective of this study was to evaluate the relationship between the polyp detection rate and its influence on post-colonoscopy colorectal cancer rate. PATIENTS AND METHODS: in this study, 12,482 colonoscopies conducted by 14 endoscopists were analyzed. The polyp detection rate was calculated for each endoscopist. Endoscopists were grouped into quartiles (Q1, Q2, Q3, and Q4), from lowest to highest polyp detection rate, in order to evaluate whether there were any differences in the development of post-colonoscopy colorectal cancer. RESULTS: the lowest polyp detection rate was 20.66% and the highest was 52.16%, with a median of 32.78 and a standard deviation of ± 8.54. A strong and positive association between polyp endoscopy diagnosis and adenoma histopathology result was observed and a linear regression was performed. A significantly higher post-colonoscopy colorectal cancer rate was observed in the group of endoscopists with a lower polyp detection rate (p < 0.02). CONCLUSION: polyp detection rate is a valuable quality indicator of colonoscopy and its calculation is much simpler than that of the adenoma detection rate. In our study, the prevalence of post-colonoscopy colorectal cancer was inversely and significantly related to the endoscopists' polyp detection rate.

Differences in gene expression profiling and biomarkers between histological colorectal carcinoma subsets from the serrated pathway.

AIMS: To discern the differences in expression profiling of two histological subtypes of colorectal carcinoma (CRC) arising from the serrated route (serrated adenocarcinoma (SAC) and CRC showing histological and molecular features of a high level of microsatellite instability (hmMSI-H) both sharing common features (female gender, right-sided location, mucinous histology, and altered CpG methylation), but dramatically differing in terms of prognosis, development of an immune response, and treatment options. METHODS AND RESULTS: Molecular signatures of SAC and hmMSI-H were obtained by the use of transcriptomic arrays; quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were used to validate differentially expressed genes. An over-representation of innate immunity functions (granulomonocytic recruitment, chemokine production, Toll-like receptor signalling, and antigen processing and presentation) was obtained from this comparison, and intercellular cell adhesion molecule-1 (ICAM1) was more highly expressed in hmMSI-H, whereas two genes [those encoding calcitonin gene-related peptide-receptor component protein and C-X-C motif chemokine ligand 14 (CXCL14)] were more highly expressed in SAC. These array results were subsequently validated by qPCR, and by IHC for CXCL14 and ICAM1. Information retrieved from public databanks confirmed our findings. CONCLUSIONS: Our findings highlight specific functions and genes that provide a better understanding of the role of the immune response in the serrated pathological route and may be of help in identifying actionable molecules.

Diagnostic Value of Elastography and Endobronchial Ultrasound in the Study of Hilar and Mediastinal Lymph Nodes.

BACKGROUND: The aim of this study was to explore elastography features and its ability to distinguish between benign and malignant lymph nodes by comparing the results with an anatomopathologic examination used as gold standard. METHODS: Patients were randomized in 2 groups [endobronchial ultrasound (EBUS) and EBUS-elastography]. Echographic characteristics of the lymph nodes were collected in both categories. In the EBUS-elastography group, elastographic data were also determined. RESULTS: A total of 100 lymph nodes were evaluated. Group 1 (EBUS) consisted of 57 lymph nodes. Group 2 (EBUS-elastography) included 43 lymph nodes. In group 2, lymph nodes with predominantly blue pattern were associated with a pathologic determination of malignancy, and the probability of presenting malignant infiltration with this color pattern was 86.7% (P=0.00004). Malignant lymph nodes presented less color dispersion (48.8 vs. 94.8, P=0.00013), higher ratio of blue pixels (66% vs. 32.5%, P=0.016), and higher strain ratio (7.1 vs. 2.48, P=0.005). The cut-off points to distinguish between benign and malignant lymph nodes were 4 for strain ratio, 61 for frequency histograms, and 52 for blue pixel ratio. The area under the curve of the ROC curves were 0.75, 0.83, and 0.87, respectively. Group 2 presented a lower number of nondiagnostic samples (2.3% vs. 21%, P=0.001) and a higher rate of malignant results (42% vs. 16%, P=0.005). CONCLUSION: EBUS-elastography is feasible during EBUS and may be helpful in predicting malignant lymph node infiltration. It could improve anatomopathologic sample collection and increase diagnostic efficiency.

Two histologically colorectal carcinomas subsets from the serrated pathway show different methylome signatures and diagnostic biomarkers.

BACKGROUND: Altered methylation patterns are driving forces in colorectal carcinogenesis. The serrated adenocarcinoma (SAC) and sporadic colorectal carcinoma showing histological and molecular features of microsatellite instability (hmMSI-H) are two endpoints of the so-called serrated pathological route sharing some characteristics but displaying a totally different immune response and clinical outcome. However, there are no studies comparing the methylome of these two subtypes of colorectal carcinomas. The methylation status of 450,000 CpG sites using the Infinium Human Methylation 450 BeadChip array was investigated in 48 colorectal specimens, including 39 SACs and 9 matched hmMSI-H. RESULTS: Microarray data comparing SAC and hmMSI-H showed an enrichment in functions related to morphogenesis, neurogenesis, cytoskeleton, metabolism, vesicle transport and immune response and also significant differential methylation of 1540 genes, including CD14 and HLA-DOA which were more methylated in hmMSI-H than in SAC and subsequently validated at the CpG, mRNA and protein level using pyrosequencing, quantitative polymerase chain reaction (qPCR) and immunohistochemistry. CONCLUSIONS: These results demonstrate particular epigenetic regulation patterns in SAC which may help to define key molecules responsible for the characteristic weak immune response of SAC and identify potential targets for treating SAC, which lacks molecular targeted therapy.

MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9.

Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.

Contribution of the TTC21B gene to glomerular and cystic kidney diseases.

Background: The TTC21B gene was initially described as causative of nephronophthisis (NPHP). Recently, the homozygous TTC21B p.P209L mutation has been identified in families with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. Heterozygous TTC21B variants have been proposed as genetic modifiers in ciliopathies. We aimed to study the causative and modifying role of the TTC21B gene in glomerular and cystic kidney diseases. Methods: Mutation analysis of the TTC21B gene was performed by massive parallel sequencing. We studied the causative role of the TTC21B gene in 17 patients with primary diagnosis of FSGS or NPHP and its modifying role in 184 patients with inherited glomerular or cystic kidney diseases. Results: Disease-causing TTC21B mutations were identified in three families presenting nephrotic proteinuria with FSGS and tubulointerstitial lesions in which some family members presented hypertension and myopia. Two families carried the homozygous p.P209L and the third was compound heterozygous for the p.P209L and a novel p.H426D mutation. Rare heterozygous TTC21B variants predicted to be pathogenic were found in five patients. These TTC21B variants were significantly more frequent in renal patients compared with controls (P = 0.0349). Two patients with a heterozygous deleterious TTC21B variant in addition to the disease-causing mutation presented a more severe phenotype than expected. Conclusions: Our results confirm the causal role of the homozygous p.P209L TTC21B mutation in two new families with FSGS and tubulointerstitial disease. We identified a novel TTC21B mutation demonstrating that p.P209L is not the unique causative mutation of this nephropathy. Thus, TTC21B mutation analysis should be considered for the genetic diagnosis of families with FSGS and tubulointerstitial lesions. Finally, we provide evidence that heterozygous deleterious TTC21B variants may act as genetic modifiers of the severity of glomerular and cystic kidney diseases.

HIF-1α expression and high microvessel density are characteristic features in serrated colorectal cancer.

Serrated colorectal adenocarcinoma (SAC) is a morphologically distinct subtype of colorectal cancer (CRC), in which increased HIF-1α mRNA expression and HIF-1α protein stabilization are typical features. Here we aimed to further elucidate HIF-1α protein expression in serrated and non-serrated colorectal carcinomas (CRCs) and their precursor lesions and its association with vascular endothelial growth factor (VEGF) and microvascular density (MVD). HIF-1α and VEGF expressions were determined immunohistochemically in 134 serrated polyps (SPs), 104 non-serrated adenomas (NSAs), 81 SACs, and 74 matched conventional adenocarcinomas (CCs) and were correlated with morphology, clinicopathological features, and MVD. In premalignant lesions, both HIF-1α and VEGF were expressed in the vast majority of SPs and NSAs. In CRCs, HIF-1α protein was also present in 77.8 % of SACs, while only 20.3 % of CCs were HIF-1α proficient. MVD was significantly higher in SACs, but the serrated morphology was the only significant predictor of MVD in CRC in multivariate analyses. HIF-1α protein is often stabilized in well-vascularized SACs, suggesting hypoxia-independent stabilization of HIF-1α. Moreover, HIF-1α stabilization did not associate with oncogenic activation of BRAF or KRAS or Von Hippel-Lindau (VHL) mutation. Prevalent HIF-1α expression in SAC and its precursors support the importance of HIF-1α-mediated pathways for the serrated route of colorectal carcinogenesis.

Tumor rabdoide extrarrenal maligno de colon: presentación de 3 casos y revisión de la literatura / Malignant extrarenal rhabdoid tumour of the colon: a report of 3 cases and a review of the literature

El tumor rabdoide extrarrenal maligno (TREM) de colon es una neoplasia maligna poco frecuente de la que solo hay 12 casos publicados en la bibliografía. Los casos suelen presentar unas características clínicas (pacientes de edad avanzada, tumores de gran tamaño y comportamiento biológico agresivo), histológicas (características típicas de tumor rabdoide) e inmunohistoquímicas (expresión de vimentina y cóctel de citoqueratinas) comunes. Presentamos 3 casos de TREM colónicos con características acordes a las observadas en la bibliografía. Uno de los 3 casos es una probable metástasis de un carcinoma de células renales con características rabdoides. A estos casos se les ha realizado un amplio estudio inmunohistoquímico, así como la determinación del estado de mutaciones en KRAS y BRAF para comparar estos hallazgos con los descritos en la bibliografía y realizar un diagnóstico diferencial con posibles neoplasias colónicas primarias o metastásicas que pueden presentar un aspecto semejante (AU)

Malignant extrarenal rhabdoid tumour (MERT) of the colon is rare, with only 12 cases published to date. Clinically, they usually occur in elderly patients and present as large, aggressive tumours; their histopathology is that typical of rhabdoid tumours and their immunohistochemistry shows expression of vimentin and cytokeratines. We present 3 cases of colonic MERTs with features similar to previously published cases. One was possibly a metastasis of a renal cell carcinoma with rhabdoid features. We carried out a extensive immunohistological analysis of all 3 cases as well as testing for KRAS and BRAF mutations. Thus we could not only compare our findings with those of the other known cases but also make a differential diagnosis with primary colonic neoplasmas and metastases of similar appearance (AU)

Biomarkers for the identification of precursor polyps of colorectal serrated adenocarcinomas.

BACKGROUND: In contrast to conventional colorectal carcinomas (CCs), which develop through a so-called chromosome instability or suppressor phenotype pathway, the sequence of events leading from precursor polyps/adenomas to serrated adenocarcinomas (SACs), which are more aggressive and exhibit a poorer survival than CCs, is as yet not clearly defined. Here, we aimed at detecting protein and DNA biomarkers for SAC in a series of primary colorectal polyps. METHODS: In total 303 colorectal polyps were included: 121 serrated polyps (33 hyperplastic polyps, 37 sessile serrated adenomas (SSA), 51 traditional serrated adenomas (TSA)), 143 conventional polyps (72 tubular polyps, 34 tubulovillous polyps, 37 villious adenomas), and 39 bi-phenotypic serrated-conventional polyps. The protein biomarkers tested were deduced from previously published SAC and CC expression profiling studies. A representative subset of 106 polyps was selected for DNA biomarker analyses, i.e., proto-oncogene mutation and microsatellite instability (MSI) status. In order to confer proper weight to each biomarker, a multivariate logistic regression model was employed. RESULTS: We found that serrated and conventional polyps differed in most of the SAC biomarkers tested. Of these biomarkers, FSCN1 showed the largest difference in expression (p = 0.0001). Despite sharing a serrated morphology, we found that SSAs and TSAs differed considerably with respect to anatomical location, expression of EPHB2 and PTCH1, presence of the V600E BRAF mutation and MSI status. Logistic regression analysis revealed that SSA was the polyp type that shared most biomarkers with SAC. CONCLUSION: Based on the shared presence of protein and molecular biomarkers, especially FSCN1 expression, SSA may serve as a precursor lesion of SAC. Biomarker assessment may help in discerning colorectal carcinogenic routes with distinct prognostic implications.

Methylome profiling reveals functions and genes which are differentially methylated in serrated compared to conventional colorectal carcinoma.

BACKGROUND: Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5-8.7 % of CRCs. It has been shown that SAC has a worse prognosis and different histological and molecular features compared to conventional carcinoma (CC) but, to date, there is no study analysing its methylome profile. RESULTS: The methylation status of 450,000 CpG sites using the Infinium Human Methylation 450 BeadChip array was investigated in 103 colorectal specimens, including 39 SACs and 34 matched CCs, from Spanish and Finnish patients. Microarray data showed a higher representation of morphogenesis-, neurogenesis-, cytoskeleton- and vesicle transport-related functions and also significant differential methylation of 15 genes, including the iodothyronine deiodinase DIO3 and the forkhead family transcription factor FOXD2 genes which were validated at the CpG, mRNA and protein level using pyrosequencing, methylation-specific PCR, quantitative polymerase chain reaction (qPCR) and immunohistochemistry. A quantification study of the methylation status of CpG sequences in FOXD2 demonstrated a novel region controlling gene expression. Moreover, differences in these markers were also evident when comparing SAC with CRC showing molecular and histological features of high-level microsatellite instability. CONCLUSIONS: This methylome study demonstrates distinct epigenetic regulation patterns in SAC which are consistent to previous expression profile studies and that DIO3 and FOXD2 might be molecular targets for a specific histology-oriented treatment of CRC.