[Show abstract][Hide abstract] ABSTRACT: LKB1 is an evolutionary conserved kinase implicated in a wide range of cellular functions including inhibition of cell proliferation, regulation of cell polarity and metabolism. When Lkb1 is inactivated in the liver, glucose homeostasis is perturbed, cellular polarity is affected and cholestasis develops. Cholestasis occurs as a result from deficient bile duct development, yet how LKB1 impacts on biliary morphogenesis is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the phenotype of mice in which deletion of the Lkb1 gene has been specifically targeted to the hepatoblasts. Our results confirmed that lack of LKB1 in the liver results in bile duct paucity leading to cholestasis. Immunostaining analysis at a prenatal stage showed that LKB1 is not required for differentiation of hepatoblasts to cholangiocyte precursors but promotes maturation of the primitive ductal structures to mature bile ducts. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We tested the hypothesis of a functional overlap between the LKB1 and Notch pathways by gene expression profiling of livers deficient in Lkb1 or in the Notch mediator RbpJκ and identified a mutual cross-talk between LKB1 and Notch signaling. In vitro experiments confirmed that Notch activity was deficient upon LKB1 loss. CONCLUSION: LKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis
[Show abstract][Hide abstract] ABSTRACT: Neuroendocrine carcinomas (NEC) of the anus or the rectum are a rare disease, accounting for less than 1% of all digestive malignancies. Most are metastatic at diagnosis and treated with a platinum-based chemotherapy. No guidelines for localized tumors exist. The purpose of this study was to describe the characteristics of anorectal localized NEC, their management and their outcomes.We retrospectively reviewed patients from 11 French centers with anorectal localized NEC. We compared 2 therapeutic managements: surgery (group A) versus chemotherapy with or without radiation (group B). Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method.A total of 24 patients were identified with a median follow-up of 25 months (3-60 months). Median age was 63 years old and 17 had a rectal tumor (71%). Mean Ki-67 was 72% (range: 20-100), and 75% of the tumors had a high proliferative index (Ki-67 > 50%). Global PFS and OS were 13.1 and 44.1 months, respectively. Thirty-seven percent of patients were in group A and 63% in group B. There was no difference between group A and group B, whether in terms of PFS (13.0 months vs. 13.2 months, P = 0.75) or OS (49.1 months vs. 39.2 months, P = 0.42).In patients with anorectal localized NEC, chemotherapy with or without radiation obtained a similar outcome as surgery and this conservative approach could be deemed a reasonable option.
[Show abstract][Hide abstract] ABSTRACT: Introduction The possible benefit of endoscopic submucosal dissection (ESD) for early neoplasia arising in Barrett’s esophagus remains controversial. We aimed to assess the efficacy and safety of ESD for the treatment of early Barrett’s neoplasia.
Full-text · Article · Sep 2015 · United European Gastroenterology Journal
[Show abstract][Hide abstract] ABSTRACT: Aim:
Most studies have considered gastroenteropancreatic neuroendocrine tumors (GEP-NETs) as a homogenous group of samples or distinguish only gastrointestinal from pancreatic endocrine tumors. This article investigates if DNA methylation patterns could distinguish subtypes of GEP-NETs.
Materials & methods:
The DNA methylation level of 807 cancer-related genes was investigated in insulinomas, gastrinomas, non-functioning pancreatic endocrine tumors and small intestine endocrine tumors.
DNA methylation patterns were found to be tumor type specific for each of the pancreatic tumor subtypes and identified two distinct methylation-based groups in small intestine endocrine tumors. Differences of DNA methylation levels were validated by pyrosequencing for 20 candidate genes and correlated with differences at the transcriptional level for four candidate genes.
The heterogeneity of DNA methylation patterns in the different subtypes of gastroenteropancreatic neuroendocrine tumors suggests different underlying pathways and, therefore, these tumors should be considered as distinct entities in molecular and clinical studies.
[Show abstract][Hide abstract] ABSTRACT: Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.
[Show abstract][Hide abstract] ABSTRACT: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using standard needles has a high diagnostic value in the evaluation of solid pancreatic masses. Fenestrated needles have been developed to improve the quality of EUS-guided tissue sampling by providing core biopsies (FNB).
Patients with solid pancreatic masses of >2 cm were prospectively included in our study and randomized to receive EUS sampling, using either a standard 22G FNA or a 22G Procore® FNB needle. The main study endpoint was the number of needle passes required to obtain a diagnosis in more than 90% of cases.
We included 100 patients (male = 63, female = 37; mean age = 68.4 years) in our study. We found that 88% of the lesions were malignant, with a mean size of 32 mm. A sample adequate for diagnosis was obtained in more than 90% of cases after the second needle pass in the FNB group, versus the third needle pass in the FNA group. Slide cellularity and presence of tissue microfragments were significantly higher in the FNB group. Sensitivity for the diagnosis of malignancy was 88.4% versus 97.8% for the EUS-FNA and EUS-FNB group, respectively, while specificity for both techniques was 100%. No complications were recorded.
Although the accuracy of both needle types for proving malignancy was similar, a lower number of passes was required with the FNB needles to achieve the same contributive sample rate as with the FNA needles. FNB also improved the histopathological quality of specimens, suggesting an overall superiority of FNB sampling.
Full-text · Article · Mar 2015 · United European Gastroenterology Journal
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis.
We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC.
We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying β-catenin activation together with an activation of caspases 2 and 3.
This work demonstrates the key oncogenic role of miR-34a in liver tumours with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4α, which targets cyclin D1, and the induction of a proapoptotic programme.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma usually afflicts individuals in their later years following longstanding liver disease. In Peru, hepatocellular carcinoma exists in a unique clinical presentation, which affects patients around age 25 with a normal, healthy liver. In order to deepen our understanding of the molecular processes ongoing in Peruvian liver tumors, mutation spectrum analysis was carried out on hepatocellular carcinomas from 80 Peruvian patients. Sequencing analysis focused on nine genes typically altered during liver carcinogenesis, i.e. ARID2, AXIN1, BRAF, CTNNB1, NFE2L2, H/K/N-RAS, and TP53. We also assessed the transcription level of factors involved in the control of the alpha-fetoprotein expression and the Hippo signaling pathway that controls contact inhibition in metazoans. The mutation spectrum of Peruvian patients was unique with a major class of alterations represented by Insertions/Deletions. There were no changes at hepatocellular carcinoma-associated mutation hotspots in more than half of the specimens analyzed. Furthermore, our findings support the theory of a consistent collapse in the Hippo axis, as well as an expression of the stemness factor NANOG in high alpha-fetoprotein-expressing hepatocellular carcinomas. These results confirm the specificity of Peruvian hepatocellular carcinoma at the molecular genetic level. The present study emphasizes the necessity to widen cancer research to include historically neglected patients from South America, and more broadly the Global South, where cancer genetics and tumor presentation are divergent from canonical neoplasms.
[Show abstract][Hide abstract] ABSTRACT: Aims Uveal melanoma (UM) is the most common malignant tumour of the eye. Diagnosis often occurs late in the course of disease, and prognosis is generally poor. Recently, recurrent somatic mutations were described, unravelling additional specific altered pathways in UM. Targeted next-generation sequencing (NGS) can now be applied to an accurate and fast identification of somatic mutations in cancer. The aim of the present study was to characterise the mutation pattern of five UM hepatic metastases with well-defined clinical and pathological features.
Methods We analysed the UM mutation spectrum using targeted NGS on 409 cancer genes.
Results Four previous reported genes were found to be recurrently mutated. All tumours presented mutually exclusive GNA11 or GNAQ missense mutations. BAP1 loss-of-function mutations were found in three UMs. SF3B1 missense mutations were found in the two UMs with no BAP1 mutations. We then searched for additional mutation targets. We identified the Arg505Cys mutation in the tumour suppressor FBXW7. The same mutation was previously described in different cancer types, and FBXW7 was recently reported to be mutated in UM exomes.
Conclusions Further studies are required to confirm FBXW7 implication in UM tumorigenesis. Elucidating the molecular mechanisms underlying UM tumorigenesis holds the promise for novel and effective targeted UM therapies.
Full-text · Article · Oct 2014 · British Journal of Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: Until the past two decades, almost all colorectal polyps were divided into two main groups: hyperplastic polyps and adenomas. Sessile serrated adenomas presented endoscopic, pathological and molecular profiles distinct from others polyps. Previously under-diagnosed, physicians now identified sessile serrated adenomas. The serrated neoplastic pathway is accounting for up to one-third of all sporadic colorectal cancers and sessile serrated adenomas have been identified as the main precursor lesions in serrated carcinogenesis. By analogy with the adenoma–adenocarcinoma sequence, the sessile serrated adenomas–adenocarcinoma sequence, has been identified. The development of endoscopic resection techniques permits the consideration of a non-surgical approach as the first option regardless of the size of the lesion. Sessile serrated adenoma warrants the watchfulness of physicians and requires an optimal quality of the colonoscopy procedure, a thorough evaluation of the lesion, an adequate endoscopic resection and follow-up colonoscopies in accordance with sessile serrated adenomas guidelines. We herein present a review on sessile serrated adenomas focusing on their pathological specificities, epidemiology, treatment modalities and follow-up.
Full-text · Article · Oct 2014 · Digestive and Liver Disease
[Show abstract][Hide abstract] ABSTRACT: Depuis l’avènement du traitement par Vemurafénib des mélanomes non résécables ou métastatiques porteurs d’une mutation BRAF sur le codon V600, les plateformes de pathologie et d’oncogénétique somatique sont de plus en plus sollicitées pour la recherche de mutation BRAF dans le mélanome. BRAF est muté dans 40 à 50 % des mélanomes, la mutation V600E représentant 80–90 % des mutations. Actuellement, les méthodes de biologie moléculaires sont le standard pour ce diagnostic. Une approche par immuno-histochimie (IHC) première utilisant un anticorps reconnaissant spécifiquement la protéine BRAF mutée V600E a été récemment proposée.
Full-text · Article · Oct 2014 · Annales de Pathologie
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Quantitative shear wave elastography was shown to be an effective tool for the non-invasive diagnosis and staging of chronic liver diseases. The liver shear modulus, estimated from the propagation velocity of shear waves, is correlated to the degree of fibrosis and can therefore be used for the non-invasive staging of fibrosis.
We performed a clinical prospective study in a total of 120 patients with various chronic liver diseases to compare the accuracy of supersonic shear imaging (SSI), a technique based on acoustic radiation and ultrafast ultrasound imaging, to 1D transient elastography (FibroScan) for the staging and grading of fibrosis as assessed by liver biopsy. Since shear wave propagation spectroscopy can also provide additional mechanical information on soft tissues, such as viscosity, we also investigated those new mechanical parameters as possible predictors of fibrosis, steatosis, and disease activity.
SSI was successfully performed in 98.3% of patients and it was shown to be as accurate as FibroScan for the staging of fibrosis both for the whole population (N=120) and for the subgroup with viral hepatitis (n=70) (AUC=0.85 [0.77-0.96] and 0.89 [0.81-0.97] for significant fibrosis, AUC=0.90 [0.83-0.97] and 0.87 [0.75-0.98] for cirrhosis, with respect to SSI [n=68/70] and FibroScan [n=66/68]). Viscosity could also be used to stage the degree of fibrosis (AUC=0.76 [0.64-0.87] for significant fibrosis and AUC=0.87 [0.74-0.99] for cirrhosis), for the subgroup of patients with viral hepatitis (n=67/70) but was a poor predictor of disease activity and steatosis levels.
Supersonic shear imaging is a robust technique for the staging of liver fibrosis. Liver viscosity was found to be correlated with fibrosis but not to steatosis or disease activity.
No preview · Article · Sep 2014 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Solid-pseudopapillary neoplasm of the pancreas (SPN) is an uncommon low-grade malignant neoplasm occurring mostly in young women. In addition to its distinctive pathological appearance of pseudopapillae with poorly cohesive neoplastic cells, rare variants exist raising the differential diagnosis especially with neuroendocrine neoplasms. The overall prognosis for patients with SPNs is excellent after surgical resection. Nevertheless, 10% of cases may have malignant behavior characterized by tumor recurrence and/or metastasis. Despite numerous studies, the histogenesis of this neoplasm remains unclear. Distinctive molecular alterations such as the presence of CTNNB1 mutations are observed in nearly all cases, while mutations classically observed in ductal adenocarcinoma, such as KRAS, TP53 and SMAD4, are not observed in SPNs, reinforcing its distinct nature compared to all other pancreatic neoplasms. Recent transcriptional studies have shown that activation of the Wnt/beta-catenin pathway in these tumors is associated with the upregulation of genes belonging to Notch, Hedgehog and androgen receptor signaling pathways.
No preview · Article · Sep 2014 · Seminars in Diagnostic Pathology
[Show abstract][Hide abstract] ABSTRACT: The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.Oncogene advance online publication, 7 July 2014; doi:10.1038/onc.2014.182.