39 results on '"Jansen, Marnix"'
Search Results
2. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer
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Kayhanian, Hamzeh, Cross, William, van der Horst, Suzanne E. M., Barmpoutis, Panagiotis, Lakatos, Eszter, Caravagna, Giulio, Zapata, Luis, Van Hoeck, Arne, Middelkamp, Sjors, Litchfield, Kevin, Steele, Christopher, Waddingham, William, Patel, Dominic, Milite, Salvatore, Jin, Chen, Baker, Ann-Marie, Alexander, Daniel C., Khan, Khurum, Hochhauser, Daniel, Novelli, Marco, Werner, Benjamin, van Boxtel, Ruben, Hageman, Joris H., Buissant des Amorie, Julian R., Linares, Josep, Ligtenberg, Marjolijn J. L., Nagtegaal, Iris D., Laclé, Miangela M., Moons, Leon M. G., Brosens, Lodewijk A. A., Pillay, Nischalan, Sottoriva, Andrea, Graham, Trevor A., Rodriguez-Justo, Manuel, Shiu, Kai-Keen, Snippert, Hugo J. G., and Jansen, Marnix
- Abstract
Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6)and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.
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- 2024
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3. The co-evolution of the genome and epigenome in colorectal cancer
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Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., and Sottoriva, Andrea
- Abstract
Colorectal malignancies are a leading cause of cancer-related death1and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4–7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.
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- 2022
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4. Phenotypic plasticity and genetic control in colorectal cancer evolution
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Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Kimberley, Chris, Zapata, Luis, Lynn, Claire, James, Chela, Mossner, Maximilian, Fernandez-Mateos, Javier, Vinceti, Alessandro, Baker, Ann-Marie, Gabbutt, Calum, Berner, Alison, Schmidt, Melissa, Chen, Bingjie, Lakatos, Eszter, Gunasri, Vinaya, Nichol, Daniel, Costa, Helena, Mitchinson, Miriam, Ramazzotti, Daniele, Werner, Benjamin, Iorio, Francesco, Jansen, Marnix, Caravagna, Giulio, Barnes, Chris P., Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Sottoriva, Andrea, and Graham, Trevor A.
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Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather ‘plastic’. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.
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- 2022
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5. LOW RECURRENCE RATES AFTER ENDOSCOPIC RESECTION (R0) OF HIGH-RISK T1 ADENOCARCINOMA IN BARRETT'S ESOPHAGUS SUPPORT A STRICT ENDOSCOPIC SURVEILLANCE STRATEGY: PRELIMINARY RESULTS OF A PROSPECTIVE, INTERNATIONAL, MULTICENTER COHORT STUDY (PREFER).
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Chan, Man Wai, Nieuwenhuis, Esther, Jansen, Marnix, Nagengast, Wouter, Westerhof, Jessie, Neuhaus, Horst, Beyna, Torsten, Koch, Arjun, Spaander, Manon, Bourke, Michael, Bisschops, Raf, De Hertogh, Gert, Weusten, Bas, Alkhalaf, A., Pech, Oliver, Seewald, Stefan, Haidry, Rehan, De Wulf, Dominiek, Schlag, Christoph, and Schoon, Erik
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- 2024
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6. ENDOSCOPY-LED RISK STRATIFICATION OF GASTRIC INTESTINAL METPLASIA – DIAGNOSTIC ACCURACY OF VIRTUAL CHROMOENDOSCOPY COMBINED WITH TARGETED BIOPSIES IN PATIENTS WITH PREMALIGNANT GASTRIC LESIONS IN A LOW INCIDENCE AREA.
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Marijnissen, Fleur E., Waddingham, William, Nieuwenburg, Stella, Graham, David, De Jonge, P.J.F., Honing, Judith, Rodriguez-Justo, Manuel, Doukas, Michail, Kuipers, Ernst, Banks, Matthew, Jansen, Marnix, and Spaander, Manon
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- 2024
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7. The Role of Serum S100B as a Clinical Follow-up Tool for Disease Recurrence in Stage III Melanoma Patients.
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Jansen, Marnix, Caini, Saverio, Been, Lukas, van Leeuwen, Barbara, and Stanganelli, Ignazio
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DISEASE relapse ,DISEASE progression ,MELANOMA - Published
- 2024
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8. Poor Diagnostic Reproducibility in the Identification of Nonconventional Dysplasia in Colitis Impacts the Application of Histologic Stratification Tools
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Nasreddin, Nadia, Jansen, Marnix, Loughrey, Maurice B., Wang, Lai Mun, Koelzer, Viktor H., Rodriguez-Justo, Manuel, Novelli, Marco, Fisher, Jennifer, Brown, Matthew W., Al Bakir, Ibrahim, Hart, Ailsa L., Dunne, Philip, Graham, Trevor A., and Leedham, Simon J.
- Abstract
Due to their increased cancer risk, patients with longstanding inflammatory bowel disease are offered endoscopic surveillance with concomitant histopathologic assessments, aimed at identifying dysplasia as a precursor lesion of colitis-associated colorectal cancer. However, this strategy is beset with difficulties and limitations. Recently, a novel classification criterion for colitis-associated low-grade dysplasia has been proposed, and an association between nonconventional dysplasia and progression was reported, suggesting the possibility of histology-based stratification of patients with colitis-associated lesions. Here, a cohort of colitis-associated lesions was assessed by a panel of 6 experienced pathologists to test the applicability of the published classification criteria and try and validate the association between nonconventional dysplasia and progression. While confirming the presence of different morphologic patterns of colitis-associated dysplasia, the study demonstrated difficulties concerning diagnostic reproducibility between pathologists and was unable to validate the association of nonconventional dysplasia with cancer progression. Our study highlights the overall difficulty of using histologic assessment of precursor lesions for cancer risk prediction in inflammatory bowel disease patients and suggests the need for a different diagnostic strategy that can objectively identify high-risk phenotypes.
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- 2024
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9. ENDOSCOPIC FOLLOW-UP OF RADICALLY RESECTED SUBMUCOSAL ADENOCARCINOMA IN BARRETT'S ESOPHAGUS: INTERIM RESULTS OF AN ONGOING PROSPECTIVE, INTERNATIONAL, MULTICENTER COHORT REGISTRY (PREFER TRIAL).
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Chan, Man Wai, Nieuwenhuis, Esther, Jansen, Marnix, Koch, Arjun, Spaander, Manon, Nagengast, Wouter, Westerhof, Jessie, Bisschops, Raf, De Hertogh, Gert, Bourke, Michael, Neuhaus, Horst, Weusten, Bas, Alkhalaf, A., Pech, Oliver, Seewald, Stefan, Haidry, Rehan, Schlag, Christoph, Schoon, Erik, Houben, Martin, and De Wulf, Dominiek
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- 2023
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10. Comparison of two multiband mucosectomy devices for endoscopic resection of Barrett’s esophagus-related neoplasia
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Alzoubaidi, Durayd, Graham, David, Bassett, Paul, Magee, Cormac, Everson, Martin, Banks, Matthew, Novelli, Marco, Jansen, Marnix, Lovat, Laurence B., and Haidry, Rehan
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Background: Esophageal adenocarcinoma carries a poor prognosis and therefore treatment of early neoplasia arising in the precursor condition Barrett’s esophagus (BE) is desirable. Visible lesions arising in BE need endoscopic mucosal resection for accurate staging and removal. Resection modalities include a cap-based system with snare and custom-made multiband mucosectomy (MBM) devices (Duette, Cook Medical Ltd). A new MBM device has recently become available (Captivator, Boston Scientific Ltd). Objectives: A retrospective pilot study to compare the efficacy, safety, specimen size and histology of endoscopic mucosal resection (EMR) specimens resected with two MBM devices (Cook Duette and Boston Captivator) in treatment naive patients undergoing endoscopic therapy for BE neoplasia. Methods: Consecutive EMR procedures carried out by a single experienced endoscopist were analysed. All visible lesions were marked and resected using one of the two MBM devices. All resected specimens were analysed by the same two experienced pathologists. The resected specimens in both groups were analysed for maximum diameter, minimum diameter, surface area and depth. Results: Twenty consecutive patients were analysed (18M?+?2F; mean age 74) in the Duette group and 20 (17M?+?3F; mean age 72) in the Captivator group. A total of 58 specimens were resected in the Duette and 63 in the Captivator group. Min diameter, max diameter, surface area and depth of the ER specimens resected by the Captivator device were significantly larger than that by the Duette device [min diameter 9.89 mm vs 9.07 mm (p?=?0.019); max diameter: 13.54 mm vs 12.38 mm (p?=?0.024); surface area: 135.40 mm
2 vs 113.89 mm2 (p?=?0.005); depth 3.71 mm vs 2.89 (p?=?0.001)]. Conclusions: These two MBM devices showed equivalent efficacy and safety outcomes, but the EMR Captivator device resected specimens with a larger area in the esophagus when compared with the Duette device. A possible advantage of this is in situations where en bloc resections with fewer EMRs are desirable for larger lesions.- Published
- 2019
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11. Deep learning for histopathological assessment of esophageal adenocarcinoma precursor lesions
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Botros, Michel, de Boer, Onno J., Cardenas, Bryan, Bekkers, Erik J., Jansen, Marnix, van der Wel, Myrtle J., Sánchez, Clara I., and Meijer, Sybren L.
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Histopathological assessment of esophageal biopsies is a key part in the management of patients with Barrett’s esophagus (BE) but prone to observer variability and reliable diagnostic methods are needed. Artificial intelligence (AI) is emerging as a powerful tool for aided diagnosis but often relies on abstract test and validation sets while real world behavior is unknown.
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- 2024
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12. Insights Into the Pathophysiology of Esophageal Adenocarcinoma.
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Quante, Michael, Graham, Trevor A., and Jansen, Marnix
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Although researchers have identified genetic alterations that contribute to development of esophageal adenocarcinoma, we know little about features of patients or environmental factors that mediate progression of chronic acid biliary reflux to Barrett’s esophagus and cancer. Increasing our understanding of the mechanisms by which normal squamous epithelium progresses to early-stage invasive cancer will help formulate rational surveillance guidelines and allow us to divest resources away from patients at low risk of malignancy. We review the cellular and genetic alterations that occur during progression of Barrett’s esophagus, based on findings from clinical studies and mouse models of disease. We review the features of the luminal and mucosal microenvironment of Barrett’s esophagus that promote, in a small proportion of patients, development of esophageal adenocarcinoma. Markers of clonal evolution can be used to determine patient risk for cancer and set surveillance intervals. [ABSTRACT FROM AUTHOR]
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- 2018
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13. Evolutionary history of human colitis-associated colorectal cancer
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Baker, Ann-Marie, Cross, William, Curtius, Kit, Al Bakir, Ibrahim, Choi, Chang-Ho Ryan, Davis, Hayley Louise, Temko, Daniel, Biswas, Sujata, Martinez, Pierre, Williams, Marc J, Lindsay, James O, Feakins, Roger, Vega, Roser, Hayes, Stephen J, Tomlinson, Ian P M, McDonald, Stuart A C, Moorghen, Morgan, Silver, Andrew, East, James E, Wright, Nicholas A, Wang, Lai Mun, Rodriguez-Justo, Manuel, Jansen, Marnix, Hart, Ailsa L, Leedham, Simon J, and Graham, Trevor A
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ObjectiveIBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing.DesignExome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.Results10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase.ConclusionsEvolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
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- 2019
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14. Crypt fusion as a homeostatic mechanism in the human colon
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Baker, Ann-Marie, Gabbutt, Calum, Williams, Marc J, Cereser, Biancastella, Jawad, Noor, Rodriguez-Justo, Manuel, Jansen, Marnix, Barnes, Chris P, Simons, Benjamin D, McDonald, Stuart AC, Graham, Trevor A, and Wright, Nicholas A
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ObjectiveThe crypt population in the human intestine is dynamic: crypts can divide to produce two new daughter crypts through a process termed crypt fission, but whether this is balanced by a second process to remove crypts, as recently shown in mouse models, is uncertain. We examined whether crypt fusion (the process of two neighbouring crypts fusing into a single daughter crypt) occurs in the human colon.DesignWe used somatic alterations in the gene cytochrome c oxidase (CCO) as lineage tracing markers to assess the clonality of bifurcating colon crypts (n=309 bifurcating crypts from 13 patients). Mathematical modelling was used to determine whether the existence of crypt fusion can explain the experimental data, and how the process of fusion influences the rate of crypt fission.ResultsIn 55% (21/38) of bifurcating crypts in which clonality could be assessed, we observed perfect segregation of clonal lineages to the respective crypt arms. Mathematical modelling showed that this frequency of perfect segregation could not be explained by fission alone (p<10−20). With the rates of fission and fusion taken to be approximately equal, we then used the distribution of CCO-deficient patch size to estimate the rate of crypt fission, finding a value of around 0.011 divisions/crypt/year.ConclusionsWe have provided the evidence that human colonic crypts undergo fusion, a potential homeostatic process to regulate total crypt number. The existence of crypt fusion in the human colon adds a new facet to our understanding of the highly dynamic and plastic phenotype of the colonic epithelium.
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- 2019
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15. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma
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Banks, Matthew, Graham, David, Jansen, Marnix, Gotoda, Takuji, Coda, Sergio, di Pietro, Massimiliano, Uedo, Noriya, Bhandari, Pradeep, Pritchard, D Mark, Kuipers, Ernst J, Rodriguez-Justo, Manuel, Novelli, Marco R, Ragunath, Krish, Shepherd, Neil, and Dinis-Ribeiro, Mario
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Gastric adenocarcinoma carries a poor prognosis, in part due to the late stage of diagnosis. Risk factors include Helicobacter pyloriinfection, family history of gastric cancer—in particular, hereditary diffuse gastric cancer and pernicious anaemia. The stages in the progression to cancer include chronic gastritis, gastric atrophy (GA), gastric intestinal metaplasia (GIM) and dysplasia. The key to early detection of cancer and improved survival is to non-invasively identify those at risk before endoscopy. However, although biomarkers may help in the detection of patients with chronic atrophic gastritis, there is insufficient evidence to support their use for population screening. High-quality endoscopy with full mucosal visualisation is an important part of improving early detection. Image-enhanced endoscopy combined with biopsy sampling for histopathology is the best approach to detect and accurately risk-stratify GA and GIM. Biopsies following the Sydney protocol from the antrum, incisura, lesser and greater curvature allow both diagnostic confirmation and risk stratification for progression to cancer. Ideally biopsies should be directed to areas of GA or GIM visualised by high-quality endoscopy. There is insufficient evidence to support screening in a low-risk population (undergoing routine diagnostic oesophagogastroduodenoscopy) such as the UK, but endoscopic surveillance every 3 years should be offered to patients with extensive GA or GIM. Endoscopic mucosal resection or endoscopic submucosal dissection of visible gastric dysplasia and early cancer has been shown to be efficacious with a high success rate and low rate of recurrence, providing that specific quality criteria are met.
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- 2019
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16. ENDOSCOPIC FOLLOW-UP OF RADICALLY RESECTED SUBMUCOSAL ADENOCARCINOMA IN BARRETT'S ESOPHAGUS: INTERIM RESULTS OF AN ONGOING PROSPECTIVE, INTERNATIONAL, MULTICENTER COHORT REGISTRY (PREFER TRIAL).
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Chan, Man Wai, Nieuwenhuis, Esther, Jansen, Marnix, Koch, Arjun, Spaander, Manon, Nagengast, Wouter, Westerhof, Jessie, Bisschops, Raf, De Hertogh, Gert, Bourke, Michael, Neuhaus, Horst, Weusten, Bas, Alkhalaf, A., Pech, Oliver, Seewald, Stefan, Haidry, Rehan, Schlag, Christoph, Schoon, Erik, Houben, Martin, and De Wulf, Dominiek
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- 2023
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17. 253e IMMUNE EDITING IN THE INVASIVE MARGIN AND NODE DEPOSITS OF COLORECTAL CANCER SELECTS FOR CELLULAR NEIGHBOURHOODS ENRICHED IN PDL1+ CANCER CELLS.
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Gunasri, Vinaya, Lakatos, Eszter, Trahearn, Nick, Cisneros, Luis, Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Mossner, Maximilian, Kimberley, Christopher, Ortiz, Luis Zapata, James, Chela, Lynn, Claire, Berner, Alison A., Costa, Helena, Mitchison, Miriam, Jansen, Marnix, Caravagna, Giulio, Rodriguez-Justo, Manuel, and Shibata, Darryl
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- 2023
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18. 223 IMMUNE CELL PHENOTYPING IN BARRETT'S ESOPHAGUS IN PATIENTS PRIOR AND AT TIME OF PROGRESSION.
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Lin, Meng-Lay, Hickey, John W., Schürch, Christian M., Passman, Adam M., Carlotti, Emanuela, Devkumar, Shruthi, Hackett, Richard J., Rodriguez-Justo, Manuel, Novelli, Marco, Jansen, Marnix, Gascard, Philippe D., Tlsty, Thea D., and McDonald, Stuart A.
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- 2023
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19. Analysis of metastases rates during follow-up after endoscopic resection of early "high-risk" esophageal adenocarcinoma.
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Nieuwenhuis, Esther A., van Munster, Sanne N., Meijer, Sybren L., Brosens, Lodewijk A.A., Jansen, Marnix, Weusten, Bas L.A. M., Alvarez Herrero, Lorenza, Alkhalaf, Alaa, Schenk, Ed, Schoon, Erik J., Curvers, Wouter L., Koch, Arjun D., van de Ven, Steffi E.M., Verheij, Eva P.D., Nagengast, Wouter B., Westerhof, Jessie, Houben, Martin H.M. G., Tang, Thjon, Bergman, Jacques J.G. H.M., and Pouw, Roos E.
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After endoscopic resection (ER) of early esophageal adenocarcinoma (EAC), the optimal management of patients with high-risk histologic features for lymph node metastases (ie, submucosal invasion, poor differentiation grade, or lymphovascular invasion) remains unclear. We aimed to evaluate outcomes of endoscopic follow-up after ER for high-risk EAC. For this retrospective cohort study, data were collected from all Dutch patients managed with endoscopic follow-up (endoscopy, EUS) after ER for high-risk EAC between 2008 and 2019. We distinguished 3 groups: intramucosal cancers with high-risk features, submucosal cancers with low-risk features, and submucosal cancers with high-risk features. The primary outcome was the annual risk for metastases during follow-up, stratified for baseline histology. One hundred twenty patients met the selection criteria. Median follow-up was 29 months (interquartile range, 15-48). Metastases were observed in 5 of 25 (annual risk, 6.9%; 95% confidence interval [CI], 3.0-15) high-risk intramucosal cancers, 1 of 55 (annual risk,.7%; 95% CI, 0-4.0) low-risk submucosal cancers, and 3 of 40 (annual risk, 3.0%; 95% CI, 0-7.0) high-risk submucosal cancers. Whereas the annual metastasis rate for high-risk submucosal EAC (3.0%) was somewhat lower than expected in comparison with previous reported percentages, the annual metastasis rate of 6.9% for high-risk intramucosal EAC is new and worrisome. This calls for further prospective studies and suggests that strict follow-up of this small subgroup is warranted until prospective data are available. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Establishing a clinical and molecular diagnosis for hereditary colorectal cancer syndromes: Present tense, future perfect?
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Jansen, Marnix, Menko, Fred H., Brosens, Lodewijk A.A., Giardiello, Francis M., and Offerhaus, G. Johan
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- 2014
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21. Is it justified to ablate flat-type esophageal squamous cancer? An analysis of endoscopic submucosal dissection specimens of lesions meeting the selection criteria of radiofrequency studies.
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Jansen, Marnix, Schölvinck, Dirk W., Kushima, Ryoji, Sekine, Shigeki, Weusten, Bas L.A.M., Wang, Guiqi Q., Fleischer, David E., Yoshinaga, Shigetaka, Dawsey, Sanford M., Meijer, Sybren L., Bergman, Jacques J.G.H.M., and Oda, Ichiro
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Background Endoscopic radiofrequency ablation (RFA) appears to be a safe and effective treatment for flat-type noninvasive squamous neoplasia of the esophagus. However, if RFA is applied to lesions containing invasive cancer (esophageal squamous cell carcinoma [ESCC]), histological features associated with lymph node metastases may remain undetected. In addition, extension of neoplasia down the ducts of esophageal submucosal glands (SMGs) may create a sheltered “niche” beyond the reach of ablation. Objective To determine the RFA eligibility of flat-type ESCC. Design Retrospective analysis of prospectively collected data of ESCC patients. Setting National Cancer Center Hospital, Tokyo, Japan. Patients Patients with flat-type ESCC larger than 3 cm removed by endoscopic submucosal dissection (ESD). Interventions Three endoscopists involved in RFA studies in China reviewed endoscopic images to select lesions eligible for RFA. Corresponding ESD resection specimens were histologically examined. Main Outcome Measurements The presence of poor histological features (ie, invasion in m3 or deeper, poor tumor differentiation, or lymphovascular invasion) and the number of involved esophageal SMGs and ducts. Results Sixty-five lesions were included, 17 (26%) of which qualified as RFA eligible by RFA endoscopists. Interobserver agreement for this assessment was poor (κ = 0.09). Six of the 17 specimens (35%) showed relevant disease: 4 lesions invaded in the muscularis mucosae, 1 of which also showed lymphovascular invasion; 2 lesions showed extension of neoplasia into SMGs. Limitations Limited number of cases. RFA eligibility status was based on analysis of still images. Conclusions One third of flat-type ESCC, deemed eligible for RFA, demonstrated histological features that are considered (relative) contraindications to endoscopic treatment. Because it appears difficult for endoscopists to identify low-risk ESCC, conservative use of RFA for flat-type ESCC is advocated until long-term follow-up data are available. [ABSTRACT FROM AUTHOR]
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- 2014
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22. Mo1164: UTILISATION OF THE CYTOSPONGE DEVICE AS A TOOL FOR RISK STRATIFICATION IN PATIENTS WITH BARRETT'S OESOPHAGUS WHO ARE OVERDUE ENDOSCOPIC SURVEILLANCE DUE TO THE COVID-19 PANDEMIC.
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Sehgal, Vinay, Aslam, Nasar, Mcguire, Joshua, Telese, Andrea, Hussein, Mohamed, Bassett, Paul, Naidoo, Dashnee, Coates, Olivia, Thorpe, Sally, Brogden, Sara E., Makahamadze, Christwishes, Sesay, Michael, Mitchison, Miriam, Jansen, Marnix, Sami, Sarmed S., Sweis, Rami, Banks, Matthew, Graham, David, Lovat, Laurence B., and Haidry, Rehan
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- 2022
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23. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity
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Andor, Noemi, Graham, Trevor A, Jansen, Marnix, Xia, Li C, Aktipis, C Athena, Petritsch, Claudia, Ji, Hanlee P, and Maley, Carlo C
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Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24–0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71–2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20–1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08–0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.
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- 2016
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24. Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus.
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Evans, James A., Carlotti, Emanuela, Lin, Meng-Lay, Hackett, Richard J., Haughey, Magnus J., Passman, Adam M., Dunn, Lorna, Elia, George, Porter, Ross J., McLean, Mairi H., Hughes, Frances, ChinAleong, Joanne, Woodland, Philip, Preston, Sean L., Griffin, S. Michael, Lovat, Laurence, Rodriguez-Justo, Manuel, Huang, Weini, Wright, Nicholas A., and Jansen, Marnix
- Abstract
Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0–2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE. [Display omitted] We do not know how Barrett's esophagus glands evolve. A link is shown between the different types, and their diversity is associated with an increased risk of developing cancer. [ABSTRACT FROM AUTHOR]
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- 2022
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25. Barrett oesophagus: lessons on its origins from the lesion itself
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McDonald, Stuart A. C., Lavery, Danielle, Wright, Nicholas A., and Jansen, Marnix
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Barrett oesophagus develops when the lower oesophageal squamous epithelium is replaced with columnar epithelium, which shows both intestinal and gastric differentiation. No consensus has been reached on the origin of Barrett oesophagus. Theories include a direct origin from the oesophageal-stratified squamous epithelium, or by proximal migration of the gastric cardiac epithelium with subsequent intestinalization. Variations of this theory suggest the origin is a distinctive cell at the squamocolumnar junction, the oesophageal gland ducts, or circulating bone-marrow-derived cells. Much of the supporting evidence comes from experimental models and not from studies of Barrett mucosa. In this Perspectives article, we look at the Barrett lesion itself: at its phenotype, its complexity, its clonal architecture and its stem cell organization. We conclude that Barrett glands are unique structures, but share many similarities with gastric glands undergoing the process of intestinal metaplasia. We conclude that current evidence most strongly supports an origin from stem cells in the cardia.
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- 2015
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26. Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon
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Baker, Ann-Marie, Cereser, Biancastella, Melton, Samuel, Fletcher, Alexander G., Rodriguez-Justo, Manuel, Tadrous, Paul J., Humphries, Adam, Elia, George, McDonald, Stuart A.C., Wright, Nicholas A., Simons, Benjamin D., Jansen, Marnix, and Graham, Trevor A.
- Abstract
Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a “functional” stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC−/+). Furthermore, we show that, in adenomatous crypts (APC−/−), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30–40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.
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- 2014
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27. Epithelial-Specific Loss of PTENResults in Colorectal Juvenile Polyp Formation and Invasive Cancer
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Marsh Durban, Victoria, Jansen, Marnix, Davies, Emma J., Morsink, Folkert H., Offerhaus, G. Johan A., and Clarke, Alan R.
- Abstract
Cowden syndrome (CS) is a rare autosomal dominant cancer-prone disorder caused by germ-line mutation of the phosphatase and tensin homolog mutated on chromosome 10 (PTEN) tumor-suppressor gene. Affected patients commonly develop juvenile polyps, and show an elevated risk of developing colorectal cancers. The etiology of these peculiar polyps remains unclear, although previous work has suggested somatic PTENalterations in the stroma of juvenile polyps. After a long latency period, we find epithelial-specific PTENdeletion to cause formation of juvenile polyps in the colorectum without stromal PTENloss. More important, we find that these lesions closely recapitulate all of the characteristic histopathological features of juvenile polyps seen in patients with CS, including stromal alterations and dysplastic transformation to colorectal carcinoma. The stromal alterations we identify after epithelial-specific PTENloss suggest that PTENmay be involved in altered epithelial-mesenchymal cross talk, which, in turn, predisposes to colorectal neoplasia and polyposis. Our transgenic model is the first to recapitulate colorectal juvenile polyposis in patients with CS. We conclude that stromal PTENloss is not a prerequisite for the formation of juvenile polyps, and that colorectal juvenile polyps in CS are bona fide neoplastic precursor lesions.
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- 2014
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28. Extension of early esophageal squamous cell neoplasia into ducts and submucosal glands and the role of endoscopic ablation therapy.
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Overwater, Anouk, van Munster, Sanne N., Offerhaus, G. Johan A., Seldenrijk, Cees A., Raicu, G. Mihaela, Koch, Arjun D., Bergman, Jacques J.G. H.M., Pouw, Roos E., Brosens, Lodewijk A.A., Jansen, Marnix, and Weusten, Bas L.A. M.
- Abstract
Early esophageal squamous cell neoplasia (ESCN) is preferably treated with en-bloc endoscopic resection. Ablation might be an alternative for flat ESCN, but ESCN extension along the epithelial lining of ducts and submucosal glands (SMGs) might jeopardize ablation efficacy. Clinical studies suggest that local recurrence might arise from such buried ESCN niches after ablation. We studied human endoscopic resection specimens of ESCN to quantify ESCN extension into ducts/SMGs and performed a prospective porcine study to evaluate the depth of radiofrequency ablation (RFA) and CryoBalloon ablation (CBA) into ducts/SMGs. Endoscopic submucosal dissection specimens of flat-type ESCN from a Japanese (n = 65) and Dutch cohort (n = 14) were evaluated for presence and neoplastic involvement of ducts/SMGs. Twenty-seven pigs were treated with circumferential RFA (c-RFA; n = 4), focal CBA (n = 20), and focal RFA (n = 3) with 4, 60, and 9 treatment areas, respectively. After prespecified survival periods (0 hours, 8 hours, 2 days, 5 days, and 28 days), treatment areas were evaluated for uniformity and depth of ablation and affected SMGs. Neoplastic extension in ducts/SMGs was observed in most lesions: 58% (38/65) in the Japanese and 64% (9/14) in the Dutch cohort. In the animal study, 33% of SMGs (95% confidence interval, 28-50) were not affected after c-RFA, although the overlying epithelium was ablated. Focal RFA and CBA resulted in uniform ablations with effective treatment of all SMGs. ESCN extends into ducts/SMGs in most patients. In an animal model, focal RFA and CBA effectively ablated SMGs, whereas c-RFA inadequately ablated SMGs. Given this potential reason for recurrence, endoscopic resection should remain the standard of care. [ABSTRACT FROM AUTHOR]
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- 2021
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29. Analysis of LKB1 mutations and other molecular alterations in pancreatic acinar cell carcinoma
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de Wilde, Roeland F, Ottenhof, Niki A, Jansen, Marnix, Morsink, Folkert H M, de Leng, Wendy W J, Offerhaus, G Johan A, and Brosens, Lodewijk A A
- Abstract
Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1 was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1 mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1 gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression. In addition, microsatellite instability and methylation of a number of tumor suppressor genes were investigated and KRAS, TP53, CDKN1A, SMAD4 and CTNNB1 were studied by mutation analysis and immunohistochemistry. No mutations, deletions or promoter hypermethylation of LKB1 were found in any of the sporadic acinar cell carcinomas, and mRNA expression of LKB1 was not altered. Amplifications at chromosome 20q and 19p were found in 100 and 80% of the cases, respectively. In addition, hypermethylation of one or more tumor suppressor genes was found in 80% of cases. One case harbored a TP53 mutation, and expression of SMAD4 and CTNNB1 was altered in one case each. No KRAS mutations or microsatellite instability were found. To conclude, no evidence for a role for LKB1 in tumorigenesis of sporadic pancreatic acinar cell carcinoma was found. However, copy number variations and hypermethylation were found in a majority of cases. Molecular pathways involved in acinar cell carcinoma-tumorigenesis differ from those involved in ductal pancreatic neoplasms. Further studies are needed to increase our understanding of molecular pathogenesis of acinar cell carcinoma, which may eventually result in development of new therapeutic targets.
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- 2011
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30. Analysis of LKB1mutations and other molecular alterations in pancreatic acinar cell carcinoma
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de Wilde, Roeland F, Ottenhof, Niki A, Jansen, Marnix, Morsink, Folkert H M, de Leng, Wendy W J, Offerhaus, G Johan A, and Brosens, Lodewijk A A
- Abstract
Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression. In addition, microsatellite instability and methylation of a number of tumor suppressor genes were investigated and KRAS, TP53, CDKN1A, SMAD4 and CTNNB1 were studied by mutation analysis and immunohistochemistry. No mutations, deletions or promoter hypermethylation of LKB1were found in any of the sporadic acinar cell carcinomas, and mRNA expression of LKB1was not altered. Amplifications at chromosome 20q and 19p were found in 100 and 80% of the cases, respectively. In addition, hypermethylation of one or more tumor suppressor genes was found in 80% of cases. One case harbored a TP53mutation, and expression of SMAD4 and CTNNB1 was altered in one case each. No KRASmutations or microsatellite instability were found. To conclude, no evidence for a role for LKB1in tumorigenesis of sporadic pancreatic acinar cell carcinoma was found. However, copy number variations and hypermethylation were found in a majority of cases. Molecular pathways involved in acinar cell carcinoma-tumorigenesis differ from those involved in ductal pancreatic neoplasms. Further studies are needed to increase our understanding of molecular pathogenesis of acinar cell carcinoma, which may eventually result in development of new therapeutic targets.
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- 2011
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31. Gastrointestinal Polyposis Syndromes
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A.A.Brosens, Lodewijk, Hattem, W. Arnout van, Jansen, Marnix, Leng, Wendy W.J. de, Giardiello, Francis M., and Offerhaus, G. Johan A.
- Abstract
Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz- Jeghers syndrome (PJS).
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- 2007
32. Aberrant Methylation of the 5' CpG Island of TSLC1 Is Common in Pancreatic Ductal Adenocarcinoma and Is First Manifest in High-Grade PanINs
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Jansen, Marnix, Fukushima, Noriyoshi, Rosty, Christophe, Walter, Kim, Altink, Renee, Heek, Tjarda van, Hruban, Ralph, Offerhaus, Johan G, and Goggins, Michael
- Abstract
The recently identified tumor-suppressor gene TSLC1 on chromosome 11q23.2 is frequently inactivated in human non-small cell lung adenocarcinoma by DNA methylation-associated silencing. The aim of this study was to determine if TSLC1 is inactivated in adenocarcinoma of the pancreas. We analyzed 17 pancreatic cancer cell lines, 91 primary pancreatic adenocarcinoma, 46 pancreatic intraepithelial (PanIN) precursor lesions and 15 microscopically normal pancreata for methylation of the 5’ CpG island of the TSLC1 gene through methylation-specific PCR. We observed 5’ CpG methylation of TSLC1 in 4 of 17 cell lines (24%). In each cell line the aberrant methylation was associated with loss of TSLC1 expression by RT-PCR that was reversible after treatment with the DNA methyltransferase inhibitor 5-aza-2’- deoxycytidine. Furthermore, we observed that TSLC1 was methylated in 25 of 91 primary pancreatic adenocarcinomas (27%), and in 2 of 7 high-grade PanIN-3 lesions (29%), but not in low-grade PanIN (0 of 9 PanIN-2 and 0 of 30 PanIN-1) lesions or in normal pancreata (n=15). We conclude that epigenetic silencing of TSLC1 expression through 5’ CpG island associated methylation is common in pancreatic adenocarcinoma and is a late event in pancreatic neoplastic development.
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- 2002
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33. Overexpression of S100A4in Pancreatic Ductal Adenocarcinomas Is Associated with Poor Differentiation and DNA Hypomethylation
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Rosty, Christophe, Ueki, Takashi, Argani, Pedram, Jansen, Marnix, Yeo, Charles J., Cameron, John L., Hruban, Ralph H., and Goggins, Michael
- Abstract
Using the National Center for Biotechnology Information Serial Analysis of Gene Expression database, we found that S100A4, a calcium-binding protein previously implicated in metastasis, was expressed in five of seven pancreatic carcinoma libraries but not in the two normal pancreatic duct libraries. We confirmed the overexpression of S100A4 using reverse transcriptase-polymerase chain reaction, which demonstrated that 18 of 19 (95%) pancreatic carcinoma cell lines expressed S100A4. Using immunohistochemistry, we found that 57 of 61 invasive pancreatic carcinomas (93%), 3 of 18 high-grade pancreatic intraepithelial neoplasia lesions (17%), and 0 of the 69 low-grade pancreatic intraepithelial neoplasia lesions expressed S100A4 protein, whereas normal pancreatic tissue and tissue affected by chronic pancreatitis did not label. Expression of S100A4 was associated with poor differentiation of the pancreatic adenocarcinomas (P= 0.001). We found that three CpG sites in the first intron of the S100A4gene were ∼90% methylated in microdissected normal pancreatic duct cells using bisulfite-modified sequencing and in two cell lines and three primary pancreatic carcinomas with a reduced or absent expression of S100A4. In contrast, these CpGs were 100% hypomethylated in 11 of 12 pancreatic cancer cell lines by methylation-specific polymerase chain reaction. The association between the expression of S100A4 and hypomethylation of the first intron of S100A4was statistically significant (P= 0.002). These data suggest that the majority of pancreatic carcinomas undergo selection for hypomethylation and overexpression of S100A4. Because most pancreatic carcinomas express S100A4, it may be a useful target for early detection strategies.
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- 2002
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34. STK11/LKB1Peutz-Jeghers Gene Inactivation in Intraductal Papillary-Mucinous Neoplasms of the Pancreas
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Sato, Norihiro, Rosty, Christophe, Jansen, Marnix, Fukushima, Noriyoshi, Ueki, Takashi, Yeo, Charles J., Cameron, John L., Iacobuzio-Donahue, Christine A., Hruban, Ralph H., and Goggins, Michael
- Abstract
Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of theSTK11/LKB1, a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of theSTK11/LKB1gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1gene. These results suggest that the STK11/LKB1gene is involved in the pathogenesis of some IPMNs.
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- 2001
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35. The complexity of cancer origins at the gastro-oesophageal junction
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Bornschein, Jan, Quante, Michael, and Jansen, Marnix
- Abstract
Chronic acid-biliary reflux and Helicobacter pyloriinfection are instrumental environmental drivers of cancer initiation and progression in the upper gastrointestinal tract. Remarkably, although these environmental carcinogens are quite dissimilar, the tumour progression cascade these carcinogens engender is highly comparable. For this reason, studies of malignant progression occurring at the anatomic borderland between the oesophagus and the stomach have traditionally lumped junctional adenocarcinomas with either oesophageal adenocarcinoma or gastric adenocarcinoma. Whilst studies have revealed remarkable epidemiological and genetic similarities of these cancers and their associated premalignant conditions, these works have also revealed some key differences. This highlights that further scientific effort demands a dedicated focus on the understanding of the cell-cell interaction between the epithelium and the local microenvironment in this anatomic region. We here review available evidence with regards to tumour progression occurring at the gastro-oesophageal junction and contrast it with available data on cancer evolution in the metaplastic oesophagus and distal stomach.
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- 2021
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36. Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon
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Baker, Ann-Marie, Cereser, Biancastella, Melton, Samuel, Fletcher, Alexander G., Rodriguez-Justo, Manuel, Tadrous, Paul J., Humphries, Adam, Elia, George, McDonald, Stuart A.C., Wright, Nicholas A., Simons, Benjamin D., Jansen, Marnix, and Graham, Trevor A.
- Published
- 2019
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37. Tu1833 - Multi-Region Exome Sequencing Reveals the Clonal Evolution of Colitis-Associated Colorectal Cancer.
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Baker, Ann-Marie, Choi, Chang Ho R., Davis, Hayley, Al-Bakir, Ibrahim, Martinez, Pierre, Temko, Daniel, Cross, William, Williams, Marc, Biswas, Sujata, McDonald, Stuart A., Wright, Nicholas A., Tomlinson, Ian, Moorghen, Morgan, Hayes, Stephen, Rodriguez-Justo, Manuel, Silver, Andrew, Wang, Lai Mun, Jansen, Marnix, Hart, Ailsa, and Leedham, Simon
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- 2017
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38. 712 - Clonal Interactions as Mechanisms of Polyclonality in Colorectal Adenomas.
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Walther, Viola, Davis, Hayley, Owusu, Christian K., Sivaharan, Ashwin, Williams, Marc, Rodriguez-Justo, Manuel, Jansen, Marnix, Leedham, Simon, Graham, Trevor A., and McDonald, Stuart A.
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- 2017
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39. Stromal Indian Hedgehog Signaling Is Required for Intestinal Adenoma Formation in Mice.
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Büller, Nikè V.J.A., Rosekrans, Sanne L., Metcalfe, Ciara, Heijmans, Jarom, van Dop, Willemijn A., Fessler, Evelyn, Jansen, Marnix, Ahn, Christina, Vermeulen, Jacqueline L.M., Westendorp, B. Florien, Robanus-Maandag, Els C., Offerhaus, G. Johan, Medema, Jan Paul, D’Haens, Geert R.A.M., Wildenberg, Manon E., de Sauvage, Frederic J., Muncan, Vanesa, and van den Brink, Gijs R.
- Abstract
Background & Aims Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice. Methods Glioma-associated oncogene ( Gli1 ) -CreERT2 and Patched ( Ptch )- lacZ reporter mice were crossed with Apc Min mice to generate Gli1CreERT2-Rosa26-ZSGreen-Apc Min and Ptch-lacZ-Apc Min mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc ( Apc HET ) mice, which develop adenomas after administration of β-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. Apc Min mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12). Results Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from Apc HET mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from Apc HET mice changed the composition of the adenoma stroma; cells that expressed α-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased. Conclusions Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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