292 results on '"Ahadova, A"'
Search Results
2. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes
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Møller, Pål, Haupt, Saskia, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., Sunde, Lone, Seppälä, Toni, Burn, John, Bernstein, Inge, Capella, Gabriel, Evans, D. Gareth, Lindblom, Annika, Winship, Ingrid, Macrae, Finlay, Katz, Lior, Laish, Ido, Vainer, Elez, Monahan, Kevin, Half, Elizabeth, Horisberger, Karoline, da Silva, Leandro Apolinário, Heuveline, Vincent, Therkildsen, Christina, Lautrup, Charlotte, Klarskov, Louise L, Cavestro, Giulia Martina, Möslein, Gabriela, Hovig, Eivind, and Dominguez-Valentin, Mev
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- 2024
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3. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated 'Big Bang' pathway to CRC in three of the four Lynch syndromes
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Pål Møller, Saskia Haupt, Aysel Ahadova, Matthias Kloor, Julian R. Sampson, Lone Sunde, Toni Seppälä, John Burn, Inge Bernstein, Gabriel Capella, D. Gareth Evans, Annika Lindblom, Ingrid Winship, Finlay Macrae, Lior Katz, Ido Laish, Elez Vainer, Kevin Monahan, Elizabeth Half, Karoline Horisberger, Leandro Apolinário da Silva, Vincent Heuveline, Christina Therkildsen, Charlotte Lautrup, Louise L Klarskov, Giulia Martina Cavestro, Gabriela Möslein, Eivind Hovig, and Mev Dominguez-Valentin
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MSI ,MLH1 ,MSH2 ,MSH6 ,PMS2 ,dMMR ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Genetics ,QH426-470 - Abstract
Abstract Background Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. Materials and methods We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.
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- 2024
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4. Das Two-in-one-hit-Modell der beschleunigten Genese von kolorektalen Karzinomen beim MLH1-assoziierten Lynch-Syndrom
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Ahadova, A., Stenzinger, A., Seppälä, T., Hüneburg, R., Kloor, M., and Bläker, H.
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- 2023
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5. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated 'Big Bang' pathway to CRC in three of the four Lynch syndromes
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Maller, Pål, Haupt, Saskia, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., Sunde, Lone, Seppälä, Toni, Burn, John, Bernstein, Inge, Capella, Gabriel, Evans, D. Gareth, Lindblom, Annika, Winship, Ingrid, Macrae, Finlay, Katz, Lior, Laish, Ido, Vainer, Elez, Monahan, Kevin, Half, Elizabeth, Horisberger, Karoline, da Silva, Leandro Apolinário, Heuveline, Vincent, Therkildsen, Christina, Lautrup, Charlotte, Klarskov, Louise L, Cavestro, Giulia Martina, Möslein, Gabriela, Hovig, Eivind, and Dominguez-Valentin, Mev
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EPUB (Standard) ,Colonoscopy -- Analysis ,Health - Abstract
Background Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. Materials and methods We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports. Keywords: MSI, MLH1, MSH2, MSH6, PMS2, dMMR, Lynch syndromes, Colorectal, cancer, Adenoma, Colonoscopy, Sojourn time, Author(s): Pål Maller[sup.1], Saskia Haupt[sup.2,3], Aysel Ahadova[sup.4,5], Matthias Kloor[sup.4,5], Julian R. Sampson[sup.6], Lone Sunde[sup.7,8,9], Toni Seppälä[sup.10,11,12], John Burn[sup.13], Inge Bernstein[sup.14,15], Gabriel Capella[sup.16], D. Gareth Evans[sup.17], Annika Lindblom[sup.18,19], Ingrid Winship[sup.20,21], Finlay [...]
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- 2024
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6. Emerge of colorectal cancer in Lynch syndrome despite colonoscopy surveillance: A challenge of hide and seek
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Helderman, Noah C., van Leerdam, Monique E., Kloor, Matthias, Ahadova, Aysel, and Nielsen, Maartje
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- 2024
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7. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
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Møller, Pal, Seppälä, Toni T., Ahadova, Aysel, Crosbie, Emma J., Holinski-Feder, Elke, Scott, Rodney, Haupt, Saskia, Möslein, Gabriela, Winship, Ingrid, Broeke, Sanne W. Bajwa-ten, Kohut, Kelly E., Ryan, Neil, Bauerfeind, Peter, Thomas, Laura E., Evans, D. Gareth, Aretz, Stefan, Sijmons, Rolf H., Half, Elizabeth, Heinimann, Karl, Horisberger, Karoline, Monahan, Kevin, Engel, Christoph, Cavestro, Giulia Martina, Fruscio, Robert, Abu-Freha, Naim, Zohar, Levi, Laghi, Luigi, Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Vaccaro, Carlos, Valle, Adriana Della, Rossi, Benedito Mauro, da Silva, Leandro Apolinário, de Oliveira Nascimento, Ivana Lucia, Rossi, Norma Teresa, Dębniak, Tadeusz, Mecklin, Jukka-Pekka, Bernstein, Inge, Lindblom, Annika, Sunde, Lone, Nakken, Sigve, Heuveline, Vincent, Burn, John, Hovig, Eivind, Kloor, Matthias, Sampson, Julian R., and Dominguez-Valentin, Mev
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- 2023
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8. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
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Pal Møller, Toni T. Seppälä, Aysel Ahadova, Emma J. Crosbie, Elke Holinski-Feder, Rodney Scott, Saskia Haupt, Gabriela Möslein, Ingrid Winship, Sanne W. Bajwa-ten Broeke, Kelly E. Kohut, Neil Ryan, Peter Bauerfeind, Laura E. Thomas, D. Gareth Evans, Stefan Aretz, Rolf H. Sijmons, Elizabeth Half, Karl Heinimann, Karoline Horisberger, Kevin Monahan, Christoph Engel, Giulia Martina Cavestro, Robert Fruscio, Naim Abu-Freha, Levi Zohar, Luigi Laghi, Lucio Bertario, Bernardo Bonanni, Maria Grazia Tibiletti, Leonardo S. Lino-Silva, Carlos Vaccaro, Adriana Della Valle, Benedito Mauro Rossi, Leandro Apolinário da Silva, Ivana Lucia de Oliveira Nascimento, Norma Teresa Rossi, Tadeusz Dębniak, Jukka-Pekka Mecklin, Inge Bernstein, Annika Lindblom, Lone Sunde, Sigve Nakken, Vincent Heuveline, John Burn, Eivind Hovig, Matthias Kloor, Julian R. Sampson, Mev Dominguez-Valentin, and On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org)
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Genetics ,QH426-470 - Abstract
Abstract The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
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- 2023
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9. Comprehensive Investigation of Neolithic Ceramic Samples: Firing Technology and Age Insights
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Sahib Mammadov and Aybeniz Ahadova
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thermogravimetry ,x-ray powder diffraction ,ancient ceramic ,firing temperature ,clay ,quartz ,feldspar ,Physics ,QC1-999 - Abstract
Thermogravimetric (TG/DTG), thermoluminescence (TL), and X-ray powder diffraction (XRD) techniques were applied to characterize samples collected from the archaeological site of Polutepe in Azerbaijan, dating to the Neolithic period, and gave new information on the firing technology. The thermogravimetric analysis of ceramic shards from Polutepe revealed that the firing temperature of the samples was in the range of 700°C, based on the presence of calcite in the sample. XRD analysis confirmed the presence of quartz, feldspar, and clay minerals in the ceramic samples. According to XTD analysis the mineral composition of the ceramic sample from Polutepe site was as follows: Quartz-33.8 mass%, Feldspar (albite)-21.7 mass%, Muscovite- 33.6 mass%, and Calcite- 10.9 mass%. TL glow-curve intensity at 325°C was measured to estimate the historical dose of the sample, which was found to be 22.19±1.36 Gy. The concentration of U, Th, and K were 2.24±0.20 ppm , 8.31±0.80 ppm, 2.39±0.23% respectively. Dose rate and age calculation were conducted using the DRAC, version 1.2 and output results are as follows: Environmental dose rate: 3.46±0.19 mGy/a; Age of the sample: 4.400±530 BC years which are in line with the stratigraphically estimated age of this area and with the radiocarbon age (4270±160 BC) reported in our previous work. The results obtained from this multidisciplinary approach provide insights into the firing technology and age of the ceramic samples.
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- 2023
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10. MLH1 Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome
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Helderman, Noah C., Andini, Katarina D., van Leerdam, Monique E., van Hest, Liselotte P., Hoekman, Daniël R., Ahadova, Aysel, Bajwa-ten Broeke, Sanne W., Bosse, Tjalling, van der Logt, Elise M.J., Imhann, Floris, Kloor, Matthias, Langers, Alexandra M.J., Smit, Vincent T.H.B.M., Terlouw, Diantha, van Wezel, Tom, Morreau, Hans, and Nielsen, Maartje
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- 2024
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11. Outcome and prognostic factors in patients undergoing salvage therapy for recurrent esophagogastric cancer after multimodal treatment
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Apostolidis, Leonidas, Lang, Kristin, Sisic, Leila, Busch, Elena, Ahadova, Aysel, Wullenkord, Ramona, Nienhüser, Henrik, Billeter, Adrian, Müller-Stich, Beat, Kloor, Matthias, Jaeger, Dirk, and Haag, Georg Martin
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- 2023
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12. A “Two-in-One Hit” Model of Shortcut Carcinogenesis in MLH1 Lynch Syndrome Carriers
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Wittemann, Jan-Niklas, Endris, Volker, Gerling, Leonie, Bertram, Veit, Neumuth, Marie Theres, Witt, Johannes, Graf, Sebastian, Kristiansen, Glen, Hommerding, Oliver, Haupt, Saskia, Zeilmann, Alexander, Heuveline, Vincent, Kazdal, Daniel, Gebert, Johannes, von Knebel Doeberitz, Magnus, Mecklin, Jukka-Pekka, Nattermann, Jacob, Ahadova, Aysel, Stenzinger, Albrecht, Seppälä, Toni, Hüneburg, Robert, Kloor, Matthias, and Bläker, Hendrik
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- 2023
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13. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
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Pål Møller, Toni Seppälä, James G. Dowty, Saskia Haupt, Mev Dominguez-Valentin, Lone Sunde, Inge Bernstein, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Dafydd Gareth Evans, John Burn, Elke Holinski-Feder, Lucio Bertario, Bernardo Bonanni, Annika Lindblom, Zohar Levi, Finlay Macrae, Ingrid Winship, John-Paul Plazzer, Rolf Sijmons, Luigi Laghi, Adriana Della Valle, Karl Heinimann, Elizabeth Half, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Rodney J. Scott, Lior Katz, Ido Laish, Elez Vainer, Carlos Alberto Vaccaro, Dirce Maria Carraro, Nathan Gluck, Naim Abu-Freha, Aine Stakelum, Rory Kennelly, Des Winter, Benedito Mauro Rossi, Marc Greenblatt, Mabel Bohorquez, Harsh Sheth, Maria Grazia Tibiletti, Leonardo S. Lino-Silva, Karoline Horisberger, Carmen Portenkirchner, Ivana Nascimento, Norma Teresa Rossi, Leandro Apolinário da Silva, Huw Thomas, Attila Zaránd, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepisto, Päivi Peltomäki, Christina Therkildsen, Lars Joachim Lindberg, Ole Thorlacius-Ussing, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hüneburg, Aída Falcón de Vargas, Andrew Latchford, Anne-Marie Gerdes, Ann-Sofie Backman, Carmen Guillén-Ponce, Carrie Snyder, Charlotte K. Lautrup, David Amor, Edenir Palmero, Elena Stoffel, Floor Duijkers, Michael J. Hall, Heather Hampel, Heinric Williams, Henrik Okkels, Jan Lubiński, Jeanette Reece, Joanne Ngeow, Jose G. Guillem, Julie Arnold, Karin Wadt, Kevin Monahan, Leigha Senter, Lene J. Rasmussen, Liselotte P. van Hest, Luigi Ricciardiello, Maija R. J. Kohonen-Corish, Marjolijn J. L. Ligtenberg, Melissa Southey, Melyssa Aronson, Mohd N. Zahary, N. Jewel Samadder, Nicola Poplawski, Nicoline Hoogerbrugge, Patrick J. Morrison, Paul James, Grant Lee, Rakefet Chen-Shtoyerman, Ravindran Ankathil, Rish Pai, Robyn Ward, Susan Parry, Tadeusz Dębniak, Thomas John, Thomas van Overeem Hansen, Trinidad Caldés, Tatsuro Yamaguchi, Verónica Barca-Tierno, Pilar Garre, Giulia Martina Cavestro, Jürgen Weitz, Silke Redler, Reinhard Büttner, Vincent Heuveline, John L. Hopper, Aung Ko Win, Noralane Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Sanne W. ten Broeke, Eivind Hovig, Sigve Nakken, Marta Pineda, Nuria Dueñas, Joan Brunet, Kate Green, Fiona Lalloo, Katie Newton, Emma J. Crosbie, Miriam Mints, Douglas Tjandra, Florencia Neffa, Patricia Esperon, Revital Kariv, Guy Rosner, Walter Hernán Pavicic, Pablo Kalfayan, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Martin, Gabriela Moslein, Aysel Ahadova, Matthias Kloor, Julian R. Sampson, Mark A. Jenkins, and The European Hereditary Tumour Group (EHTG) and the International Mismatch Repair Consortium (IMRC)
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Lynch Syndrome ,Epidemiology ,Prevention ,Penetrance ,Colorectal cancer ,Segregation analysis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Genetics ,QH426-470 - Abstract
Abstract Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
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- 2022
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14. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement
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Maller, Pal, Seppälä, Toni T., Ahadova, Aysel, Crosbie, Emma J., Holinski-Feder, Elke, Scott, Rodney, Haupt, Saskia, Möslein, Gabriela, Winship, Ingrid, Broeke, Sanne W. Bajwa-ten, Kohut, Kelly E., Ryan, Neil, Bauerfeind, Peter, Thomas, Laura E., Evans, D. Gareth, Aretz, Stefan, Sijmons, Rolf H., Half, Elizabeth, Heinimann, Karl, Horisberger, Karoline, Monahan, Kevin, Engel, Christoph, Cavestro, Giulia Martina, Fruscio, Robert, Abu-Freha, Naim, Zohar, Levi, Laghi, Luigi, Bertario, Lucio, Bonanni, Bernardo, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Vaccaro, Carlos, Valle, Adriana Della, Rossi, Benedito Mauro, da Silva, Leandro Apolinário, de Oliveira Nascimento, Ivana Lucia, Rossi, Norma Teresa, DÄbniak, Tadeusz, Mecklin, Jukka-Pekka, Bernstein, Inge, Lindblom, Annika, Sunde, Lone, Nakken, Sigve, Heuveline, Vincent, Burn, John, Hovig, Eivind, Kloor, Matthias, Sampson, Julian R., and Dominguez-Valentin, Mev
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Aspirin ,Stochastic processes ,Colorectal cancer -- Genetic aspects -- Development and progression ,Immunotherapy ,Cancer -- Development and progression -- Genetic aspects ,Ovarian cancer -- Development and progression -- Genetic aspects ,Health - Abstract
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an 'average sex 'or a pathogenic variant in an 'average Lynch syndrome gene' and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer., Author(s): Pal Maller[sup.1], Toni T. Seppälä[sup.2,3,4], Aysel Ahadova[sup.5,6,7], Emma J. Crosbie[sup.8,9], Elke Holinski-Feder[sup.10,11], Rodney Scott[sup.12], Saskia Haupt[sup.13,14], Gabriela Möslein[sup.15], Ingrid Winship[sup.16,17], Sanne W. Bajwa-ten Broeke[sup.18], Kelly E. Kohut[sup.19], Neil Ryan[sup.20,21], [...]
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- 2023
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15. The Thermoluminescence Parameters of Irradiated K-Feldspar
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Sahib Mammadov, Aybeniz Ahadova, Aqshin Abishov, and Ahmad Ahadov
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Feldspar ,Isothermal decay ,Activation energy ,Frequency factor ,Physics ,QC1-999 - Abstract
Isothermal decay of the TL glow curve has been studied at ambient temperature. Heating of feldspar at 600ºC leads to increased sensitivity of the samples upon irradiation for the whole range of glow curve. In general, we observe a sensitivity increase of about five times. Fading of the glow curve is observed at the low-temperature part of the glow curve while it has been kept in the dark at the ambient, constant temperature. After a certain period, approximately in 40 to 50 days, the low-temperature region of the glow curve fades down while the high-temperature part remains unchanged. Peaks at the low-temperature region of the TL glow curve were isolated by the curve subtraction method. Activation energy and frequency factor parameters of the isolated peaks were calculated, taking first and second-order kinetics into account. The values of the calculated activation energy vary between 0.7 to 1.1 eV, and frequency factor values of the isolated peaks change within the order of 109 to 1013s-1. The µ values clearly indicate that all isolated peaks are more likely to be second-order kinetics.
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- 2023
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16. Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies
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Shizuko Sei, Aysel Ahadova, Derin B. Keskin, Lena Bohaumilitzky, Johannes Gebert, Magnus von Knebel Doeberitz, Steven M. Lipkin, and Matthias Kloor
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lynch syndrome ,DNA mismatch repair deficiency ,microsatellite instability ,frameshift mutations ,tumor neoantigens ,cancer vaccines ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Hereditary cancer syndromes (HCS) account for 5~10% of all cancer diagnosis. Lynch syndrome (LS) is one of the most common HCS, caused by germline mutations in the DNA mismatch repair (MMR) genes. Even with prospective cancer surveillance, LS is associated with up to 50% lifetime risk of colorectal, endometrial, and other cancers. While significant progress has been made in the timely identification of germline pathogenic variant carriers and monitoring and early detection of precancerous lesions, cancer-risk reduction strategies are still centered around endoscopic or surgical removal of neoplastic lesions and susceptible organs. Safe and effective cancer prevention strategies are critically needed to improve the life quality and longevity of LS and other HCS carriers. The era of precision oncology driven by recent technological advances in tumor molecular profiling and a better understanding of genetic risk factors has transformed cancer prevention approaches for at-risk individuals, including LS carriers. MMR deficiency leads to the accumulation of insertion and deletion mutations in microsatellites (MS), which are particularly prone to DNA polymerase slippage during DNA replication. Mutations in coding MS give rise to frameshift peptides (FSP) that are recognized by the immune system as neoantigens. Due to clonal evolution, LS tumors share a set of recurrent and predictable FSP neoantigens in the same and in different LS patients. Cancer vaccines composed of commonly recurring FSP neoantigens selected through prediction algorithms have been clinically evaluated in LS carriers and proven safe and immunogenic. Preclinically analogous FSP vaccines have been shown to elicit FSP-directed immune responses and exert tumor-preventive efficacy in murine models of LS. While the immunopreventive efficacy of “off-the-shelf” vaccines consisting of commonly recurring FSP antigens is currently investigated in LS clinical trials, the feasibility and utility of personalized FSP vaccines with individual HLA-restricted epitopes are being explored for more precise targeting. Here, we discuss recent advances in precision cancer immunoprevention approaches, emerging enabling technologies, research gaps, and implementation barriers toward clinical translation of risk-tailored prevention strategies for LS carriers. We will also discuss the feasibility and practicality of next-generation cancer vaccines that are based on personalized immunogenic epitopes for precision cancer immunoprevention.
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- 2023
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17. PMS2-associated Lynch syndrome: Past, present and future
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Katarina D. Andini, Maartje Nielsen, Manon Suerink, Noah C. Helderman, Jan Jacob Koornstra, Aysel Ahadova, Matthias Kloor, Marian J.E. Mourits, Klaas Kok, Rolf H. Sijmons, and Sanne W. Bajwa–ten Broeke
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Lynch syndrome (hereditary nonpolyposis colorectal cancer) ,mismatch repair (MMR) ,PMS2 gene ,colorectal cancer ,endometrial cancer ,carcinonogenesis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Carriers of any pathogenic variant in one of the MMR genes (path_MMR carriers) were traditionally thought to be at comparable risk of developing a range of different malignancies, foremost colorectal cancer (CRC) and endometrial cancer. However, it is now widely accepted that their cancer risk and cancer spectrum range notably depending on which MMR gene is affected. Moreover, there is increasing evidence that the MMR gene affected also influences the molecular pathogenesis of Lynch syndrome CRC. Although substantial progress has been made over the past decade in understanding these differences, many questions remain unanswered, especially pertaining to path_PMS2 carriers. Recent findings show that, while the cancer risk is relatively low, PMS2-deficient CRCs tend to show more aggressive behaviour and have a worse prognosis than other MMR-deficient CRCs. This, together with lower intratumoral immune infiltration, suggests that PMS2-deficient CRCs might have more in common biologically with sporadic MMR-proficient CRCs than with other MMR-deficient CRCs. These findings could have important consequences for surveillance, chemoprevention and therapeutic strategies (e.g. vaccines). In this review we discuss the current knowledge, current (clinical) challenges and knowledge gaps that should be targeted by future studies.
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- 2023
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18. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
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Møller, Pål, Seppälä, Toni, Dowty, James G., Haupt, Saskia, Dominguez-Valentin, Mev, Sunde, Lone, Bernstein, Inge, Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John-Paul, Sijmons, Rolf, Laghi, Luigi, Valle, Adriana Della, Heinimann, Karl, Half, Elizabeth, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Scott, Rodney J., Katz, Lior, Laish, Ido, Vainer, Elez, Vaccaro, Carlos Alberto, Carraro, Dirce Maria, Gluck, Nathan, Abu-Freha, Naim, Stakelum, Aine, Kennelly, Rory, Winter, Des, Rossi, Benedito Mauro, Greenblatt, Marc, Bohorquez, Mabel, Sheth, Harsh, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Horisberger, Karoline, Portenkirchner, Carmen, Nascimento, Ivana, Rossi, Norma Teresa, da Silva, Leandro Apolinário, Thomas, Huw, Zaránd, Attila, Mecklin, Jukka-Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Peltomäki, Päivi, Therkildsen, Christina, Lindberg, Lars Joachim, Thorlacius-Ussing, Ole, von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, de Vargas, Aída Falcón, Latchford, Andrew, Gerdes, Anne-Marie, Backman, Ann-Sofie, Guillén-Ponce, Carmen, Snyder, Carrie, Lautrup, Charlotte K., Amor, David, Palmero, Edenir, Stoffel, Elena, Duijkers, Floor, Hall, Michael J., Hampel, Heather, Williams, Heinric, Okkels, Henrik, Lubiński, Jan, Reece, Jeanette, Ngeow, Joanne, Guillem, Jose G., Arnold, Julie, Wadt, Karin, Monahan, Kevin, Senter, Leigha, Rasmussen, Lene J., van Hest, Liselotte P., Ricciardiello, Luigi, Kohonen-Corish, Maija R. J., Ligtenberg, Marjolijn J. L., Southey, Melissa, Aronson, Melyssa, Zahary, Mohd N., Samadder, N. Jewel, Poplawski, Nicola, Hoogerbrugge, Nicoline, Morrison, Patrick J., James, Paul, Lee, Grant, Chen-Shtoyerman, Rakefet, Ankathil, Ravindran, Pai, Rish, Ward, Robyn, Parry, Susan, Dębniak, Tadeusz, John, Thomas, van Overeem Hansen, Thomas, Caldés, Trinidad, Yamaguchi, Tatsuro, Barca-Tierno, Verónica, Garre, Pilar, Cavestro, Giulia Martina, Weitz, Jürgen, Redler, Silke, Büttner, Reinhard, Heuveline, Vincent, Hopper, John L., Win, Aung Ko, Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., ten Broeke, Sanne W., Hovig, Eivind, Nakken, Sigve, Pineda, Marta, Dueñas, Nuria, Brunet, Joan, Green, Kate, Lalloo, Fiona, Newton, Katie, Crosbie, Emma J., Mints, Miriam, Tjandra, Douglas, Neffa, Florencia, Esperon, Patricia, Kariv, Revital, Rosner, Guy, Pavicic, Walter Hernán, Kalfayan, Pablo, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia, Moslein, Gabriela, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., and Jenkins, Mark A.
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- 2022
- Full Text
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19. The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients
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Bohaumilitzky, Lena, Kluck, Klaus, Hüneburg, Robert, Gallon, Richard, Nattermann, Jacob, Kirchner, Martina, Kristiansen, Glen, Hommerding, Oliver, Pfuderer, Pauline L., Wagner, Lelia, Echterdiek, Fabian, Kösegi, Svenja, Müller, Nico, Fischer, Konstantin, Nelius, Nina, Hartog, Ben, Borthwick, Gillian, Busch, Elena, Haag, Georg Martin, Bläker, Hendrik, Möslein, Gabriela, von Knebel Doeberitz, Magnus, Seppälä, Toni T., Ahtiainen, Maarit, Mecklin, Jukka-Pekka, Bishop, D. Timothy, Burn, John, Stenzinger, Albrecht, Budczies, Jan, Kloor, Matthias, and Ahadova, Aysel
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- 2022
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20. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes
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Møller, Pål, primary, Haupt, Saski, additional, Ahadova, Aysel, additional, Kloor, Matthias, additional, Sampson, Julian, additional, Sunde, Lone, additional, Seppälä, Toni Toni, additional, Burn, John, additional, Bernstein, Inge, additional, Capella, Gabriel, additional, Evans, D Gareth, additional, Lindblom, Annika, additional, Winship, Ingrid, additional, Macrae, Finlay, additional, Katz, Lior, additional, Laish, Ido, additional, Vainer, Elez, additional, Monahan, Kevin, additional, Half, Elizabeth, additional, Horisberger, Karoline, additional, Silva, Leandro Apolinário da, additional, Heuveline, Vincent, additional, Therkildsen, Christina, additional, Lautrup, Charlotte, additional, Klarskov, Louvise L, additional, Cavestro, Giulia Martina, additional, Möslein, Gabriela, additional, Hovig, Eivind, additional, and Dominguez-Valentin, Mev, additional
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- 2024
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21. Evaluation of the Tax Policy Efficiency Under Uncertainty
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Musayeva, Aygun A., Madatova, Shahzada G., Mammadov, Yashar A., Gasimov, Alislam I., Ahadova, Kamala N., Kacprzyk, Janusz, Series Editor, Pal, Nikhil R., Advisory Editor, Bello Perez, Rafael, Advisory Editor, Corchado, Emilio S., Advisory Editor, Hagras, Hani, Advisory Editor, Kóczy, László T., Advisory Editor, Kreinovich, Vladik, Advisory Editor, Lin, Chin-Teng, Advisory Editor, Lu, Jie, Advisory Editor, Melin, Patricia, Advisory Editor, Nedjah, Nadia, Advisory Editor, Nguyen, Ngoc Thanh, Advisory Editor, Wang, Jun, Advisory Editor, Aliev, Rafik A., editor, Pedrycz, Witold, editor, Jamshidi, Mo, editor, Babanli, Mustafa B., editor, and Sadikoglu, Fahreddin M., editor
- Published
- 2020
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22. Treatment resistance analysis reveals GLUT‐1‐mediated glucose uptake as a major target of synthetic rocaglates in cancer cells
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Julia Sieber‐Frank, Hans‐Jürgen Stark, Simon Kalteis, Elena‐Sophie Prigge, Richard Köhler, Carolin Andresen, Thomas Henkel, Georg Casari, Tobias Schubert, Wolfgang Fischl, Min Li‐Weber, Peter H. Krammer, Magnus vonKnebel Doeberitz, Jürgen Kopitz, Matthias Kloor, and Aysel Ahadova
- Subjects
cancer biology ,colorectal cancer ,drug design ,metabolic studies ,molecular biology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Rocaglates are natural compounds that have been extensively studied for their ability to inhibit translation initiation. Rocaglates represent promising drug candidates for tumor treatment due to their growth‐inhibitory effects on neoplastic cells. In contrast to natural rocaglates, synthetic analogues of rocaglates have been less comprehensively characterized, but were also shown to have similar effects on the process of protein translation. Here, we demonstrate an enhanced growth‐inhibitory effect of synthetic rocaglates when combined with glucose anti‐metabolite 2‐deoxy‐D‐glucose (2DG) in different cancer cell lines. Moreover, we unravel a new aspect in the mechanism of action of synthetic rocaglates involving reduction of glucose uptake mediated by downregulation or abrogation of glucose transporter GLUT‐1 expression. Importantly, cells with genetically induced resistance to synthetic rocaglates showed substantially less pronounced treatment effect on glucose metabolism and did not demonstrate GLUT‐1 downregulation, pointing at the crucial role of this mechanism for the anti‐tumor activity of the synthetic rocaglates. Transcriptome profiling revealed glycolysis as one of the major pathways differentially regulated in sensitive and resistant cells. Analysis of synthetic rocaglate efficacy in a 3D tissue context with a co‐culture of tumor and normal cells demonstrated a selective effect on tumor cells and substantiated the mechanistic observations obtained in cancer cell lines. Increased glucose uptake and metabolism is a universal feature across different tumor types. Therefore, targeting this feature by synthetic rocaglates could represent a promising direction for exploitation of rocaglates in novel anti‐tumor therapies.
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- 2021
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23. The coding microsatellite mutation profile of PMS2-deficient colorectal cancer
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Bajwa - ten Broeke, Sanne W., Ballhausen, Alexej, Ahadova, Aysel, Suerink, Manon, Bohaumilitzky, Lena, Seidler, Florian, Morreau, Hans, van Wezel, Tom, Krzykalla, Julia, Benner, Axel, de Miranda, Noel F., von Knebel Doeberitz, Magnus, Nielsen, Maartje, and Kloor, Matthias
- Published
- 2021
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24. Developing a Decision-Making Support Information System for the Operational Control of Industrial Technological Processes
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Ahadova, Adelina, primary
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- 2022
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25. MLH1 Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome
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Helderman, Noah C., primary, Andini, Katarina D., additional, van Leerdam, Monique E., additional, van Hest, Liselotte P., additional, Hoekman, Daniël R., additional, Ahadova, Aysel, additional, Bajwa-ten Broeke, Sanne W., additional, Bosse, Tjalling, additional, van der Logt, Elise M.J., additional, Imhann, Floris, additional, Kloor, Matthias, additional, Langers, Alexandra M.J., additional, Smit, Vincent T.H.B.M., additional, Terlouw, Diantha, additional, van Wezel, Tom, additional, Morreau, Hans, additional, and Nielsen, Maartje, additional
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- 2023
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26. The majority of β-catenin mutations in colorectal cancer is homozygous
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Alexander Arnold, Moritz Tronser, Christine Sers, Ayel Ahadova, Volker Endris, Soulafa Mamlouk, David Horst, Markus Möbs, Philip Bischoff, Michael Kloor, and Hendrik Bläker
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Colorectal cancer (CRC) ,ß-catenin (CTNNB1) ,E-cadherin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background β-catenin activation plays a crucial role for tumourigenesis in the large intestine but except for Lynch syndrome (LS) associated cancers stabilizing mutations of β-catenin gene (CTNNB1) are rare in colorectal cancer (CRC). Previous animal studies provide an explanation for this observation. They showed that CTNNB1 mutations induced transformation in the colon only when CTNNB1 was homozygously mutated or when membranous β-catenin binding was hampered by E-cadherin haploinsufficiency. We were interested, if these mechanisms are also found in human CTNNB1 mutated CRCs. Results Among 869 CRCs stabilizing CTNNB1 mutations were found in 27 cases. Homo- or hemizygous CTNNB1 mutations were detected in 74% of CTNNB1 mutated CRCs (13 microsatellite instabile (MSI-H), 7 microsatellite stabile (MSS)) but only in 3% (1/33) of extracolonic CTNNB1 mutated cancers. In contrast to MSS CRC, CTNNB1 mutations at codon 41 or 45 were highly selected in MSI-H CRC. Of the examined three CRC cell lines, β-catenin and E-cadherin expression was similar in cell lines without or with hetereozygous CTNNB1 mutations (DLD1 and HCT116), while a reduced E-cadherin expression combined with cytoplasmic accumulation of β-catenin was found in a cell line with homozygous CTNNB1 mutation (LS180). Reduced expression of E-cadherin in human MSI-H CRC tissue was identified in 60% of investigated cancers, but no association with the CTNNB1 mutational status was found. Conclusions In conclusion, this study shows that in contrast to extracolonic cancers stabilizing CTNNB1 mutations in CRC are commonly homo- or hemizygous indicating a higher threshold of β-catenin stabilization to be required for transformation in the colon as compared to extracolonic sites. Moreover, we found different mutational hotspots in CTNNB1 for MSI-H and MSS CRCs suggesting a selection of different effects on β-catenin stabilization according to the molecular pathway of tumourigenesis. Reduced E-cadherin expression in CRC may further contribute to higher levels of transcriptionally active β-catenin, but it is not directly linked to the CTNNB1 mutational status.
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- 2020
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27. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
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Alexej Ballhausen, Moritz Jakob Przybilla, Michael Jendrusch, Saskia Haupt, Elisabeth Pfaffendorf, Florian Seidler, Johannes Witt, Alejandro Hernandez Sanchez, Katharina Urban, Markus Draxlbauer, Sonja Krausert, Aysel Ahadova, Martin Simon Kalteis, Pauline L. Pfuderer, Daniel Heid, Damian Stichel, Johannes Gebert, Maria Bonsack, Sarah Schott, Hendrik Bläker, Toni Seppälä, Jukka-Pekka Mecklin, Sanne Ten Broeke, Maartje Nielsen, Vincent Heuveline, Julia Krzykalla, Axel Benner, Angelika Beate Riemer, Magnus von Knebel Doeberitz, and Matthias Kloor
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Science - Abstract
DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.
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- 2020
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28. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
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Maller, Pål, Seppälä, Toni, Dowty, James G., Haupt, Saskia, Dominguez-Valentin, Mev, Sunde, Lone, Bernstein, Inge, Engel, Christoph, Aretz, Stefan, Nielsen, Maartje, Capella, Gabriel, Evans, Dafydd Gareth, Burn, John, Holinski-Feder, Elke, Bertario, Lucio, Bonanni, Bernardo, Lindblom, Annika, Levi, Zohar, Macrae, Finlay, Winship, Ingrid, Plazzer, John-Paul, Sijmons, Rolf, Laghi, Luigi, Valle, Adriana Della, Heinimann, Karl, Half, Elizabeth, Lopez-Koestner, Francisco, Alvarez-Valenzuela, Karin, Scott, Rodney J., Katz, Lior, Laish, Ido, Vainer, Elez, Vaccaro, Carlos Alberto, Carraro, Dirce Maria, Gluck, Nathan, Abu-Freha, Naim, Stakelum, Aine, Kennelly, Rory, Winter, Des, Rossi, Benedito Mauro, Greenblatt, Marc, Bohorquez, Mabel, Sheth, Harsh, Tibiletti, Maria Grazia, Lino-Silva, Leonardo S., Horisberger, Karoline, Portenkirchner, Carmen, Nascimento, Ivana, Rossi, Norma Teresa, da Silva, Leandro Apolinário, Thomas, Huw, Zaránd, Attila, Mecklin, Jukka-Pekka, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Lepisto, Anna, Peltomäki, Päivi, Therkildsen, Christina, Lindberg, Lars Joachim, Thorlacius-Ussing, Ole, von Knebel Doeberitz, Magnus, Loeffler, Markus, Rahner, Nils, Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Perne, Claudia, Hüneburg, Robert, de Vargas, Aída Falcón, Latchford, Andrew, Gerdes, Anne-Marie, Backman, Ann-Sofie, Guillén-Ponce, Carmen, Snyder, Carrie, Lautrup, Charlotte K., Amor, David, Palmero, Edenir, Stoffel, Elena, Duijkers, Floor, Hall, Michael J., Hampel, Heather, Williams, Heinric, Okkels, Henrik, LubiÅski, Jan, Reece, Jeanette, Ngeow, Joanne, Guillem, Jose G., Arnold, Julie, Wadt, Karin, Monahan, Kevin, Senter, Leigha, Rasmussen, Lene J., van Hest, Liselotte P., Ricciardiello, Luigi, Kohonen-Corish, Maija R. J., Ligtenberg, Marjolijn J. L., Southey, Melissa, Aronson, Melyssa, Zahary, Mohd N., Samadder, N. Jewel, Poplawski, Nicola, Hoogerbrugge, Nicoline, Morrison, Patrick J., James, Paul, Lee, Grant, Chen-Shtoyerman, Rakefet, Ankathil, Ravindran, Pai, Rish, Ward, Robyn, Parry, Susan, DÄbniak, Tadeusz, John, Thomas, van Overeem Hansen, Thomas, Caldés, Trinidad, Yamaguchi, Tatsuro, Barca-Tierno, Verónica, Garre, Pilar, Cavestro, Giulia Martina, Weitz, Jürgen, Redler, Silke, Büttner, Reinhard, Heuveline, Vincent, Hopper, John L., Win, Aung Ko, Lindor, Noralane, Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane, Buchanan, Daniel D., Thibodeau, Stephen N., ten Broeke, Sanne W., Hovig, Eivind, Nakken, Sigve, Pineda, Marta, Dueéas, Nuria, Brunet, Joan, Green, Kate, Lalloo, Fiona, Newton, Katie, Crosbie, Emma J., Mints, Miriam, Tjandra, Douglas, Neffa, Florencia, Esperon, Patricia, Kariv, Revital, Rosner, Guy, Pavicic, Walter Hernán, Kalfayan, Pablo, Torrezan, Giovana Tardin, Bassaneze, Thiago, Martin, Claudia, Moslein, Gabriela, Ahadova, Aysel, Kloor, Matthias, Sampson, Julian R., and Jenkins, Mark A.
- Subjects
EPUB (Standard) -- Comparative analysis ,Colonoscopy -- Comparative analysis ,Colorectal cancer -- Comparative analysis ,Health - Abstract
Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so. Keywords: Lynch Syndrome, Epidemiology, Prevention, Penetrance, Colorectal cancer, Segregation analysis, Prospective, Incidence, Over-diagnosis, Colonoscopy, Author(s): Pål Maller[sup.1], Toni Seppälä[sup.2,3,4], James G. Dowty[sup.5], Saskia Haupt[sup.6,7], Mev Dominguez-Valentin[sup.1], Lone Sunde[sup.8,9], Inge Bernstein[sup.10,11], Christoph Engel[sup.12], Stefan Aretz[sup.13], Maartje Nielsen[sup.14], Gabriel Capella[sup.15], Dafydd Gareth Evans[sup.16], John Burn[sup.17], Elke [...]
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- 2022
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29. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
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Moller, P, Seppala, T, Ahadova, A, Crosbie, E, Holinski-Feder, E, Scott, R, Haupt, S, Moslein, G, Winship, I, Broeke, S, Kohut, K, Ryan, N, Bauerfeind, P, Thomas, L, Evans, D, Aretz, S, Sijmons, R, Half, E, Heinimann, K, Horisberger, K, Monahan, K, Engel, C, Cavestro, G, Fruscio, R, Abu-Freha, N, Zohar, L, Laghi, L, Bertario, L, Bonanni, B, Tibiletti, M, Lino-Silva, L, Vaccaro, C, Valle, A, Rossi, B, da Silva, L, de Oliveira Nascimento, I, Rossi, N, Debniak, T, Mecklin, J, Bernstein, I, Lindblom, A, Sunde, L, Nakken, S, Heuveline, V, Burn, J, Hovig, E, Kloor, M, Sampson, J, Dominguez-Valentin, M, Moller P., Seppala T. T., Ahadova A., Crosbie E. J., Holinski-Feder E., Scott R., Haupt S., Moslein G., Winship I., Broeke S. W. B. -T., Kohut K. E., Ryan N., Bauerfeind P., Thomas L. E., Evans D. G., Aretz S., Sijmons R. H., Half E., Heinimann K., Horisberger K., Monahan K., Engel C., Cavestro G. M., Fruscio R., Abu-Freha N., Zohar L., Laghi L., Bertario L., Bonanni B., Tibiletti M. G., Lino-Silva L. S., Vaccaro C., Valle A. D., Rossi B. M., da Silva L. A., de Oliveira Nascimento I. L., Rossi N. T., Debniak T., Mecklin J. -P., Bernstein I., Lindblom A., Sunde L., Nakken S., Heuveline V., Burn J., Hovig E., Kloor M., Sampson J. R., Dominguez-Valentin M., Moller, P, Seppala, T, Ahadova, A, Crosbie, E, Holinski-Feder, E, Scott, R, Haupt, S, Moslein, G, Winship, I, Broeke, S, Kohut, K, Ryan, N, Bauerfeind, P, Thomas, L, Evans, D, Aretz, S, Sijmons, R, Half, E, Heinimann, K, Horisberger, K, Monahan, K, Engel, C, Cavestro, G, Fruscio, R, Abu-Freha, N, Zohar, L, Laghi, L, Bertario, L, Bonanni, B, Tibiletti, M, Lino-Silva, L, Vaccaro, C, Valle, A, Rossi, B, da Silva, L, de Oliveira Nascimento, I, Rossi, N, Debniak, T, Mecklin, J, Bernstein, I, Lindblom, A, Sunde, L, Nakken, S, Heuveline, V, Burn, J, Hovig, E, Kloor, M, Sampson, J, Dominguez-Valentin, M, Moller P., Seppala T. T., Ahadova A., Crosbie E. J., Holinski-Feder E., Scott R., Haupt S., Moslein G., Winship I., Broeke S. W. B. -T., Kohut K. E., Ryan N., Bauerfeind P., Thomas L. E., Evans D. G., Aretz S., Sijmons R. H., Half E., Heinimann K., Horisberger K., Monahan K., Engel C., Cavestro G. M., Fruscio R., Abu-Freha N., Zohar L., Laghi L., Bertario L., Bonanni B., Tibiletti M. G., Lino-Silva L. S., Vaccaro C., Valle A. D., Rossi B. M., da Silva L. A., de Oliveira Nascimento I. L., Rossi N. T., Debniak T., Mecklin J. -P., Bernstein I., Lindblom A., Sunde L., Nakken S., Heuveline V., Burn J., Hovig E., Kloor M., Sampson J. R., and Dominguez-Valentin M.
- Abstract
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
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- 2023
30. Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers
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Elena Busch, Aysel Ahadova, Kosima Kosmalla, Lena Bohaumilitzky, Pauline L. Pfuderer, Alexej Ballhausen, Johannes Witt, Jan-Niklas Wittemann, Hendrik Bläker, Elke Holinski-Feder, Dirk Jäger, Magnus von Knebel Doeberitz, Georg Martin Haag, and Matthias Kloor
- Subjects
MSI cancer ,metastatic pattern ,immune checkpoint blockade ,B2M mutation ,prognosis ,therapy response ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of Beta-2-microglobulin (B2M) mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients’ survival under ICB. Twenty-five patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab/ipilimumab. Sequencing was performed to determine B2M mutation status. B2M mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. B2M mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% vs. 46.6%, p>0.99) and survival (median PFS: 19.5 vs 33.0 months, p=0.74; median OS 39 months vs. not reached, p>0.99) were observed between B2M-mutant and B2M-wild type tumor patients. Among metastatic MSI GI cancers, B2M-mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in B2M-mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with B2M-mutant MSI cancer may be longer than of patients with B2M-wild type MSI cancer.
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- 2021
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31. A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
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Saskia Haupt, Nils Gleim, Aysel Ahadova, Hendrik Bläker, Magnus vonKnebel Doeberitz, Matthias Kloor, and Vincent Heuveline
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Colonic Crypts ,Colorectal Cancer ,Carcinogenesis ,Lynch Syndrome ,Computational Modeling ,Voronoi Tessellation Model ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Abstract Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra‐crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non‐Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS‐associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non‐transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency‐inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.
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- 2021
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32. Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure.
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Saskia Haupt, Alexander Zeilmann, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, and Vincent Heuveline
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Biology (General) ,QH301-705.5 - Abstract
Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.
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- 2021
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33. Comprehensive Investigation of Neolithic Ceramic Samples: Firing Technology and Age Insights
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Mammadov, Sahib, primary and Ahadova, Aybeniz, additional
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- 2023
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34. Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report
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Mev Dominguez-Valentin, Toni T. Seppälä, Julian R. Sampson, Finlay Macrae, Ingrid Winship, D. Gareth Evans, Rodney J. Scott, John Burn, Gabriela Möslein, Inge Bernstein, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Annika Lindblom, John-Paul Plazzer, Douglas Tjandra, Huw Thomas, Kate Green, Fiona Lalloo, Emma J. Crosbie, James Hill, Gabriel Capella, Marta Pineda, Matilde Navarro, Joan Brunet Vidal, Karina Rønlund, Randi Thyregaard Nielsen, Mette Yilmaz, Louise Laurberg Elvang, Lior Katz, Maartje Nielsen, Sanne W. ten Broeke, Sigve Nakken, Eivind Hovig, Lone Sunde, Matthias Kloor, Magnus v Knebel Doeberitz, Aysel Ahadova, Noralane Lindor, Verena Steinke-Lange, Elke Holinski-Feder, Jukka-Pekka Mecklin, and Pål Møller
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Lynch syndrome ,Survival ,Colonoscopy ,Surveillance ,Cancer stage ,Colon cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Genetics ,QH426-470 - Abstract
Abstract Background We previously reported that in pathogenic mismatch repair (path_MMR) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. Methods The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Results Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5–3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively (p 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91). Conclusions In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.
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- 2019
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35. Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report
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Toni T. Seppälä, Aysel Ahadova, Mev Dominguez-Valentin, Finlay Macrae, D. Gareth Evans, Christina Therkildsen, Julian Sampson, Rodney Scott, John Burn, Gabriela Möslein, Inge Bernstein, Elke Holinski-Feder, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Charlotte Kvist Lautrup, Annika Lindblom, John-Paul Plazzer, Ingrid Winship, Douglas Tjandra, Lior H. Katz, Stefan Aretz, Robert Hüneburg, Stefanie Holzapfel, Karl Heinimann, Adriana Della Valle, Florencia Neffa, Nathan Gluck, Wouter H. de Vos tot Nederveen Cappel, Hans Vasen, Monika Morak, Verena Steinke-Lange, Christoph Engel, Nils Rahner, Wolff Schmiegel, Deepak Vangala, Huw Thomas, Kate Green, Fiona Lalloo, Emma J. Crosbie, James Hill, Gabriel Capella, Marta Pineda, Matilde Navarro, Ignacio Blanco, Sanne ten Broeke, Maartje Nielsen, Ken Ljungmann, Sigve Nakken, Noralane Lindor, Ian Frayling, Eivind Hovig, Lone Sunde, Matthias Kloor, Jukka-Pekka Mecklin, Mette Kalager, and Pål Møller
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Mismatch repair ,Microsatellite instability ,Lynch syndrome ,Hereditary cancer ,Colorectal cancer ,Hereditary nonpolyposis colorectal cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Genetics ,QH426-470 - Abstract
Abstract Background Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.
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- 2019
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36. Evaluation of the Tax Policy Efficiency Under Uncertainty
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Musayeva, Aygun A., primary, Madatova, Shahzada G., additional, Mammadov, Yashar A., additional, Gasimov, Alislam I., additional, and Ahadova, Kamala N., additional
- Published
- 2019
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37. The majority of β-catenin mutations in colorectal cancer is homozygous
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Arnold, Alexander, Tronser, Moritz, Sers, Christine, Ahadova, Aysel, Endris, Volker, Mamlouk, Soulafa, Horst, David, Möbs, Markus, Bischoff, Philip, Kloor, Matthias, and Bläker, Hendrik
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- 2020
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38. Correction to: The majority of β-catenin mutations in colorectal cancer is homozygous
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Arnold, Alexander, Tronser, Moritz, Sers, Christine, Ahadova, Aysel, Endris, Volker, Mamlouk, Soulafa, Horst, David, Möbs, Markus, Bischoff, Philip, Kloor, Matthias, and Bläker, Hendrik
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- 2020
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39. The Thermoluminescence Parameters of Irradiated K-Feldspar
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Mammadov, Sahib, primary, Ahadova, Aybeniz, additional, Abishov, Aqshin, additional, and Ahadov, Ahmad, additional
- Published
- 2023
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40. MLH1Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome
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Helderman, Noah C., Andini, Katarina D., van Leerdam, Monique E., van Hest, Liselotte P., Hoekman, Daniël R., Ahadova, Aysel, Bajwa-ten Broeke, Sanne W., Bosse, Tjalling, van der Logt, Elise M.J., Imhann, Floris, Kloor, Matthias, Langers, Alexandra M.J., Smit, Vincent T.H.B.M., Terlouw, Diantha, van Wezel, Tom, Morreau, Hans, and Nielsen, Maartje
- Abstract
Screening for Lynch syndrome (LS) in colorectal cancer (CRC) and endometrial cancer patients generally involves immunohistochemical staining of the mismatch repair (MMR) proteins. In case of MLH1 protein loss, MLH1promotor hypermethylation (MLH1-PM) testing is performed to indirectly distinguish the constitutional MLH1variants from somatic epimutations. Recently, multiple studies have reported that MLH1-PM and pathogenic constitutional MMR variants are not mutually exclusive. This study describes 6 new and 86 previously reported MLH1-PM CRCs or endometrial cancers in LS patients. Of these, methylation of the MLH1gene promotor C region was reported in 30 MLH1, 6 MSH2, 6 MSH6, and 3 PMS2variant carriers at a median age at diagnosis of 48.5 years [interquartile range (IQR), 39–56.75 years], 39 years (IQR, 29–51 years), 58 years (IQR, 53.5–67 years), and 68 years (IQR, 65.6–68.5 years), respectively. For 31 MLH1-PM CRCs in LS patients from the literature, only the B region of the MLH1gene promotor was tested, whereas for 13 cases in the literature the tested region was not specified. Collectively, these data indicate that a diagnosis of LS should not be excluded when MLH1-PM is detected. Clinicians should carefully consider whether follow-up genetic MMR gene testing should be offered, with age <60 to 70 years and/or a positive family history among other factors being suggestive for a potential constitutional MMR gene defect.
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- 2024
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41. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
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Ballhausen, Alexej, Przybilla, Moritz Jakob, Jendrusch, Michael, Haupt, Saskia, Pfaffendorf, Elisabeth, Seidler, Florian, Witt, Johannes, Hernandez Sanchez, Alejandro, Urban, Katharina, Draxlbauer, Markus, Krausert, Sonja, Ahadova, Aysel, Kalteis, Martin Simon, Pfuderer, Pauline L., Heid, Daniel, Stichel, Damian, Gebert, Johannes, Bonsack, Maria, Schott, Sarah, Bläker, Hendrik, Seppälä, Toni, Mecklin, Jukka-Pekka, Ten Broeke, Sanne, Nielsen, Maartje, Heuveline, Vincent, Krzykalla, Julia, Benner, Axel, Riemer, Angelika Beate, von Knebel Doeberitz, Magnus, and Kloor, Matthias
- Published
- 2020
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42. Is <scp>HLA</scp> type a possible cancer risk modifier in Lynch syndrome?
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Aysel Ahadova, Johannes Witt, Saskia Haupt, Richard Gallon, Robert Hüneburg, Jacob Nattermann, Sanne ten Broeke, Lena Bohaumilitzky, Alejandro Hernandez‐Sanchez, Mauro Santibanez‐Koref, Michael S. Jackson, Maarit Ahtiainen, Kirsi Pylvänäinen, Katarina Andini, Vince Kornel Grolmusz, Gabriela Möslein, Mev Dominguez‐Valentin, Pål Møller, Daniel Fürst, Rolf Sijmons, Gillian M. Borthwick, John Burn, Jukka‐Pekka Mecklin, Vincent Heuveline, Magnus von Knebel Doeberitz, Toni Seppälä, and Matthias Kloor
- Subjects
personalized cancer risk ,Cancer Research ,Lynch syndrome ,HLA genotype ,Oncology ,cancer immunoediting ,immune surveillance ,immuunivaste ,syöpätaudit ,Lynchin oireyhtymä - Abstract
Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30-80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from pre-cancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors. peerReviewed
- Published
- 2022
43. Liquid biopsy-based early tumor and minimal residual disease detection: New perspectives for cancer predisposition syndromes.
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Bohaumilitzky 1,2, Lena, Gebert 1,2, Johannes, Doeberitz 1,2, Magnus von Knebel, Kloor 1,2, Matthias, and Ahadova 1,2, Aysel
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GENETICS of disease susceptibility ,CANCER risk factors ,EARLY detection of cancer ,BIOPSY ,CANCER invasiveness - Abstract
Genetic predisposition is one of the major measurable cancer risk factors. Affected patients have an enhanced risk for cancer and require life-long surveillance. However, current screening measures are mostly invasive and only available for certain tumor types. Particularly in hereditary cancer syndromes, liquid biopsy, in addition to monitoring therapy response and assessing minimal residual disease, holds great potential for surveillance at the precancerous stage and potentially even diagnostics. Exploring these options and future clinical translation could help reduce cancer risk and mortality in high-risk individuals and enhance patients' adherence to tailored surveillance protocols. [ABSTRACT FROM AUTHOR]
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- 2023
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44. DIAGNOSIS AND TREATMENT OF HEMATOGENIC OSTEOMYELITIS
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Berdiyarova Shokhida Shukurullaevna, Yusupova Nargiza Abdikodirovna, and Ahadova Mahliyo Mukhtar qizi
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Keywords: Osteomyelitis, children, bacterial, pathogenesis, immuno - Abstract
Inflammatory diseases of the skeleton are one of the most severe and common diseases of the musculoskeletal system in children and adolescents, including a large group of destructive bone lesions of various etiologies, united by the general term "osteomyelitis". At the same time, the clinical, laboratory and radiological picture of both infectious (specific granulomatous and nonspecific purulent) and non-infectious ("non-bacterial, abacterial") osteomyelitis may have a similar picture, which leads to inevitable diagnostic errors and, accordingly, the choice of erroneous treatment methods.
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- 2023
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45. EDUCATION SYSTEM IN UZBEKISTAN AND UNITED KINGDOM
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Kodirova Holida Khayriddinovna, Turobova Kamola, and Ahadova Sabina
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education, system, school, university, primary school, nursery education, curriculum - Abstract
Education is the milestone of the each nation and society as without it we can not imagine how the life we are living would like be. In this article, the researchers will concentrate on the importance of education and discuss about the differences and similarities between Uzbek and English education systems. 
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- 2023
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46. Differential Glycosite Profiling—A Versatile Method to Compare Membrane Glycoproteomes
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Malwina Michalak, Martin Simon Kalteis, Aysel Ahadova, Matthias Kloor, Mark Kriegsmann, Katharina Kriegsmann, Uwe Warnken, Dominic Helm, and Jürgen Kopitz
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glycoproteomics ,glycosite ,colorectal cancer ,glycosylation ,glycoprotein ,mass spectrometry ,Organic chemistry ,QD241-441 - Abstract
Glycosylation is the most prevalent and varied form of post-translational protein modifications. Protein glycosylation regulates multiple cellular functions, including protein folding, cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis. In particular, membrane proteins are frequently highly glycosylated, which is both linked to physiological processes and of high relevance in various disease mechanisms. The cellular glycome is increasingly considered to be a therapeutic target. Here we describe a new strategy to compare membrane glycoproteomes, thereby identifying proteins with altered glycan structures and the respective glycosites. The workflow started with an optimized procedure for the digestion of membrane proteins followed by the lectin-based isolation of glycopeptides. Since alterations in the glycan part of a glycopeptide cause mass alterations, analytical size exclusion chromatography was applied to detect these mass shifts. N-glycosidase treatment combined with nanoUPLC-coupled mass spectrometry identified the altered glycoproteins and respective glycosites. The methodology was established using the colon cancer cell line CX1, which was treated with 2-deoxy-glucose—a modulator of N-glycosylation. The described methodology is not restricted to cell culture, as it can also be adapted to tissue samples or body fluids. Altogether, it is a useful module in various experimental settings that target glycan functions.
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- 2021
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47. Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies
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Sei, Shizuko, primary, Ahadova, Aysel, additional, Keskin, Derin B., additional, Bohaumilitzky, Lena, additional, Gebert, Johannes, additional, von Knebel Doeberitz, Magnus, additional, Lipkin, Steven M., additional, and Kloor, Matthias, additional
- Published
- 2023
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48. A “two-in-one hit” model of shortcut carcinogenesis in MLH1 Lynch syndrome carriers
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Ahadova, Aysel, primary, Stenzinger, Albrecht, additional, Seppälä, Toni, additional, Hüneburg, Robert, additional, Kloor, Matthias, additional, Bläker, Hendrik, additional, Wittemann, Jan-Niklas, additional, Endris, Volker, additional, Gerling, Leonie, additional, Bertram, Veit, additional, Neumuth, Marie Theres, additional, Witt, Johannes, additional, Graf, Sebastian, additional, Kristiansen, Glen, additional, Hommerding, Oliver, additional, Haupt, Saskia, additional, Zeilmann, Alexander, additional, Heuveline, Vincent, additional, Kazdal, Daniel, additional, Gebert, Johannes, additional, von Knebel Doeberitz, Magnus, additional, Mecklin, Jukka-Pekka, additional, and Nattermann, Jacob, additional
- Published
- 2023
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49. PMS2-associated Lynch syndrome: Past, present and future
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Andini, Katarina D., primary, Nielsen, Maartje, additional, Suerink, Manon, additional, Helderman, Noah C., additional, Koornstra, Jan Jacob, additional, Ahadova, Aysel, additional, Kloor, Matthias, additional, Mourits, Marian J.E., additional, Kok, Klaas, additional, Sijmons, Rolf H., additional, and Bajwa–ten Broeke, Sanne W., additional
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- 2023
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50. SYSTEM OF LAND STRUCTURE DESIGN IN UZBEKISTAN AND ITS MAIN CONTENT
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Egamova Dilchehra Adizovna and Ahadova Nilufar Komiljon kizi
- Abstract
At the present time, a precise land formation system has been established in Uzbekistan, which is included in the field of land resources management of our country and includes the implementation of land laws, organization of effective and full use of land, land protection, creation of a clean ecological environment and natural landscapes. performs tasks such as improvement.
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- 2023
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