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18 results on '"Cavestro G. M."'

1. Decline in the incidence of colorectal cancer and the associated mortality in young Italian adults

Author

Zorzi M., Cavestro G. M., Guzzinati S., Dal Maso L., Rugge M., Mazzoleni G., Morrone G., Caputo E., Galasso R., Citarella A., Sampietro G., Magoni M., Cavalieri D'Oro L., Ardizzone A., D'Argenzio A., Sciacca S., Pisani S., Ricci P., Giorno A., Ferretti S., Palma F., Serraino D., Iacovacci S., Quarta F., Filiberti R. A., Vitarelli S., Russo A. G., Carrozzi G., D'Orsi G., Fusco M., Sini G. M., Vitale F., Michiara M., Boschetti L., Chiaranda G., Rosso S., Tumino R., Mangone L., Valenti Clemente S., Falcini F., Caiazzo A. L., Cesaraccio R., Madeddu A., Fanetti A. C., Minerba S., Caldarella A., Candela G., Piffer S., Stracci F., Tagliabue G., Tolin M., Brustolin A., Castelli M., Zorzi M., Cavestro G.M., Guzzinati S., Dal Maso L., Rugge M., Mazzoleni G., Morrone G., Caputo E., Galasso R., Citarella A., Sampietro G., Magoni M., Cavalieri D'Oro L., Ardizzone A., D'Argenzio A., Sciacca S., Pisani S., Ricci P., Giorno A., Ferretti S., Palma F., Serraino D., Iacovacci S., Quarta F., Filiberti R.A., Vitarelli S., Russo A.G., Carrozzi G., D'Orsi G., Fusco M., Sini G.M., Vitale F., Michiara M., Boschetti L., Chiaranda G., Rosso S., Tumino R., Mangone L., Valenti Clemente S., Falcini F., Caiazzo A.L., Cesaraccio R., Madeddu A., Fanetti A.C., Minerba S., Caldarella A., Candela G., Piffer S., Stracci F., Tagliabue G., Tolin M., Brustolin A., Castelli M., Zorzi, M., Cavestro, G. M., Guzzinati, S., Dal Maso, L., and Rugge, M

Subjects
0301 basic medicine, Colon, Population, Socio-culturale, colorectal cancer, colorectal cancer screening, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Epidemiology of cancer, Medicine, Humans, Risk factor, education, education.field_of_study, cancer epidemiology, Colorectal cancer, colorectal cancer screening, business.industry, Incidence (epidemiology), Mortality rate, screening, Incidence, Gastroenterology, Cancer, medicine.disease, Obesity, Annual Percent Change, Europe, 030104 developmental biology, Italy, 030211 gastroenterology & hepatology, epidemiology, business, Colorectal Neoplasms, Demography, cancer epidemiology, SEER Program
Abstract

Objective The incidence of colorectal cancer (CRC) declines among subjects aged 50 years and above. An opposite trend appears among younger adults. In Europe, data on CRC incidence among younger adults are lacking. We therefore aimed to analyse European trends in CRC incidence and mortality in subjects younger than 50 years. Design Data on age-related CRC incidence and mortality between 1990 and 2016 were retrieved from national and regional cancer registries. Trends were analysed by Joinpoint regression and expressed as annual percent change. Results We retrieved data on 143.7 million people aged 20–49 years from 20 European countries. Of them, 187 918 (0.13%) were diagnosed with CRC. On average, CRC incidence increased with 7.9% per year among subjects aged 20–29 years from 2004 to 2016. The increase in the age group of 30–39 years was 4.9% per year from 2005 to 2016, the increase in the age group of 40–49 years was 1.6% per year from 2004 to 2016. This increase started earliest in subjects aged 20–29 years, and 10–20 years later in those aged 30–39 and 40–49 years. This is consistent with an age-cohort phenomenon. Although in most European countries the CRC incidence had risen, some heterogeneity was found between countries. CRC mortality did not significantly change among the youngest adults, but decreased with 1.1%per year between 1990 and 2016 and 2.4% per year between 1990 and 2009 among those aged 30–39 years and 40–49 years, respectively. Conclusion CRC incidence rises among young adults in Europe. The cause for this trend needs to be elucidated. Clinicians should be aware of this trend. If the trend continues, screening guidelines may need to be reconsidered.

Published
2020

2. Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum

Author

Dominguez-Valentin M., Sampson J. R., Moller P., Seppala T. T., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., Nielsen M., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Valle A. D., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., von Knebel Doeberitz M., Loeffler M., Rahner N., Weitz J., Steinke-Lange V., ten Broeke S. W., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Jensen L. H., Madsen M. B., Kroldrup L., Nilbert M., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Vidal J. B., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Dominguez-Valentin, M., Sampson, J. R., Moller, P., Seppala, T. T., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., Nielsen, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Valle, A. D., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., ten Broeke, S. W., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Jensen, L. H., Madsen, M. B., Kroldrup, L., Nilbert, M., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Vidal, J. B., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., and Mecklin, J. -P.

Subjects
Male, Adult, Oncology, Cancer Research, 2019-20 coronavirus outbreak, medicine.medical_specialty, sarcoma, Databases, Factual, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Sarcoma/diagnosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Aged, business.industry, Sarcoma, Syndrome, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, MSH2, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, 030211 gastroenterology & hepatology, business
Published
2020
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3. Analysis of GPRC6A variants in different pancreatitis etiologies

Author

Markus M. Lerch, Emmanuelle Masson, Joost P.H. Drenth, Peter Bugert, Jian-Min Chen, Wen Bin Zou, Marko Damm, Matthias Sendler, Jonas Rosendahl, Heidi Griesmann, Holger Kirsten, Claudia Ruffert, Ewa Małecka-Panas, Markus Scholz, Nico Hesselbarth, Tom Kaune, Rene H. M. te Morsche, Péter Hegyi, Stanisław Głuszek, Zhuan Liao, Julian Cardinal von Widdern, Heiko Witt, Raffaella Alessia Zuppardo, Robert Grützmann, Louis Buscail, Sebastian Krug, Shun Jiang Deng, Frank Ulrich Weiss, Vinciane Rebours, Giulia Martina Cavestro, Claude Férec, Adrian Saftoiu, Patrick Michl, Kaune, T., Ruffert, C., Hesselbarth, N., Damm, M., Krug, S., Cardinal von Widdern, J., Masson, E., Chen, J. -M., Rebours, V., Buscail, L., Ferec, C., Grutzmann, R., te Morsche, R. H. M., Drenth, J. P., Cavestro, G. M., Zuppardo, R. A., Saftoiu, A., Malecka-Panas, E., Gluszek, S., Bugert, P., Lerch, M. M., Sendler, M., Weiss, F. U., Zou, W. -B., Deng, S. -J., Liao, Z., Scholz, M., Kirsten, H., Hegyi, P., Witt, H., Michl, P., Griesmann, H., and Rosendahl, J.

Subjects
Adult, Male, Candidate gene, Pancreatitis, Alcoholic, Endocrinology, Diabetes and Metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, Genetics, Humans, Medicine, SNP, Genetic Predisposition to Disease, Aged, Inflammation, Hepatology, G-Protein coupled receptor, business.industry, Gastroenterology, Genetic Variation, Inflammasome, DNA, Odds ratio, Middle Aged, Tag SNP, medicine.disease, Europe, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Pancreatitis, 030220 oncology & carcinogenesis, Cohort, Immunology, Female, Calcium, 030211 gastroenterology & hepatology, business, Receptors, Calcium-Sensing, Genome-Wide Association Study, Signal Transduction, medicine.drug
Abstract

Contains fulltext : 229360.pdf (Publisher’s version ) (Closed access) BACKGROUND: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10(-5)) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.

Published
2020
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4. Expression of glucose transporters in duodenal mucosa of patients with type 1 diabetes

Author

Emanuele Bosi, Riccardo Bonfanti, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Valeria Sordi, Graziano Barera, Silvia Pellegrini, Amelia Caretto, Andrea Mario Bolla, Elena Butera, Bolla, A. M., Butera, E., Pellegrini, S., Caretto, A., Bonfanti, R., Zuppardo, R. A., Barera, G., Cavestro, G. M., Sordi, V., and Bosi, E.

Subjects
Male, Biopsy, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, SGLT2, SGLT1, 0302 clinical medicine, Endocrinology, Gene expression, Intestinal Mucosa, Child, Glucose Transporter Type 2, Glucose Transporter Type 1, medicine.diagnostic_test, biology, General Medicine, Middle Aged, Glucose transporters, Type 1 diabetes, Female, Adult, endocrine system, medicine.medical_specialty, Adolescent, Duodenum, 030209 endocrinology & metabolism, Immunofluorescence, Young Adult, 03 medical and health sciences, Sodium-Glucose Transporter 1, Sodium-Glucose Transporter 2, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Humans, Aged, business.industry, Glucose transporter, nutritional and metabolic diseases, medicine.disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Gut mucosa, biology.protein, GLUT2, GLUT1, business
Abstract

Aims: A higher SGLT1 and GLUT2 gene expression was shown in the intestine of subjects with type 2 diabetes, while no data have been reported in type 1 diabetes (T1D). The purpose of our study was to evaluate the expression of glucose transporters in duodenal mucosa of subjects with T1D, compared to healthy controls (CTRL) and to patients with celiac disease (CD), as gut inflammatory disease control group. Materials and methods: Gene expression of GLUT1, GLUT2, SGLT1 and SGLT2 was quantified on duodenal mucosa biopsies of subjects with T1D (n = 19), CD (n = 16), T1D and CD (n = 6) and CTRL (n = 12), recruited at San Raffaele Hospital (Milan, Italy), between 2009 and 2018. SGLT2 expression was further evaluated by immunohistochemical and immunofluorescence staining. Results: The expression of all four glucose transporters was detected in duodenal mucosa of all groups. A reduced GLUT2, SGLT1 and SGLT2 expression was observed in CD in comparison with T1D and CTRL, as expected; GLUT1 was significantly more expressed in T1D compared to CTRL. SGLT2 expression was quantified at much lower levels than other transporters, with no differences between groups. SGLT2 expression was confirmed by immunohistochemistry in a restricted number of enterocytes lining in the mucosa of intestinal villi, also shown on immunofluorescence. Conclusions: Our results show that glucose transporters expression in duodenal mucosa of subjects with T1D, except an increased GLUT1, is not different from that observed in healthy controls. The expression of SGLT2 in human duodenal mucosa, although at low intensity, represents a novel finding.

Published
2020
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5. MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer

Author

Dejan Lazarevic, Pier Alberto Testoni, Annalisa Russo Raucci, Giovanni Tonon, Paola Carrera, Raffaella Alessia Zuppardo, Maria Grazia Patricelli, Giulia Martina Cavestro, Francesca Giannese, Maurizio Ferrari, Alessandro Mannucci, F Calabrese, Stefano Crippa, Mannucci, A., Zuppardo, R. A., Crippa, S., Carrera, P., Patricelli, M. G., Russo Raucci, A., Calabrese, F., Lazarevic, D., Giannese, F., Tonon, G., Ferrari, M., Testoni, P. A., and Cavestro, G. M.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Colorectal cancer, pancreatic cancer, colorectal cancer, familial pancreatic cancer, Adenocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Pancreatic cancer, medicine, Humans, Hepatology, business.industry, Endometrial cancer, hereditary pancreatic cancer, Gastroenterology, nutritional and metabolic diseases, Cancer, MSH6, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Penetrance, digestive system diseases, Lynch syndrome, DNA-Binding Proteins, Pancreatic Neoplasms, mismatch repair, 030220 oncology & carcinogenesis, Colonic Neoplasms, Cancer research, 030211 gastroenterology & hepatology, business
Abstract

Objectives Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia. Methods Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes. Results We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet. Conclusions Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.

Published
2020
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6. European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC)

Author

Eva Karamitopoulou, Hanna Seppänen, Giulia Zamboni, Marc Zins, Giulia Martina Cavestro, Thomas Brunner, Alberto Costa, Filippo de Braud, Danila Valenti, Franco Orsi, Francesco Sclafani, Sorin T. Barbu, Martina Torchio, Cindy Neuzillet, Marc Beishon, Ken Herrmann, Mirjam Crul, Pierluigi Bonomo, Philip Poortmans, S. Partelli, Piero Ferolla, Maria Die Trill, Graça Braz, Partelli, S., Sclafani, F., Barbu, S. T., Beishon, M., Bonomo, P., Braz, G., de Braud, F., Brunner, T., Cavestro, G. M., Crul, M., Trill, M. D., Ferolla, P., Herrmann, K., Karamitopoulou, E., Neuzillet, C., Orsi, F., Seppanen, H., Torchio, M., Valenti, D., Zamboni, G., Zins, M., Costa, A., and Poortmans, P.

Subjects
Clinical audit, Medizin, gastroenterology, Review, Medical Oncology, 0302 clinical medicine, nursing, Multidisciplinary approach, cancer control, Health care, Epidemiology of cancer, Cancer screening, genetics, nuclear medicine, health care organization, General Medicine, 3. Good health, nutrition, health care quality, risk factor, 030220 oncology & carcinogenesis, oncology, Practice Guidelines as Topic, 030211 gastroenterology & hepatology, neuroendocrine tumor, Health care quality, cancer epidemiology, palliative therapy, perioperative period, pancreas tumor, cancer registry, cancer screening, cancer staging, clinical audit, endocrinology, health care access, health education, human, interventional radiology, pancreas cancer, pathology, patient care, survivorship, treatment outcome, 03 medical and health sciences, Nursing, medicine, Humans, Radiology, Nuclear Medicine and imaging, Quality of Health Care, business.industry, Cancer, medicine.disease, Cancer registry, Pancreatic Neoplasms, Human medicine, business
Abstract

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Pancreatic cancer is an increasing cause of cancer mortality and has wide variation in treatment and care in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must be carried out only in pancreatic cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

Published
2021
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7. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Author

Guy Rosner, Walter Hernán Pavicic, Claudia Perne, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, Wouter H. de Vos tot Nederveen Cappel, Stefan Aretz, Einar Andreas Rødland, Polly A. Newcomb, Karin Alvarez, Ariadna Sánchez, Lone Sunde, Wolff Schmiegel, Joan Brunet, Marc S. Greenblatt, Christina Therkildsen, Karl Heinimann, Lior H. Katz, Fiona Lalloo, Jürgen Weitz, Anna Lepistö, Rolf H. Sijmons, Maartje Nielsen, Hans F. A. Vasen, Deepak Vangala, Monika Morak, Jukka-Pekka Mecklin, Toni T. Seppälä, Sigve Nakken, Stefanie Holzapfel, Douglas Tjandra, Finlay A. Macrae, Päivi Peltomäki, Daniel D. Buchanan, Stephen N. Thibodeau, Adriana Della Valle, James Hill, Annika Lindblom, Bernardo Bonanni, Reinhard Büttner, Francisco López-Köstner, Giulia Martina Cavestro, John Burn, Emma J Crosbie, Lucio Bertario, Sanne W. ten Broeke, D. G. R. Evans, Kate Green, Verena Steinke-Lange, Eivind Hovig, Miquel Serra-Burriel, Francesc Balaguer, Kirsi Pylvänäinen, Gabriela Möslein, Revital Kariv, Thomas Hansen, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Nils Rahner, Magnus von Knebel Doeberitz, Ingrid Winship, Nathan Gluck, Lars Joachim Lindberg, Christoph Engel, Mev Dominguez-Valentin, John-Paul Plazzer, Julian R. Sampson, Marta Pineda, John L. Hopper, Pablo Kalfayan, Heike Görgens, Aung Ko Win, Steven Gallinger, Loic Le Marchand, Mark A. Jenkins, Markus Loeffler, Noralane M. Lindor, Inge Bernstein, Pål Møller, Laura Renkonen-Sinisalo, Florencia Neffa, Huw Thomas, Gabriel Capellá, Jane C. Figueiredo, Miriam Mints, Patricia Esperon, Matilde Navarro, Robert Hüneburg, Guided Treatment in Optimal Selected Cancer Patients (GUTS), HUS Abdominal Center, Department of Surgery, Genome-Scale Biology (GSB) Research Program, II kirurgian klinikka, ATG - Applied Tumor Genomics, Research Programs Unit, Clinicum, Department of Medical and Clinical Genetics, Dominguez-Valentin, M., Plazzer, J. -P., Sampson, J. R., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Macrae, F., Winship, I. M., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Nielsen, M., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Alvarez, K., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Nakken, S., Hovig, E., Green, K., Lalloo, F., Hill, J., Vasen, H. F. A., Perne, C., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Doeberitz, M. V. K., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., Schmiegel, W., Vangala, D., Crosbie, E. J., Pineda, M., Navarro, M., Brunet, J., Moreira, L., Sanchez, A., Serra-Burriel, M., Mints, M., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W. H., Kalfayan, P., Ten Broeke, S. W., Mecklin, J. -P., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomaki, P., Hopper, J. L., Win, A. K., Buchanan, D. D., Lindor, N. M., Gallinger, S., Marchand, L. L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Hansen, T. V. O., Lindberg, L., Rodland, E. A., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Seppala, T. T., and Moller, P.

Subjects
cancer incidence, 0302 clinical medicine, Malalties hereditàries, Missense mutation, 8Q23.3, Càncer, Cancer, Genetics, 0303 health sciences, medicine.diagnostic_test, Factors de risc en les malalties, MISMATCH REPAIR GENES, MLH1, General Medicine, Penetrance, Lynch syndrome, 3. Good health, syöpägeenit, 030220 oncology & carcinogenesis, Medicine, syöpätaudit, ilmaantuvuus, Genetic diseases, congenital, hereditary, and neonatal diseases and abnormalities, missense, 11Q23.1, Risk factors in diseases, CANCER-RISK, Article, aberrant splicing, 03 medical and health sciences, AGE, medicine, Genetic predisposition, ddc:610, MSH2, Lynchin oireyhtymä, penetrance, 030304 developmental biology, Genetic testing, truncating, perinnölliset taudit, business.industry, MUTATIONS, HMSH2, nutritional and metabolic diseases, medicine.disease, digestive system diseases, 3121 General medicine, internal medicine and other clinical medicine, business
Abstract

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Published
2021
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8. Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants:a Prospective Lynch Syndrome Database report

Author

Einar Andreas Rødland, Joan B. Vida, Heike Görgens, Eivind Hovig, Kirsi Pylvänäinen, Monika Morak, Wouter H. de Vos tot Nederveen Cappel, Lone Sunde, Mark A. Jenkins, Lucio Bertario, Patricia Esperon, Reinhard Büttner, Finlay A. Macrae, Inge Bernstein, Marc S. Greenblatt, Wolff Schmiegel, Giulia Martina Cavestro, Maria Grazia Tibiletti, Silke Redler, Zohreh Ketabi, Karl Heinimann, Fiona Lalloo, Huw Thomas, Christina Therkildsen, Deepak Vangala, Magnus von Knebel Doeberitz, Matilde Navarro, Erik Rokkones, Douglas Tjandra, D. G. Evans, Marta Pineda, Marian J.E. Mourits, Lior H. Katz, Bernardo Bonanni, Pablo Kalfayan, Stephen N. Thibodeau, Loic Le Marchand, Revital Kariv, Maartje Nielsen, Emma J Crosbie, Oliver G. Denton, Stefanie Holzapfel, Guy Rosner, Mev Dominguez-Valentin, John Burn, Verena Steinke-Lange, Carlos A. Vaccaro, Gabriela Möslein, Elke Holinski-Feder, Gabriel Capellá, Johanna Tecklenburg, Karin Wadt, Kate Green, Christoph Engel, Miriam Mints, Anna Lepistö, Tamara Alejandra Piñero, Jukka-Pekka Mecklin, John L. Hopper, Robert Hüneburg, Markus Loeffler, Florencia Neffa, Toni T. Seppälä, Claudia Perne, Polly A. Newcomb, Karin Alvarez, Adriana Della Valle, Julian R. Sampson, Sanne W. ten Broeke, Francisco Lopez-Koestner, John-Paul Plazzer, James Hill, Hans Georg Strauß, Ingrid Winship, Nathan Gluck, Aung Ko Win, Jane C. Figueiredo, Jürgen Weitz, Hans F. A. Vasen, Rolf H. Sijmons, Walter Hernán Pavicic, Stefan Aretz, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Seppala, T. T., Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vida, J. B., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W., Kalfayan, P., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Redler, S., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Hopper, J. L., Win, A. K., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Wadt, K. A. W., Mourits, M. J. E., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Rokkones, E., Sampson, J. R., Evans, D. G., Moller, P., Genome-Scale Biology (GSB) Research Program, HUS Abdominal Center, Clinicum, II kirurgian klinikka, Department of Surgery, and Doctoral Programme in Clinical Research

Subjects
0301 basic medicine, Cancer Research, Oophorectomy, Databases, Factual, Colorectal cancer, SURGERY, medicine.medical_treatment, Càncer d'ovari, computer.software_genre, DNA Mismatch Repair, 0302 clinical medicine, Endometrial cancer, munasarjasyöpä, Medicine, Prospective Studies, Colectomy, Salpingo-oophorectomy/methods, Database, Manchester Cancer Research Centre, COLON-CANCER, MLH1, WOMEN, Middle Aged, Prognosis, Lynch syndrome, 3. Good health, kohdunrungon syöpä, Oncology, COLECTOMY, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Adult, Heterozygote, Genital Neoplasms, Female, Salpingo-oophorectomy, Hysterectomy, 03 medical and health sciences, Genital Neoplasms, Female/prevention & control, Ovarian cancer, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Biomarkers, Tumor, Mortalitat, Humans, Hysterectomy/methods, Mortality, Lynchin oireyhtymä, Risk-reducing surgery, Aged, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Cancer, MSH6, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, MSH2, 030104 developmental biology, Cross-Sectional Studies, PMS2, Càncer d'endometri, Mutation, kohdunpoisto, business, computer, Follow-Up Studies
Abstract

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Published
2021
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9. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author

Eivind Hovig, Bernardo Bonanni, Monika Morak, Mark A. Jenkins, Patricia Esperon, Toni T. Seppälä, Lone Sunde, Pablo Kalfayan, Gabriel Capellá, Inge Bernstein, Matilde Navarro, Marc S. Greenblatt, John Burn, Zohreh Ketabi, Johanna Tecklenburg, Francisco Lopez-Koestner, Miriam Mints, Heike Görgens, Neil A J Ryan, Kate Green, Annika Auranen, Douglas Tjandra, Robert W. Haile, Marta Pineda, Tamara Alejandra Piñero, Stefan Aretz, Robert Hüneburg, Verena Steinke-Lange, Markus Loeffler, Christina Therkildsen, John L. Hopper, Deepak Vangala, Huw Thomas, Reinhard Büttner, James Hill, Einar Andreas Rødland, Revital Kariv, Maria Grazia Tibiletti, Sigve Nakken, Stefanie Holzapfel, D. Gareth Evans, Oliver G. Denton, Julian R. Sampson, Henrik Okkels, Joan Vidal, Loic Le Marchand, Hans Georg Strauß, Gabriela Möslein, Claudia Perne, Ingrid Winship, Nathan Gluck, Jane C. Figueiredo, Mev Dominguez-Valentin, Wolff Schmiegel, Karl Heinimann, Kirsi Pylvänäinen, Karin Alvarez, Maartje Nielsen, Wouter H. de Vos tot Nederveen Cappel, Fiona Lalloo, Aung Ko Win, Guy Rosner, Carlos A. Vaccaro, Polly A. Newcomb, Elke Holinski-Feder, John-Paul Plazzer, Lior H. Katz, Christoph Engel, Anna Lepistö, Jukka-Pekka Mecklin, Giulia Martina Cavestro, Adriana Della Valle, Finlay A. Macrae, Sanne W. ten Broeke, Florencia Neffa, Rolf H. Sijmons, María Laura Gonzalez, Nils Rahner, Jürgen Weitz, Hans F. A. Vasen, Stephen N. Thibodeau, Emma J Crosbie, Lucio Bertario, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Magnus von Knebel Doeberitz, Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Nakken, S., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vidal, J. B., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Ryan, N., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Auranen, A., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Okkels, H., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Sampson, J. R., Evans, D. G., Seppala, T. T., Moller, P., ATG - Applied Tumor Genomics, HUS Abdominal Center, II kirurgian klinikka, Department of Surgery, Clinicum, Helsinki University Hospital Area, and University of Helsinki

Subjects
0301 basic medicine, medicine.medical_treatment, DNA Mismatch Repair, Gynecologic surgery, 0302 clinical medicine, Malalties hereditàries, Prospective Studies, Prospective cohort study, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Incidence (epidemiology), Middle Aged, 16. Peace & justice, Lynch syndrome, 3. Good health, 030220 oncology & carcinogenesis, Female, syöpätaudit, MutL Protein Homolog 1, Genetic diseases, Heterozygote, medicine.medical_specialty, Salpingo-oophorectomy, Cirurgia ginecològica, Hysterectomy, Article, 03 medical and health sciences, Càncer colorectal, CAPP2, medicine, Humans, Lynchin oireyhtymä, Gynecology, perinnölliset taudit, HEREDITARY COLORECTAL-CANCER, business.industry, Endometrial cancer, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Colorectal cancer, ASPIRIN, 030104 developmental biology, Clinical research, 3121 General medicine, internal medicine and other clinical medicine, kohdunpoisto, 3111 Biomedicine, Ovarian cancer, business
Abstract

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Published
2021
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10. Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

Author

John P. Neoptolemos, Krzysztof Jamroziak, Manuel Gentiluomo, Edita Kreivenaite, Oliver Strobel, Martin Lovecek, Núria Malats, Rita T. Lawlor, Angelica Macauda, Yogesh K. Vashist, Sabrina Gloria Giulia Testoni, Paolo Giorgio Arcidiacono, Raffaele Pezzilli, Gabriele Capurso, George Theodoropoulos, Andrea Szentesi, Giuseppe Vanella, Michael F. Nentwich, Pavel Vodicka, Luca Morelli, Audrius Ivanauskas, Angelo Andriulli, Giulia Martina Cavestro, Emanuele Federico Kauffmann, Renata Talar-Wojnarowska, Raffaella Alessia Zuppardo, Pavel Soucek, Viktor Hlavac, Daniele Campa, Laura Pistoni, PanGenEU Study Investigators, Evangelina López de Maturana, Milena Di Leo, Livia Archibugi, Maria Gazouli, Federico Canzian, Péter Hegyi, Cosimo Sperti, Anna Caterina Milanetto, László Gajdán, Domenica Gioffreda, Martin Oliverius, Beatrice Mohelnikova-Duchonova, Dania Bozzato, Maria Chiara Petrone, Stefano Landi, Thilo Hackert, Luca Pollina, Hermann Brenner, Ye Lu, Cristian Gheorghe, Daniela Basso, Giuseppe Malleo, Erika Darvasi, Ludmila Vodickova, Juozas Kupcinskas, Jakob R. Izbicki, Francesca Tavano, Pistoni, L., Gentiluomo, M., Lu, Y., de Maturana, E. L., Hlavac, V., Vanella, G., Darvasi, E., Milanetto, A. C., Oliverius, M., Vashist, Y., Leo, M. D., Mohelnikova-Duchonova, B., Talar-Wojnarowska, R., Gheorghe, C., Petrone, M. C., Strobel, O., Arcidiacono, P. G., Vodickova, L., Szentesi, A., Capurso, G., Gajdan, L., Malleo, G., Theodoropoulos, G. E., Basso, D., Soucek, P., Brenner, H., Lawlor, R. T., Morelli, L., Ivanauskas, A., Kauffmann, E. F., Macauda, A., Gazouli, M., Archibugi, L., Nentwich, M., Loveeek, M., Cavestro, G. M., Vodicka, P., Landi, S., Tavano, F., Sperti, C., Hackert, T., Kupcinskas, J., Pezzilli, R., Andriulli, A., Pollina, L., Kreivenaite, E., Gioffreda, D., Jamroziak, K., Hegyi, P., Izbicki, J. R., Testoni, S. G. G., Zuppardo, R. A., Bozzato, D., Neoptolemos, J. P., Malats, N., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Male, Cancer Research, endocrine system diseases, Population, Quantitative Trait Loci, association study, eQTLs, pancreatic cancer, single nucleotide polymorphisms, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Pancreatic cancer, medicine, Humans, Genetic Predisposition to Disease, 03.02. Klinikai orvostan, Polymorphism, Allele, education, Alleles, Aged, education.field_of_study, Carcinoma, Pancreatic Ductal, Case-Control Studies, Female, GTPase-Activating Proteins, Middle Aged, Pancreatic Neoplasms, Genome-Wide Association Study, Carcinoma, Single Nucleotide, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Pancreatic Ductal, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Cancer research, Pancreas
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10−10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10–6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

Published
2021

11. The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline †

Author

Anja Wagner, Emma J Crosbie, Annika Auranen, Marta Puzzono, Marco J. Bruno, Andrew Latchford, Giulia Martina Cavestro, Monique E. van Leerdam, Ingrid Winship, Anne Goverde, Stefan Aretz, Gabriela Möslein, Anne Marie Jelsig, Anna Lepistö, Veronica Zuber, Wagner, A., Aretz, S., Auranen, A., Bruno, M. J., Cavestro, G. M., Crosbie, E. J., Goverde, A., Jelsig, A. M., Latchford, A., van Leerdam, M. E., Lepisto, A., Puzzono, M., Winship, I., Zuber, V., Moslein, G., Clinical Genetics, and Gastroenterology & Hepatology

Subjects
medicine.medical_specialty, MEDLINE, Delphi method, lcsh:Medicine, Peutz–Jeghers syndrome, Review, Guideline, Practical guideline, 03 medical and health sciences, 0302 clinical medicine, Medicine, Grading (education), business.industry, lcsh:R, STK11, Subject (documents), General Medicine, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Family medicine, Keywords: Peutz–Jeghers syndrome, 030211 gastroenterology & hepatology, business, Variable number, guideline
Abstract

The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

Published
2021

12. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

Author

Ewa Małecka-Panas, Jakob R. Izbicki, Krzysztof Jamroziak, Claudio Pasquali, Sabrina Gloria Giulia Testoni, Silvia Carrara, Livia Archibugi, Domenica Gioffreda, Francesca Tavano, Matteo Giaccherini, Gregorio Di Franco, Niccolò Napoli, Viktor Hlavac, Yogesh K. Vashist, Oliver Strobel, Martin Lovecek, Paolo Giorgio Arcidiacono, Thilo Hackert, Klara Cervena, Stefano Landi, Claudio Luchini, Andrea Szentesi, Maria Gazouli, Giulia Martina Cavestro, Daniele Campa, Gabriele Capurso, Rita T. Lawlor, Martin Oliverius, Edita Kreivenaite, Audrius Ivanauskas, Luca Morelli, Raffaele Pezzilli, Maria Chiara Petrone, Chiara Corradi, Stefania Moz, George Theodoropoulos, Michael F. Nentwich, Pavel Vodicka, Giuseppe Vanella, Hermann Brenner, Manuel Gentiluomo, John P. Neoptolemos, Cosimo Sperti, Angelo Andriulli, Ye Lu, Péter Hegyi, Cristian Gheorghe, Anna Caterina Milanetto, Pavel Soucek, László Gajdán, Erika Darvasi, Juozas Kupcinskas, Federico Canzian, Raffaella Alessia Zuppardo, Corradi, C., Gentiluomo, M., Gajdan, L., Cavestro, G. M., Kreivenaite, E., Di Franco, G., Sperti, C., Giaccherini, M., Petrone, M. C., Tavano, F., Gioffreda, D., Morelli, L., Soucek, P., Andriulli, A., Izbicki, J. R., Napoli, N., Malecka-Panas, E., Hegyi, P., Neoptolemos, J. P., Landi, S., Vashist, Y., Pasquali, C., Lu, Y., Cervena, K., Theodoropoulos, G. E., Moz, S., Capurso, G., Strobel, O., Carrara, S., Hackert, T., Hlavac, V., Archibugi, L., Oliverius, M., Vanella, G., Vodicka, P., Arcidiacono, P. G., Pezzilli, R., Milanetto, A. C., Lawlor, R. T., Ivanauskas, A., Szentesi, A., Kupcinskas, J., Testoni, S. G. G., Lovecek, M., Nentwich, M., Gazouli, M., Luchini, C., Zuppardo, R. A., Darvasi, E., Brenner, H., Gheorghe, C., Jamroziak, K., Canzian, F., and Campa, D.

Subjects
Male, Cancer Research, association study, long noncoding RNA, pancreatic cancer, single nucleotide polymorphism, Aged, Carcinoma, Pancreatic Ductal, Case-Control Studies, Computational Biology, Cyclin-Dependent Kinase Inhibitor p15, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, MicroRNAs, Middle Aged, Pancreatic Neoplasms, RNA, Long Noncoding, Polymorphism, Single Nucleotide, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, SNP, Genetic variability, Polymorphism, Gene, Genetics, Carcinoma, Single Nucleotide, Long non-coding RNA, Oncology, Pancreatic Ductal, 030220 oncology & carcinogenesis, RNA, Long Noncoding
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Published
2021

13. Correction:Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Author

Gabriel Capellá, Patricia Esperon, Christoph Engel, Rolf H. Sijmons, María Laura Gonzalez, Matilde Navarro, Francisco López-Köstner, Julian R. Sampson, Miquel Serra-Burriel, Karin Alvarez, Ingrid Winship, Nathan Gluck, Lone Sunde, Reinhard Büttner, Giulia Martina Cavestro, Wouter H. de Vos tot Nederveen Cappel, Jukka-Pekka Mecklin, Marc S. Greenblatt, Kate Green, Robert Hüneburg, Markus Loeffler, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Florencia Neffa, Lucio Bertario, Ariadna Sánchez, Verena Steinke-Lange, Christina Therkildsen, Jane C. Figueiredo, Douglas Tjandra, Magnus von Knebel Doeberitz, Lior H. Katz, Steven Gallinger, Noralane M. Lindor, Gabriela Möslein, Adriana Della Valle, John L. Hopper, Einar Andreas Rødland, Miriam Mints, Annika Lindblom, Ian M. Frayling, Polly A. Newcomb, Pål Møller, Sanne W. ten Broeke, Laura Renkonen-Sinisalo, Sigve Nakken, Stefanie Holzapfel, Finlay A. Macrae, Stefan Aretz, Nils Rahner, Karin Wadt, Robert W. Haile, Francesc Balaguer, Revital Kariv, Stephen N. Thibodeau, Huw D. Thomas, Emma J Crosbie, Deepak Vangala, Monika Morak, Ignacio Blanco, Hans K. Schackert, Henrik Okkels, Mev Dominguez-Valentin, Oliver G. Denton, John-Paul Plazzer, Zohreh Ketabi, James Hill, Loic Le Marchand, Mark A. Jenkins, Inge Bernstein, D. Gareth Evans, Heike Görgens, Marta Pineda, John Burn, Kirsi Pylvänäinen, Eivind Hovig, Hans F. A. Vasen, Pablo Kalfayan, Toni T. Seppälä, Aung Ko Win, Maartje Nielsen, Wolff Schmiegel, Guy Rosner, Karl Heinimann, Fiona Lalloo, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, HUS Abdominal Center, Clinicum, II kirurgian klinikka, University of Helsinki, Department of Surgery, ATG - Applied Tumor Genomics, Research Programs Unit, Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., Moller, P., and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Oncology, Male, Colorectal cancer, Lynch syndrome, Penetrance, DNA Mismatch Repair, 0302 clinical medicine, Databases, Genetic, Malalties hereditàries, Prospective Studies, Càncer, PMS2, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Cancer, 0303 health sciences, Sex Characteristics, Factors de risc en les malalties, 1184 Genetics, developmental biology, physiology, MLH1, Middle Aged, 16. Peace & justice, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, syöpägeenit, MSH2, 030220 oncology & carcinogenesis, MSH6, 030211 gastroenterology & hepatology, DNA mismatch repair, Female, geneettiset tekijät, MutL Protein Homolog 1, Genetic diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Risk factors in diseases, suolistosyövät, MUTATION CARRIERS, Risk Assessment, Article, sukupuoli, Age and gender, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Lynchin oireyhtymä, Gene, 030304 developmental biology, Aged, business.industry, Endometrial cancer, Correction, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Survival Analysis, digestive system diseases, Mutation, 3111 Biomedicine, ikä, business, Ovarian cancer
Abstract

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Published
2020
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14. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Author

John P. Neoptolemos, Markus W. Büchler, Jakob R. Izbicki, Ben Schöttker, Cosmeri Rizzato, Cornelia Schroeder, Salvatore Paiella, Hanneke W. M. van Laarhoven, William Greenhalf, Simona Bursi, Renata Talar-Wojnarowska, Christos Dervenis, Ludmila Vodickova, Francesca Tavano, Giulia Martina Cavestro, Thilo Hackert, Claudio Pasquali, Ewa Małecka-Panas, Gabriele Capurso, Andrea Mambrini, Daniele Campa, Andrea Padoan, Ioannis S. Papanikolaou, Raffaele Pezzilli, Péter Hegyi, Beatrice Mohelnikova-Duchonova, Federica Gemignani, Michael F. Nentwich, Pavel Vodicka, Stefano Landi, Richárd Szmola, Anna Caterina Milanetto, Eithne Costello, Rudolf Kaaks, Laura Ginocchi, Bernd Holleczek, Erika Darvasi, Verena Katzke, Evaristo Maiello, Manuel Gentiluomo, Ondrej Strouhal, Orazio Palmieri, Juozas Kupcinskas, Alice Alessandra Galeotti, Viktor Hlavac, George Theodoropoulos, Audrius Ivanauskas, Maria Gazouli, Ferenc Izbéki, Federico Canzian, Oliver Strobel, Ofure Obazee, Martin Lovecek, Timothy J. Key, Domenica Gioffreda, Pavel Soucek, Ugo Boggi, Krzysztof Jamroziak, Cosimo Sperti, Maarten F. Bijlsma, Yogesh K. Vashist, Andrea Szentesi, Hermann Brenner, Livia Archibugi, Giuseppe Vanella, Daniela Basso, Radiotherapy, Center of Experimental and Molecular Medicine, CCA - Cancer Treatment and Quality of Life, Oncology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Galeotti, A. A., Gentiluomo, M., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwich, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Schroeder, C., Schottker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., Basso, D., Sperti, C., Bijlsma, M. F., Palmieri, O., Hlavac, V., Talar-Wojnarowska, R., Mohelnikova-Duchonova, B., Hackert, T., Vashist, Y., Strouhal, O., Van Laarhoven, H., Tavano, F., Lovecek, M., Dervenis, C., Izbeki, F., Padoan, A., Malecka-Panas, E., Maiello, E., Vanella, G., Capurso, G., Izbicki, J. R., Theodoropoulos, G. E., Jamroziak, K., Katzke, V., Kaaks, R., Mambrini, A., Papanikolaou, I. S., Szmola, R., Szentesi, A., Kupcinskas, J., Bursi, S., Costello, E., Boggi, U., Milanetto, A. C., Landi, S., Gazouli, M., Vodickova, L., Soucek, P., Gioffreda, D., Gemignani, F., Brenner, H., Strobel, O., Buchler, M., Vodicka, P., Paiella, S., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Multifactorial Inheritance, Pancreatic disease, genetic epidemiology, Population, Single-nucleotide polymorphism, Disease, pancreas and biliary tract, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Pancreatic cancer, Internal medicine, Genetics, medicine, oncology, Humans, education, Genetics (clinical), Alleles, Early Detection of Cancer, Genetic association, education.field_of_study, business.industry, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Genetic epidemiology, 030220 oncology & carcinogenesis, Cohort, Female, business, Carcinoma, Pancreatic Ductal
Abstract

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Published
2020

15. Genome-wide association study identifies an early onset pancreatic cancer risk locus

Author

Verena Katzke, Jakob R. Izbicki, Francesca Tavano, Rita T. Lawlor, Thilo Hackert, Raffaella Alessia Zuppardo, Giulia Martina Cavestro, Federico Canzian, Frederike Dijk, Martin Oliverius, George Theodoropoulos, Pavel Soucek, Manuel Gentiluomo, Rudolf Kaaks, Erika Darvasi, Yogesh K. Vashist, Bill Greenhalf, Juozas Kupcinskas, Maurizio Lucchesi, Borislav Rusev, Andrea Szentesi, Gabriele Capurso, Ewa Małecka-Panas, Lucia Moletta, Beatrice Mohelnikova-Duchonova, Franco Bambi, Ugo Boggi, Alba Ballerini, Krzysztof Jamroziak, Ben Schöttker, Simona Bursi, Raffaele Pezzilli, Gyula Farkas, Dania Bozzato, Áron Vincze, Stefano Landi, Anna Caterina Milanetto, Péter Hegyi, Michael F. Nentwich, Laura Ginocchi, Pavel Vodicka, Stefania Moz, Ludmila Vodickova, Hermann Brenner, Olivier R. Busch, Viktor Hlavac, Audrius Ivanauskas, John P. Neoptolemos, Domenica Gioffreda, Ofure Obazee, Livia Archibugi, Nathalia A. Giese, Giuseppe Vanella, Xin Gao, Renata Talar-Wojnarowska, Angelo Andriulli, Oliver Strobel, Daniele Campa, Maria Gazouli, Pathology, CCA - Cancer biology and immunology, Surgery, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Re-generation and cancer of the digestive system, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, D., Gentiluomo, M., Obazee, O., Ballerini, A., Vodickova, L., Hegyi, P., Soucek, P., Brenner, H., Milanetto, A. C., Landi, S., Gao, X., Bozzato, D., Capurso, G., Tavano, F., Vashist, Y., Hackert, T., Bambi, F., Bursi, S., Oliverius, M., Gioffreda, D., Schottker, B., Ivanauskas, A., Mohelnikova-Duchonova, B., Darvasi, E., Pezzilli, R., Malecka-Panas, E., Strobel, O., Gazouli, M., Katzke, V., Szentesi, A., Cavestro, G. M., Farkas, G., Izbicki, J. R., Moz, S., Archibugi, L., Hlavac, V., Vincze, A., Talar-Wojnarowska, R., Rusev, B., Kupcinskas, J., Greenhalf, B., Dijk, F., Giese, N., Boggi, U., Andriulli, A., Busch, O. R., Vanella, G., Vodicka, P., Nentwich, M., Lawlor, R. T., Theodoropoulos, G. E., Jamroziak, K., Zuppardo, R. A., Moletta, L., Ginocchi, L., Kaaks, R., Neoptolemos, J. P., Lucchesi, M., and Canzian, F.

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Pancreatic disease, pancreatic cancer, early onset, Single-nucleotide polymorphism, Genome-wide association study, very early onset pancreatic cancer, Polymorphism, Single Nucleotide, 03 medical and health sciences, single nucleotide polymorphisms, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Pancreas, Genetic association, genome-wide association study, business.industry, Middle Aged, medicine.disease, Pancreatic Neoplasms, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Age of onset, business, Carcinoma, Pancreatic Ductal
Abstract

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1x10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset≤50, and 4142 controls from the PANDoRA consortium while in the in silico data we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15x10-4 ). In conclusion we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. This article is protected by copyright. All rights reserved.

Published
2020

16. Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients

Author

Rita T. Lawlor, Raffaele Pezzilli, Péter Hegyi, Andrea Szentesi, Eithne Costello, Paula Puchalt García, John P. Neoptolemos, Alice Alessandra Galeotti, Cosimo Sperti, Giulia Martina Cavestro, Pavel Vodicka, Federico Canzian, Thilo Hackert, Renata Talar-Wojnarowska, Daniele Campa, Oliver Strobel, Francesca Tavano, Martin Lovecek, Gabriele Capurso, Christine Tjaden, Pavel Soucek, Manuel Gentiluomo, Anna Caterina Milanetto, Juozas Kupcinskas, Gentiluomo, M., Garcia, P. P., Galeotti, A. A., Talar-Wojnarowska, R., Tjaden, C., Tavano, F., Strobel, O., Kupcinskas, J., Neoptolemos, J., Hegyi, P., Costello, E., Pezzilli, R., Sperti, C., Lawlor, R. T., Capurso, G., Szentesi, A., Soucek, P., Vodicka, P., Lovecek, M., Hackert, T., Cavestro, G. M., Milanetto, A. C., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Pancreatic disease, Genotype, alleles polymorphism gemcitabine genes single nucleotide polymorphism genetics treatment outcome pancreatic cancer mrp2 protein, human pancreatic ductal adenocarcinoma, Single-nucleotide polymorphism, Disease, Polymorphism, Single Nucleotide, 03 medical and health sciences, human pancreatic ductal adenocarcinoma, 0302 clinical medicine, alleles polymorphism gemcitabine genes single nucleotide polymorphism genetics treatment outcome pancreatic cancer mrp2 protein, Pancreatic cancer, Internal medicine, Biomarkers, Tumor, Medicine, Humans, Genetic variability, Allele, Aged, business.industry, Hazard ratio, General Medicine, Middle Aged, medicine.disease, Prognosis, Combined Modality Therapy, Gemcitabine, Multidrug Resistance-Associated Protein 2, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Multidrug Resistance-Associated Proteins, business, medicine.drug, Carcinoma, Pancreatic Ductal, Follow-Up Studies
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.

Published
2019

17. Association of polyps with early-onset colorectal cancer and throughout surveillance: Novel clinical and molecular implications

Author

Edurne Álvaro, Julia Arribas, Damián García-Olmo, Rogelio González-Sarmiento, Giulia Martina Cavestro, Lorena Brandáriz, Jessica Pérez-García, Daniel Rueda, Alfredo Vivas, Ajay Goel, Miguel Urioste, Cristina Narváez, Susana Olmedillas-López, Yolanda Rodríguez, José Perea García, Sandra Tapial, Juan Luis García, Sergio Hernández-Villafranca, Ángel Cañete, UAM. Departamento de Cirugía, Garcia, J. P., Arribas, J., Canete, A., Garcia, J. L., Alvaro, E., Tapial, S., Narvaez, C., Vivas, A., Brandariz, L., Hernandez-Villafranca, S., Rueda, D., Rodriguez, Y., Perez-Garcia, J., Olmedillas-Lopez, S., Garcia-Olmo, D., Cavestro, G. M., Urioste, M., Goel, A., Gonzalez-Sarmiento, R., Ministerio de Sanidad y Consumo (España), European Commission, National Cancer Institute (US), and National Institutes of Health (US)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Prognostic factor, Colorectal cancer, Medicina, Rectum, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, polyp development, Internal medicine, medicine, follow-up, SMARCB1, Early onset, business.industry, Advanced stage, early-onset colorectal cancer, medicine.disease, digestive system diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, prognosis, business, Comparative genomic hybridization
Abstract

© 2019 by the authors., Early-onset colorectal cancer (EOCRC) is an increasing and worrisome entity. The aim of this study was to analyze its association with polyps concerning prognosis and surveillance. EOCRC cases were compared regarding the presence or absence of associated polyps (clinical and molecular features), during a minimum of 7 years of follow-up. Of 119 cases, 56 (47%) did not develop polyps (NP group), while 63 (53%) did (P group). The NP group showed a predominant location of the CRC in the rectum (50%), of sporadic cases (54%), and diagnosis at advanced stages: Only P53 and SMARCB1 mutations were statistically linked to this group. The P group, including mainly early-diagnosed tumors, was linked with the most frequent and differential altered chromosomal regions in the array comparative genomic hybridization. The two most frequent groups according to the follow-up were the NP group (40%), and patients developing polyps in the first 5 years of follow-up (P < 5FU) (34%) (these last groups predominantly diagnosed at the earliest stage and with adenomatous polyps (45%)). EOCRC with polyps that developed during the entire follow-up (PDFU group) were mainly located in the right colon (53%), diagnosed in earlier stages, and 75% had a familial history of CRC. Patients developing polyps after the first 5 years (P > 5FU) showed a mucinous component (50%). Our results show that the absence or presence of polyps in EOCRC is an important prognostic factor with differential phenotypes. The development of polyps during surveillance shows that it is necessary to extend the follow-up time, also in those cases with microsatellite-stable EOCRC, This work was funded by the Spanish Ministry of Health and Consumer Affairs and FEDER, grant number PI10/00683 and PI16/01650 to J.P.G., PI16/01920 to R.G.S., and PI14/00459 to M.U., and by the National Cancer Institute, National Institutes of Health, grant number R01 CA72851, CA18172, CA184792 and U01 CA187956 to A.G.

Published
2019

18. Colorectal cancer screening from 45 years of age: Thesis, antithesis and synthesis

Author

Giulia Martina Cavestro, Raffaella Alessia Zuppardo, José Perea, Alessandro Mannucci, Riccardo Rosati, Milena Di Leo, Mannucci, A., Zuppardo, R. A., Rosati, R., Di Leo, M., Perea, J., and Cavestro, G. M.

Subjects
Gerontology, medicine.medical_specialty, Colorectal cancer, Clinical Decision-Making, Colonoscopy, Disease, Review, Guidelines, Guideline, Medical Oncology, Early-onset colorectal cancer, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Mass Screening, In patient, Mortality, Pros and cons, Early Detection of Cancer, Societies, Medical, Entire population, medicine.diagnostic_test, business.industry, Public health, Incidence, Age Factors, Gastroenterology, General Medicine, Middle Aged, medicine.disease, Decision Support Systems, Clinical, United States, Europe, Colorectal cancer screening, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, 030211 gastroenterology & hepatology, Personalized medicine, Guideline Adherence, business, Colorectal Neoplasms, Software, Early onset
Abstract

Colorectal cancer incidence and mortality in patients younger than 50 years are increasing, but screening before the age of 50 is not offered in Europe. Advanced-stage diagnosis and mortality from colorectal cancer before 50 years of age are increasing. This is not a detection-bias effect; it is a real issue affecting the entire population. Three independent computational models indicate that screening from 45 years of age would yield a better balance of benefits and risks than the current start at 50 years of age. Experimental data support these predictions in a sex- and race-independent manner. Earlier screening is seemingly affordable, with minimal impediments to providing younger adults with colonoscopy. Indeed, the American Cancer Society has already started to recommend screening from 45 years of age in the United States. Implementing early screening is a societal and public health problem. The three independent computational models that suggested earlier screening were criticized for assuming perfect compliance. Guidelines and recommendations should be derived from well-collected and reproducible data, and not from mathematical predictions. In the era of personalized medicine, screening decisions might not be based solely on age, and sophisticated prediction software may better guide screening. Moreover, early screening might divert resources away from older individuals with greater biological risks. Finally, it is still unknown whether early colorectal cancer is part of a continuum of disease or a biologically distinct disease and, as such, it might not benefit from screening at all. The increase in early-onset colorectal cancer incidence and mortality demonstrates an obligation to take actions. Earlier screening would save lives, and starting at the age of 45 years may be a robust screening option.

Published
2019
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