Article
Medicine, General & Internal
Mev Dominguez-Valentin, Saskia Haupt, Toni T. Seppaelae, Julian R. Sampson, Lone Sunde, Inge Bernstein, Mark A. Jenkins, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Francesc Balaguer, 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, Tadeusz Debniak, Robert Fruscio, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Lor H. Katz, Ido Laish, Elez Vainer, Carlos Vaccaro, Dirce Maria Carraro, Kevin Monahan, Elizabeth Half, Aine Stakelum, Des Winter, Rory Kennelly, Nathan Gluck, Harsh Sheth, Naim Abu-Freha, Marc Greenblatt, Benedito Mauro Rossi, Mabel Bohorquez, Giulia Martina Cavestro, Leonardo S. Lino-Silva, Karoline Horisberger, Maria Grazia Tibiletti, Ivana do Nascimento, Huw Thomas, Norma Teresa Rossi, Leandro Apolinario da Silva, Attila Zarand, Juan Ruiz-Banobre, Vincent Heuveline, Jukka-Pekka Mecklin, Kirsi Pylvaenaeinen, Laura Renkonen-Sinisalo, Anna Lepistoe, Paeivi Peltomaeki, Christina Therkildsen, Mia Gebauer Madsen, Stefan Kobbelgaard Burgdorf, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane Lindor, Steven Gallinge, Loic Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Evelin Schroeck, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hueneburg, Silke Redler, Reinhard Buettner, Jurgen Weitz, Marta Pineda, Nuria Duenas, Joan Brunet Vidal, Leticia Moreira, Ariadna Sanchez, Eivind Hovig, Sigve Nakken, Kate Green, Fiona Lalloo, James Hill, Emma Crosbie, Miriam Mints, Yael Goldberg, Douglas Tjandra, Sanne W. ten Broeke, Revital Kariv, Guy Rosner, Suresh H. Advani, Lidiya Thomas, Pankaj Shah, Mithun Shah, Florencia Neffa, Patricia Esperon, Walter Pavicic, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Alejandra Martin, Gabriela Moslein, Pal Moller
Summary: This study used the latest PLSD cohort to investigate the mortality rates and age of cancer diagnoses in carriers of pathogenic MMR variants. The results showed that non-colorectal Lynch syndrome cancers caused more deaths than colorectal cancers in these carriers. Reducing deaths from non-colorectal cancers is a crucial challenge for the medical care of Lynch syndrome.
Article
Medicine, General & Internal
Mev Dominguez-Valentin, John-Paul Plazzer, Julian R. Sampson, Christoph Engel, Stefan Aretz, Mark A. Jenkins, Lone Sunde, Inge Bernstein, Gabriel Capella, Francesc Balaguer, Finlay Macrae, Ingrid M. Winship, Huw Thomas, Dafydd Gareth Evans, John Burn, Marc Greenblatt, Wouter H. de Vos Tot Nederveen Cappel, Rolf H. Sijmons, Maartje Nielsen, Lucio Bertario, Bernardo Bonanni, Maria Grazia Tibiletti, Giulia Martina Cavestro, Annika Lindblom, Adriana Della Valle, Francisco Lopez-Kostner, Karin Alvarez, Nathan Gluck, Lior Katz, Karl Heinimann, Carlos A. Vaccaro, Sigve Nakken, Eivind Hovig, Kate Green, Fiona Lalloo, James Hill, Hans F. A. Vasen, Claudia Perne, Reinhard Buettner, Heike Goergens, Elke Holinski-Feder, Monika Morak, Stefanie Holzapfel, Robert Hueneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Juergen Weitz, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Emma J. Crosbie, Marta Pineda, Matilde Navarro, Joan Brunet, Leticia Moreira, Ariadna Sanchez, Miquel Serra-Burriel, Miriam Mints, Revital Kariv, Guy Rosner, Tamara Alejandra Pinero, Walter Hernan Pavicic, Pablo Kalfayan, Sanne W. ten Broeke, Jukka-Pekka Mecklin, Kirsi Pylvanainen, Laura Renkonen-Sinisalo, Anna Lepisto, Paivi Peltomaki, John L. Hopper, Aung Ko Win, Daniel D. Buchanan, Noralane M. Lindor, Steven Gallinger, Loic Le Marchand, Polly A. Newcomb, Jane C. Figueiredo, Stephen N. Thibodeau, Christina Therkildsen, Thomas V. O. Hansen, Lars Lindberg, Einar Andreas Rodland, Florencia Neffa, Patricia Esperon, Douglas Tjandra, Gabriela Moslein, Toni T. Seppala, Pal Moller
Summary: The study aimed to determine the cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Results showed that there were no significant differences in cancer incidence between the two groups, indicating a similar relationship between cancer occurrence and truncating versus missense or aberrant splicing pathogenic variants in Lynch syndrome carriers.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Oncology
Annukka Pasanen, Mikko Loukovaara, Elina Kaikkonen, Alisa Olkinuora, Kirsi Pylvaenaeinen, Pia Alhopuro, Paeivi Peltomaeki, Jukka-Pekka Mecklin, Ralf Buetzow
Summary: International guidelines recommend universal screening of endometrial carcinoma patients for Lynch syndrome. This study found that limiting methylation testing to patients under 65 years would reduce the testing effort while maintaining a low false negative rate.
Review
Oncology
Julie Leclerc, Catherine Vermaut, Marie-Pierre Buisine
Summary: Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors, but it is not exclusive to LS, as most MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Advances in diagnostic and screening strategies have evolved in recent years, focusing on identifying LS patients and distinguishing LS-related from sporadic MSI tumors. Discussions on pitfalls associated with current strategies aim to improve LS diagnosis and prevent inappropriate clinical management.
Article
Oncology
Santiago Cabezas-Camarero, Rebeca Perez-Alfayate, Vanesa Garcia-Barberan, Maria Carmen Polidura, Maria Natividad Gomez-Ruiz, Isabel Casado-Farinas, Issa Ahmad Subhi-Issa, Jose Carlos Plaza Hernandez, Pilar Garre, Isabel Diaz-Millan, Pedro Perez-Segura
Summary: Germline replication-repair deficient (gRRD) gliomas are rare and few patients have been treated with immune checkpoint inhibitors (ICIs). Unlike sporadic gliomas, gRRD glioma patients seem to benefit from PD-1 inhibitors, such as nivolumab or pembrolizumab, in terms of durable responses or survival. This study analyzed T-cell quantity and clonarity before and after nivolumab treatment in a Lynch syndrome-associated glioma patient with a germline hMLH1 mutation to understand the role of acquired immunity in gRRD gliomas. The lack of objective response to anti-PD-1 therapy may be explained by the scant T-cell infiltrate, and the change in TCR clonality reflects the molecular heterogeneity in a highly pre-treated disease. A review of the literature on the role of ICIs in sporadic and gRRD gliomas was also conducted.
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
(2022)
Article
Clinical Neurology
Mengqi Zhang, Haojun Yang, Zhuohui Chen, Yishu Fan, Xinhang Hu, Weiping Liu
Summary: Lynch syndrome is an autosomal dominant inherited disease caused by mutations in MMR genes, increasing the risk of various malignant neoplasms among family members. Patients with these cancers may have synchronous and metachronous tumors simultaneously.
NEUROLOGICAL SCIENCES
(2021)
Review
Oncology
Alan Hodges, Kai Sun, Tiffany G. Sheu, Eric H. Bernicker
Summary: This article presents a case of a 62-year-old Vietnamese woman with Lynch syndrome who developed lung adenocarcinoma with EGFR L858R mutation. The case highlights the complex interplay between genetic cancer predisposition syndromes and spontaneous driver mutations in the disease course and subsequent tumor management.
FRONTIERS IN ONCOLOGY
(2023)
Article
Oncology
Toni T. Seppala, Mev Dominguez-Valentin, Emma J. Crosbie, Christoph Engel, Stefan Aretz, Finlay Macrae, Ingrid Winship, Gabriel Capella, Huw Thomas, Eivind Hovig, Maartje Nielsen, Rolf H. Sijmons, Lucio Bertario, Bernardo Bonanni, Maria G. Tibiletti, Giulia M. Cavestro, Miriam Mints, Nathan Gluck, Lior Katz, Karl Heinimann, Carlos A. Vaccaro, Kate Green, Fiona Lalloo, James Hill, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Hans-Georg Strauss, Johanna Tecklenburg, Elke Holinski-Feder, Verena Steinke-Lange, Jukka-Pekka Mecklin, John-Paul Plazzer, Marta Pineda, Matilde Navarro, Joan B. Vida, Revital Kariv, Guy Rosner, Tamara A. Pinero, Walter Pavicic, Pablo Kalfayan, Sanne W. Ten Broeke, Mark A. Jenkins, Lone Sunde, Inge Bernstein, John Burn, Marc Greenblatt, Wouter H. de Vos Tot Nederveen Cappel, Adriana Della Valle, Francisco Lopez-Koestner, Karin Alvarez, Reinhard Buettner, Heike Goergens, Monika Morak, Stefanie Holzapfel, Robert Hueneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Silke Redler, Jurgen Weitz, Kirsi Pylvaenaeinen, Laura Renkonen-Sinisalo, Anna Lepisto, John L. Hopper, Aung K. Win, Noralane M. Lindor, Steven Gallinger, Loic Le Marchand, Polly A. Newcomb, Jane C. Figueiredo, Stephen N. Thibodeau, Christina Therkildsen, Karin A. W. Wadt, Marian J. E. Mourits, Zohreh Ketabi, Oliver G. Denton, Einar A. Rodland, Hans Vasen, Florencia Neffa, Patricia Esperon, Douglas Tjandra, Gabriela Moeslein, Erik Rokkones, Julian R. Sampson, D. G. Evans, Pal Moller
Summary: The uptake of risk-reducing surgery before the age of 50 was low among carriers of pathogenic MMR variants, and these surgeries were rarely performed in conjunction with colorectal cancer surgery. The alignment of risk-reducing surgery uptake with gene-and age-associated risk estimates for endometrial or ovarian cancer was poor, highlighting a need for better decision-making processes in opting for or against risk-reducing surgery.
EUROPEAN JOURNAL OF CANCER
(2021)
Article
Oncology
Yoland Antill, Daniel D. Buchanan, Clare L. Scott
Summary: Endometrial cancer patients with Lynch gene or POLE/POLD1 gene mutations are more likely to respond well to immune therapy, while those with silencing of the MLH1 gene may not be as responsive. Combination therapies may be important to consider for these patients.
Article
Genetics & Heredity
Kul S. Shrestha, Elli-Mari Aska, Minna M. Tuominen, Liisa Kauppi
Summary: Tumors of LS patients display high levels of MSI due to complete loss of MMR, especially in the GI tract. Research found that MLH1 expression levels are particularly labile in the intestine of Mlh1(+/-) mice, giving rise to tissue-specific MSI long before neoplasia, which may also operate in the human GI epithelium, explaining the wide range in age-of-onset of LS-associated tumorigenesis.
Article
Oncology
Jihoon E. Joo, Khalid Mahmood, Romy Walker, Peter Georgeson, Ida Candiloro, Mark Clendenning, Julia Como, Sharelle Joseland, Susan Preston, Lise Graversen, Mathilda Wilding, Michael Field, Michelle Lemon, Janette Wakeling, Helen Marfan, Rachel Susman, Joanne Isbister, Emma Edwards, Michelle Bowman, Judy Kirk, Emilia Ip, Lynne McKay, Yoland Antill, John L. Hopper, Alex Boussioutas, Finlay A. Macrae, Alexander Dobrovic, Mark A. Jenkins, Christophe Rosty, Ingrid M. Winship, Daniel D. Buchanan
Summary: MLH1 epimutation can cause colorectal cancer, and it can be classified into germline MLH1 promoter variants and MLH1 methylated early-onset CRCs based on tumour molecular profiles. Genome-wide DNA methylation and somatic mutational profiles were compared between different types of MLH1 epimutation CRCs and reference CRCs. Mosaic MLH1 methylation can be detected in blood, normal mucosa, and buccal DNA using methylation-sensitive ddPCR.
CLINICAL EPIGENETICS
(2023)
Article
Genetics & Heredity
Ileana Wanda Carnevali, Giulia Cini, Laura Libera, Nora Sahnane, Sofia Facchi, Alessandra Viel, Fausto Sessa, Maria Grazia Tibiletti, Paolo Cinelli
Summary: MLH1 hypermethylation is not exclusively a sporadic cancer mechanism, as a significant number of LS-related cancers also exhibit MLH1 hypermethylation. Current flow charts for universal LS screening should include MLH1 methylation to be applied, taking into account a patient's family and personal history.
Article
Multidisciplinary Sciences
James London, Juana Martin-Lopez, Inho Yang, Jiaquan Liu, Jong-Bong Lee, Richard Fishel
Summary: The study reveals that HsMSH2-HsMSH6 serves as a platform for the formation of a stable sliding clamp by HsMLH1-HsPMS2 on mismatched DNA. This mechanism solves an operational puzzle in MMR and can predict the distribution of clinically relevant HsMLH1 missense mutations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Zachary P. Schwartz, Andrew J. Li, Christine S. Walsh, B. J. Rimel, Monica M. Alvarado, Scott E. Lentz, Ilana Cass
Summary: This study aimed to investigate the practice patterns and frequency of occult gynecologic cancers in women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes who underwent risk-reducing bilateral salpingo-oophorectomy (RRSO). The results showed no cases of occult ovarian or fallopian tube cancer in both groups, but 2 patients (3%) in the Lynch group had occult endometrial cancer. The use of hormone replacement therapy (HRT) was rare despite reported menopausal symptoms.
GYNECOLOGIC ONCOLOGY
(2023)
Article
Medicine, Research & Experimental
Romy Walker, Khalid E. Mahmood, Jihoon Joo, Mark Clendenning, Peter Georgeson, Julia Como, Sharelle G. Joseland, Susan Preston, Yoland Antill, Rachel Austin, Alex Boussioutas, Michelle Bowman, Jo Burke, Ainsley Campbell, Simin Daneshvar, Emma Edwards, Margaret Gleeson, Annabel T. Goodwin, Marion Harris, Alex Henderson, Megan L. Higgins, John A. Hopper, Ryan Hutchinson, Emilia Ip, Joanne Isbister, Kais Kasem, Helen Marfan, Di Milnes, Annabelle Ng, Cassandra Nichols, Shona O'Connell, Nicholas J. Pachter, Bernard Pope, Nicola Poplawski, Abiramy Ragunathan, Courtney Smyth, Allan Spigelman, Kirsty Storey, Rachel A. Susman, Jessica Taylor, Linda Warwick, Mathilda Wilding, Rachel K. Williams, Aung D. Win, Michael A. Walsh, Finlay A. Macrae, Mark Jenkins, Christophe M. Rosty, Ingrid D. Winship, Daniel Buchanan
Summary: Routine screening of tumors for DNA mismatch repair deficiency (dMMR) in certain cancers leads to unresolved cases classified as suspected Lynch syndrome (SLS). In this study, targeted panel sequencing was performed on SLS tumors to assess their MMR status and identify gene variants. The findings support the use of tumor sequencing and alternate MLH1 methylation assays in clinical diagnostics to provide more appropriate recommendations for surveillance and screening.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Anne Ackermann, Christopher Schrecker, Dimitra Bon, Nicolaus Friedrichs, Katrin Bankov, Peter Wild, Guido Plotz, Stefan Zeuzem, Eva Herrmann, Martin-Leo Hansmann, Angela Brieger
Article
Pathology
Maribel Gonzalez-Acosta, Inga Hinrichsen, Anna Fernandez, Conxi Lazaro, Marta Pineda, Guido Plotz, Gabriel Capella
JOURNAL OF MOLECULAR DIAGNOSTICS
(2020)
Article
Oncology
Anne Ackermann, Barbara Lafferton, Guido Plotz, Stefan Zeuzem, Angela Brieger
INTERNATIONAL JOURNAL OF ONCOLOGY
(2020)
Review
Oncology
Mef Nilbert, Linda Aagaard Thomsen, Jens Winther Jensen, Henrik Moller, Michael Borre, Arvid Widenlou Nordmark, Mats Lambe, Helena Brandstrom, Hartwig Korner, Bjorn Moller, Giske Ursin
Article
Multidisciplinary Sciences
Guido Plotz, Laura A. Lopez-Garcia, Angela Brieger, Stefan Zeuzem, Ricardo M. Biondi
Article
Multidisciplinary Sciences
Clemens Hoeflich, Angela Brieger, Stefan Zeuzem, Guido Plotz
Summary: The study revealed that single-nucleotide alterations of conserved bases in the core promoter of the ATP7B gene have a moderate impact on transcriptional activity, with few clearly pathogenic mutations reported. Two frequent polymorphisms in the core promoter were identified, but they did not affect copper metabolism parameters in healthy individuals, indicating that genetic variations in this region do not significantly contribute to Wilson disease pathogenesis.
SCIENTIFIC REPORTS
(2021)
Article
Health Care Sciences & Services
Jessica Wihl, Linn Rosell, Kirsten Frederiksen, Sara Kinhult, Gert Lindell, Mef Nilbert
Summary: The study found that in cancer care, although significant resources are spent on MDT meetings, team members' contributions are unbalanced and patient-related information provision is limited. Leadership skills may positively influence the quality of case presentations.
JOURNAL OF MULTIDISCIPLINARY HEALTHCARE
(2021)
Article
Oncology
Katharina Ulreich, May-Britt Firnau, Nina Tagscherer, Sandra Beyer, Anne Ackermann, Guido Plotz, Angela Brieger
Summary: High nuclear/cytoplasmic expression of CK2 alpha in colorectal cancer correlates with enhanced MLH1 phosphorylation and may cause increased mutation rates. These findings suggest important new therapeutic targets.
Article
Oncology
Rikke Langballe, Mef Christina Nilbert, Jane Christensen, Anne Julie Tybjerg, Pernille Envold Bidstrup
Summary: This study aimed to examine the association between preferred data presentation format and the interpretation of quality data among cancer patients and relatives. The results showed that longer education and the presentation of data in a league table format were associated with correct interpretation of quality data.
Editorial Material
Oncology
Mef Nilbert
Article
Biochemistry & Molecular Biology
Karla Wolf, Jan Kosinski, Toby J. Gibson, Nicole Wesch, Volker Doetsch, Maurizio Genuardi, Emanuela Lucci Cordisco, Stefan Zeuzem, Angela Brieger, Guido Plotz
Summary: DNA mismatch repair is crucial for correcting replication errors, and mutations in the MLH1 gene can lead to Lynch syndrome. The non-conserved linker region of MLH1 was previously thought to be flexible and non-pathogenic, but our study identified a conserved motif (ConMot) within this region that is essential for mismatch repair activity. Mutations in ConMot can cause Lynch syndrome, but the defect can be overcome by adding a small peptide containing the deleted sequence.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Oncology
Helena Nystrom, Mats Jonsson, Mef Nilbert, Ana Carneiro
Summary: Immunological landscape of soft tissue sarcoma was characterized, revealing a predominance of tumor-infiltrating macrophages over lymphocytes. CD163-positive macrophages were associated with tumor necrosis and predicted an increased risk of metastasis. CD20-positive B cells were scarce in soft tissue sarcoma and correlated with improved overall survival.
Letter
Oncology
Mef Nilbert, Jakob Eberhard, Jenny Engdahl Severin, Marcus Edelhamre, Filip Torle, Dejan Korkocic, Fredrik Jorgren
Article
Oncology
Christopher Schrecker, Sophia Behrens, Rebecca Schoenherr, Anne Ackermann, Daniel Pauli, Guido Plotz, Stefan Zeuzem, Angela Brieger
Summary: This study highlights the significance of SPTAN1 in CRC development and chemotherapy response, identifying it as a potential biomarker for predicting patient survival and treatment outcomes.
Article
Oncology
Jonas Henn, Isabel Spier, Ronja S. Adam, Stefanie Holzapfel, Siegfried Uhlhaas, Katrin Kayser, Guido Plotz, Sophia Peters, Stefan Aretz
HEREDITARY CANCER IN CLINICAL PRACTICE
(2019)