Citations 2
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
Dominguez–Valentin, Mev , Plazzer, John‐Paul , Sampson, Julian R. , Engel, Christoph , Aretz, Stefan , Sunde, Lone , Capellá, Gabriel , Balaguer, Francesc , Thomas, Huw , Evans, D. Gareth , Burn, John , Greenblatt, Marc S. , Cappel, Wouter H. de Vos tot Nederveen , Nielsen, Maartje , Bonanni, Bernardo , Tibiletti, Maria Grazia , Lindblom, Annika , Valle, Adriana Della , López-Köstner, Francisco, Gluck, Nathan , Katz, Lior H. , Heinimann, Karl , Vaccaro, Carlos , Nakken, Sigve , Hovig, Eivind , Green, Kate, Lalloo, Fiona, Hill, James , Perne, Claudia , Görgens, Heike, Holinski‐Feder, Elke , Holzapfel, Stefanie, Hüneburg, Robert , Doeberitz, Magnus von Knebel , Loeffler, Markus , Rahner, Nils, Steinke‐Lange, Verena , Schmiegel, Wolff , Vangala, Deepak , Crosbie, Emma J. , Pineda, Marta , Navarro, Matilde, Brunet, Joan , Moreira, Leticia , Sánchez, Ariadna , Serra‐Burriel, Miquel , Mints, Miriam, Kariv, Revital , Rosner, Guy , Piñero, Tamara Alejandra , Pavicic, Walter , Kalfayan, Pablo, Broeke, Sanne W. ten , Mecklin, Jukka‐Pekka , Pylvänäinen, Kirsi , Renkonen‐Sinisalo, Laura , Lepistö, Anna , Peltomäki, Païvi , Win, Aung Ko , Buchanan, Daniel D. , Lindor, Noralane M. , Gallinger, Steven , Marchand, Loı̈c Le , Figueiredo, Jane C. , Thibodeau, Stephen N. , Hansen, Thomas van Overeem , Lindberg, Lars Joachim , Rødland, Einar Andreas , Neffa, Florencia , Esperón, Patricia, Tjandra, Douglas , Seppälä, Toni T. , Møller, Pål , Capella, Gabriel , Balaguer, Francesc , Evans, D Gareth , Burn, John , de Vos Tot Nederveen Cappel, Wouter H , Nielsen, Maartje , Bonanni, Bernardo , Gluck, Nathan , Vaccaro, Carlos A , Nakken, Sigve , Hovig, Eivind , Hüneburg, Robert , Steinke-Lange, Verena , Vangala, Deepak , Crosbie, Emma J , Pineda, Marta , Brunet, Joan , Moreira, Leticia , Sánchez, Ariadna , Pavicic, Walter Hernán , Broeke, Sanne W Ten , Pylvänäinen, Kirsi , Win, Aung K , Buchanan, Daniel D , Marchand, Loïc Le , Rødland, Einar Andreas , Esperon, Patricia , Tjandra, Douglas , Seppälä, Toni T , Sunde, Lone , Engel, Christoph , Hansen, Thomas van Overeem , Lindblom, Annika , Jenkins, Mark A. , Bernstein, Inge , Macrae, Finlay , Winship, Ingrid , Sijmons, Rolf H. , Bertario, Lucio , Cavestro, Giulia Martina , Álvarez, Karin , Vasen, Hans F. A. , Büttner, Reinhard , Morak, Monika , Weitz, Jürgen , Mints, Miriam , Hopper, John L. , Newcomb, Polly A. , Therkildsen, Christina , Möslein, Gabriela
Journal of Clinical Medicine | June 28, 2021 | Volume: 10 | Issue: 13 | Pages: 2856
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.
Activated Eosinophils Exert Antitumorigenic Activities in Colorectal Cancer
Reichman, Hadar , Itan, Michal, Rozenberg, Perri, Yarmolovski, Tal, Brazowski, Eli, Varol, Chen , Shapira, Shiran , Arber, Nadir , Qimron, Udi , Karo‐Atar, Danielle , Lee, James J. , Munitz, Ariel , Munitz, Ariel , Gluck, Nathan
Cancer Immunology Research | January 21, 2019 | Volume: 7 | Issue: 3 | Pages: 388-400
Abstract Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow–derived cells that have been largely studied in the context of allergic diseases and parasite infections. Although tumor-associated eosinophilia has been described in various solid tumors including colorectal cancer, knowledge is still missing regarding eosinophil activities and even the basic question of whether the TME promotes eosinophil recruitment without additional manipulation (e.g., immunotherapy) is unclear. Herein, we report that eosinophils are recruited into developing tumors during induction of inflammation-induced colorectal cancer and in mice with the Apcmin/+ genotype, which develop spontaneous intestinal adenomas. Using adoptive transfer and cytokine neutralization experiments, we demonstrate that the TME supported prolonged eosinophil survival independent of IL5, an eosinophil survival cytokine. Tumor-infiltrating eosinophils consisted of degranulating eosinophils and were essential for tumor rejection independently of CD8+ T cells. Transcriptome and proteomic analysis revealed an IFNγ-linked signature for intratumoral eosinophils that was different from that of macrophages. Our data establish antitumorigenic roles for eosinophils in colorectal cancer. These findings may facilitate the development of pharmacologic treatments that could unleash antitumor responses by eosinophils, especially in colorectal cancer patients displaying eosinophilia.