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1. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

Author

DePaolo, R.W., Abadie, V., Tang, F., Fehlner-Peach, H., Hall, J.A., Wang, W., Marietta, E.V., Kasarda, D.D., Waldmann, T.A., Murray, J.A., Semrad, C., Kupfer, S.S., Belkaid, Y., Guandalini, S., and Jabri, B.

Subjects
Tretinoin -- Health aspects -- Physiological aspects, Immune response -- Research, Antigens -- Health aspects -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens (1,2). A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat (3). The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses (4-6). Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients (3,7), retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens., Induction of regulatory intestinal responses to oral antigens prevents the subsequent development of systemic T-helper type-1 ([T.sub.H]1) responses to those antigens, a phenomenon referred to as oral tolerance (2). An [...]

Published
2011
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2. Hereditary diffuse gastric cancer: updated clinical practice guidelines

Author

Blair, V.R., McLeod, M., Carneiro, F., Coit, D.G., D'Addario, J.L., Dieren, J.M. van, Harris, K.L., Hoogerbrugge, N., Oliveira, C. de, Post, R.S. van der, Arnold, J., Benusiglio, P.R., Bisseling, T.M., Boussioutas, A., Cats, A., Charlton, A., Schreiber, K.E., Davis, J.L., Pietro, M.D., Fitzgerald, R.C., Ford, J.M., Gamet, K., Gullo, I., Hardwick, R.H., Huntsman, D.G., Kaurah, P., Kupfer, S.S., Latchford, A., Mansfield, P.F., Nakajima, T., Parry, S., Rossaak, J., Sugimura, H., Svrcek, M., Tischkowitz, M., Ushijima, T., Yamada, H., Yang, H.Keri, Claydon, A., Figueiredo, J., Paringatai, K., Seruca, R., Bougen-Zhukov, N., Brew, T., Busija, S., Carneiro, P., DeGregorio, L., Fisher, H., Gardner, E., Godwin, T.D., Holm, K.N., Humar, B., Lintott, C.J., Monroe, E.C., Muller, M.D., Norero, E., Nouri, Y., Paredes, J., Sanches, J.M., Schulpen, E., Ribeiro, A.S., Sporle, A., Whitworth, J., Zhang, L., Reeve, A.E., Guilford, P., Blair, V.R., McLeod, M., Carneiro, F., Coit, D.G., D'Addario, J.L., Dieren, J.M. van, Harris, K.L., Hoogerbrugge, N., Oliveira, C. de, Post, R.S. van der, Arnold, J., Benusiglio, P.R., Bisseling, T.M., Boussioutas, A., Cats, A., Charlton, A., Schreiber, K.E., Davis, J.L., Pietro, M.D., Fitzgerald, R.C., Ford, J.M., Gamet, K., Gullo, I., Hardwick, R.H., Huntsman, D.G., Kaurah, P., Kupfer, S.S., Latchford, A., Mansfield, P.F., Nakajima, T., Parry, S., Rossaak, J., Sugimura, H., Svrcek, M., Tischkowitz, M., Ushijima, T., Yamada, H., Yang, H.Keri, Claydon, A., Figueiredo, J., Paringatai, K., Seruca, R., Bougen-Zhukov, N., Brew, T., Busija, S., Carneiro, P., DeGregorio, L., Fisher, H., Gardner, E., Godwin, T.D., Holm, K.N., Humar, B., Lintott, C.J., Monroe, E.C., Muller, M.D., Norero, E., Nouri, Y., Paredes, J., Sanches, J.M., Schulpen, E., Ribeiro, A.S., Sporle, A., Whitworth, J., Zhang, L., Reeve, A.E., and Guilford, P.

Abstract

Contains fulltext : 225261.pdf (Publisher’s version ) (Closed access), Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Published
2020

3. Chronic Inflammation Permanently Reshapes Tissue-Resident Immunity in Celiac Disease

Author

Mayassi, T., Ladell, K., Gudjonson, H., McLaren, J.E., Shaw, D.G., Tran, M.T., Rokicka, J.J., Lawrence, I., Grenier, J.C., Unen, V. van, Ciszewski, C., Dimaano, M., Sayegh, H.E., Kumar, V., Wijmenga, C., Green, P.H., Gokhale, R., Jericho, H., Semrad, C.E., Guandalini, S., Dinner, A.R., Kupfer, S.S., Reid, H.H., Barreiro, L.B., Rossjohn, J., Price, D.A., Jabri, B., Mayassi, T., Ladell, K., Gudjonson, H., McLaren, J.E., Shaw, D.G., Tran, M.T., Rokicka, J.J., Lawrence, I., Grenier, J.C., Unen, V. van, Ciszewski, C., Dimaano, M., Sayegh, H.E., Kumar, V., Wijmenga, C., Green, P.H., Gokhale, R., Jericho, H., Semrad, C.E., Guandalini, S., Dinner, A.R., Kupfer, S.S., Reid, H.H., Barreiro, L.B., Rossjohn, J., Price, D.A., and Jabri, B.

Abstract

Contains fulltext : 215586.pdf (publisher's version ) (Open Access), Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vgamma4(+)/Vdelta1(+) intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vgamma4(+)/Vdelta1(+) IELs was accompanied by the expansion of gluten-sensitive, interferon-gamma-producing Vdelta1(+) IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vgamma4(+)/Vdelta1(+) subset among TCRgammadelta(+) IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRgammadelta(+) IEL compartment in CeD. VIDEO ABSTRACT.

Published
2019

4. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease

Author

Bouziat, R. (Romain), Hinterleitner, R. (Reinhard), Brown, J.J. (Judy J.), Stencel-Baerenwald, J.E. (Jennifer E.), Ikizler, M. (Mine), Mayassi, T. (Toufic), Meisel, M. (Marlies), Kim, S.M. (Sangman M.), Discepolo, V. (Valentina), Pruijssers, A.J. (Andrea J.), Ernest, J.D. (Jordan D.), Iskarpatyoti, J.A. (Jason A.), Costes, L.M.M. (Léa), Lawrence, I. (Ian), Palanski, B.A. (Brad A.), Varma, M. (Mukund), Zurenski, M.A. (Matthew A.), Khomandiak, S. (Solomiia), McAllister, N. (Nicole), Aravamudhan, P. (Pavithra), Boehme, K.W. (Karl W.), Hu, F. (Fengling), Samsom, J.N. (Janneke), Reinecker, H.-C. (Hans-Christian), Kupfer, S.S. (Sonia S.), Guandalini, S. (Stefano), Semrad, C.E. (Carol E.), Abadie, V. (Valérie), Khosla, C. (Chaitan), Barreiro, L.B. (Luis B.), Xavier, R.J. (Ramnik J.), Ng, A. (Aylwin), Dermody, T.S. (Terence S.), Jabri, B. (Bana), Bouziat, R. (Romain), Hinterleitner, R. (Reinhard), Brown, J.J. (Judy J.), Stencel-Baerenwald, J.E. (Jennifer E.), Ikizler, M. (Mine), Mayassi, T. (Toufic), Meisel, M. (Marlies), Kim, S.M. (Sangman M.), Discepolo, V. (Valentina), Pruijssers, A.J. (Andrea J.), Ernest, J.D. (Jordan D.), Iskarpatyoti, J.A. (Jason A.), Costes, L.M.M. (Léa), Lawrence, I. (Ian), Palanski, B.A. (Brad A.), Varma, M. (Mukund), Zurenski, M.A. (Matthew A.), Khomandiak, S. (Solomiia), McAllister, N. (Nicole), Aravamudhan, P. (Pavithra), Boehme, K.W. (Karl W.), Hu, F. (Fengling), Samsom, J.N. (Janneke), Reinecker, H.-C. (Hans-Christian), Kupfer, S.S. (Sonia S.), Guandalini, S. (Stefano), Semrad, C.E. (Carol E.), Abadie, V. (Valérie), Khosla, C. (Chaitan), Barreiro, L.B. (Luis B.), Xavier, R.J. (Ramnik J.), Ng, A. (Aylwin), Dermody, T.S. (Terence S.), and Jabri, B. (Bana)

Abstract

Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.

Published
2017
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6. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author

Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.

Subjects
0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Published
2021
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