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1. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author

Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., Jenkins, M.A., Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., and Jenkins, M.A.

Abstract

Item does not contain fulltext

Published
2022

2. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., Voer, R.M. de, Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., and Voer, R.M. de

Abstract

Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access), We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

3. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Author

Prentzell, M.T. (Mirja Tamara), Rehbein, U. (Ulrike), Cadena Sandoval, M. (Marti), De Meulemeester, A.-S. (Ann-Sofie), Baumeister, R. (Ralf), Brohée, L. (Laura), Berdel, B. (Bianca), Bockwoldt, M. (Mathias), Carroll, B. (Bernadette), Chowdhury, S.R. (Suvagata Roy), Deimling, A. (Andreas) von, Demetriades, C. (Constantinos), Figlia, G. (Gianluca), de Araujo, M.E.G. (Mariana Eca Guimaraes), Heberle, A.M. (Alexander M.), Heiland, I. (Ines), Holzwarth, B. (Birgit), Huber, L.A. (Lukas A.), Jaworski, J. (Jacek), Kedra, M. (Magdalena), Kern, K. (Katharina), Kopach, A. (Andrii), Korolchuk, V.I. (Viktor I.), van 't Land-Kuper, I. (Ineke), Macias, M. (Matylda), Nellist, M.D. (Mark), Palm, W. (Wilhelm), Pusch, S. (Stefan), Ramos Pittol, J.M. (Jose Miguel), Reil, M. (Michèle), Reintjes, A. (Anja), Reuter, F. (Friederike), Sampson, J.R. (Julian R.), Scheldeman, C. (Chloë), Siekierska, A. (Aleksandra), Stefan, E. (Eduard), Teleman, A.A. (Aurelio A.), Thomas, L.E. (Laura E.), Torres-Quesada, O. (Omar), Trump, S. (Saskia), West, H.D. (Hannah D.), de Witte, P. (Peter), Woltering, S. (Sandra), Yordanov, T.E. (Teodor E.), Zmorzynska, J. (Justyna), Opitz, C.A. (Christiane A.), Thedieck, K. (Kathrin), Prentzell, M.T. (Mirja Tamara), Rehbein, U. (Ulrike), Cadena Sandoval, M. (Marti), De Meulemeester, A.-S. (Ann-Sofie), Baumeister, R. (Ralf), Brohée, L. (Laura), Berdel, B. (Bianca), Bockwoldt, M. (Mathias), Carroll, B. (Bernadette), Chowdhury, S.R. (Suvagata Roy), Deimling, A. (Andreas) von, Demetriades, C. (Constantinos), Figlia, G. (Gianluca), de Araujo, M.E.G. (Mariana Eca Guimaraes), Heberle, A.M. (Alexander M.), Heiland, I. (Ines), Holzwarth, B. (Birgit), Huber, L.A. (Lukas A.), Jaworski, J. (Jacek), Kedra, M. (Magdalena), Kern, K. (Katharina), Kopach, A. (Andrii), Korolchuk, V.I. (Viktor I.), van 't Land-Kuper, I. (Ineke), Macias, M. (Matylda), Nellist, M.D. (Mark), Palm, W. (Wilhelm), Pusch, S. (Stefan), Ramos Pittol, J.M. (Jose Miguel), Reil, M. (Michèle), Reintjes, A. (Anja), Reuter, F. (Friederike), Sampson, J.R. (Julian R.), Scheldeman, C. (Chloë), Siekierska, A. (Aleksandra), Stefan, E. (Eduard), Teleman, A.A. (Aurelio A.), Thomas, L.E. (Laura E.), Torres-Quesada, O. (Omar), Trump, S. (Saskia), West, H.D. (Hannah D.), de Witte, P. (Peter), Woltering, S. (Sandra), Yordanov, T.E. (Teodor E.), Zmorzynska, J. (Justyna), Opitz, C.A. (Christiane A.), and Thedieck, K. (Kathrin)

Abstract

Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.

Published
2021
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4. European guidelines from the EHTG and ESCP for Lynch syndrome : an updated third edition of the Mallorca guidelines based on gene and gender

Author

Seppälä, T.T., Latchford, A., Negoi, I., Sampaio Soares, A., Jimenez-Rodriguez, R., Sánchez-Guillén, L., Evans, D.G., Ryan, N., Crosbie, E.J., Dominguez-Valentin, M., Burn, J., Kloor, M., von Knebel Doeberitz, M., van Duijnhoven, F.J.B., Quirke, P., Sampson, J.R., Møller, P., Möslein, G., Seppälä, T.T., Latchford, A., Negoi, I., Sampaio Soares, A., Jimenez-Rodriguez, R., Sánchez-Guillén, L., Evans, D.G., Ryan, N., Crosbie, E.J., Dominguez-Valentin, M., Burn, J., Kloor, M., von Knebel Doeberitz, M., van Duijnhoven, F.J.B., Quirke, P., Sampson, J.R., Møller, P., and Möslein, G.

Abstract

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. Methods: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. Results: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. Conclusion: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.

Published
2021

5. Peutz-Jeghers syndrome: a systematic review and recommendations for management

Author

Beggs, A.D., Latchford, A.R., Vasen, H.F.A., Moslein, G., Alonso, A., Aretz, S., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Friedl, W., Moller, P., Hes, F.J., Jarvinen, H., Mecklin, J.-P., Nagengast, F.M., Parc, Y., Phillips, R.K.S., Hyer, W., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J.W., Wijnen, J.T., Clark, S.K., and Hodgson, S.V.

Subjects
Peutz-Jeghers syndrome -- Diagnosis, Peutz-Jeghers syndrome -- Care and treatment, Peutz-Jeghers syndrome -- Development and progression, Peutz-Jeghers syndrome -- Risk factors, Medical literature -- Analysis, Health
Published
2010

6. Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3

Author

Dallosso, A.R., Dolwani, S., Jones, N., Jones, S., Colley, J., Maynard, J., Idziaszczyk, S., Humphreys, V., Arnold, J., Donaldson, A., Eccles, D., Ellis, A., Evans, D.G., Frayling, I.M., Hes, F.J., Houlston, R.S., Maher, E.R., Nielsen, M., Parry, S., Tyler, E., Moskvina, V., Cheadle, J.P., and Sampson, J.R.

Subjects
Colorectal cancer -- Genetic aspects, Colorectal cancer -- Development and progression, Colorectal cancer -- Research, Colorectal cancer -- Risk factors, Gene mutations -- Analysis, Adenoma -- Genetic aspects, Adenoma -- Risk factors, Adenoma -- Research, Health
Published
2008

7. Guidelines for the clinical management of familial adenomatous polyposis (FAP)

Author

Vasen, H.F.A., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Jarvinen, H., Mecklin, J.-P., Moller, P., Myrhoi, T., Nagengast, F.M., Parc, Y., Phillips, R., Clark, S.K., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J.W., and Wijnen, J.

Subjects
Polyposis, Familial -- Care and treatment, Practice guidelines (Medicine) -- Evaluation, Colorectal cancer -- Risk factors, Colorectal cancer -- Prevention, Health
Published
2008

8. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer)

Author

Vasen, H.F.A., Moslein, G., Alonso, A., Bernstein, I., Bertario, L., Blanco, I., Burn, J., Capella, G., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Mecklin, J.-P., Moller, P., Nagengast, F., Parc, Y., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., and Wijnen, J.

Subjects
Colorectal cancer -- Care and treatment, Colorectal cancer -- Genetic aspects, Practice guidelines (Medicine) -- Evaluation, Cancer -- Diagnosis, Cancer -- Standards, Health
Published
2007

9. Genotype and psychological phenotype in tuberous sclerosis

Author

Lewis, J.C., Thomas, H.V., Murphy, K.C., and Sampson, J.R.

Subjects
Health
Abstract

J Med Genet 2004;41:203-207. doi: 10.1136/jmg.2003.012757 Tuberous sclerosis complex (TSC, MIM 191090 and 191100) is an autosomal dominant, multisystem disorder characterised by the development of a variety of hamartomatous growths. [...]

Published
2004

10. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). (Letter to JMG)

Author

Maher, E.R., Brueton, L.A., Bowdin, S.C., Luharia, A., Cooper, W., Cole, T.R., Macdonald, F., Sampson, J.R., Barratt, C.L., Reik, W., and Hawkins, M.M.

Subjects
Birth defects -- Research -- Genetic aspects, Beckwith-Wiedemann syndrome -- Genetic aspects -- Research, Reproductive technology -- Health aspects -- Statistics -- Usage -- Research, Health
Abstract

Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epimutations affecting imprinted genes on chromosome 11p15.5. (1) The classical clinical features of BWS are macroglossia, pre- and/or [...]

Published
2003

16. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

Author

Vasen, H.F.A., Blanco, I., Aktan-Collan, K., Gopie, J.P., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I.M., Genuardi, M., Heinimann, K., Hes, F.J., Hodgson, S.V., Karagiannis, J.A., Lalloo, F., Lindblom, A., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Leon, M.P. de, Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Sijmons, R.H., Tejpar, S., Thomas, H.J.W., Rahner, N., Wijnen, J.T., Jarvinen, H.J., Moslein, G., Mallorca Grp, Clinical sciences, and Medical Genetics

Subjects
Male, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Public health surveillance, QUALITY-OF-LIFE, Risk Factors, Neoplasms, Medicine, Public Health Surveillance, Lynch syndrome (HNPCC, Gastroenterology, NONPOLYPOSIS COLORECTAL-CANCER, MSH2 MUTATION CARRIERS, Cost-effectiveness analysis, Colonoscopy, Middle Aged, Lynch syndrome, 3. Good health, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Systematic search, Adult, medicine.medical_specialty, MEDLINE, BLADDER-CANCER, COST-EFFECTIVENESS ANALYSIS, guidelines, HNPCC, RC0254, 03 medical and health sciences, Young Adult, Quality of life (healthcare), Translational research [ONCOL 3], Humans, PROPHYLACTIC SALPINGO-OOPHORECTOMY, Aged, Gynecology, business.industry, Endometrial cancer, DRAKE HEALTH REGISTRY, Colonoscopy/standards, ENDOMETRIAL CANCER, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, BODY-MASS INDEX, MSH6, Family medicine, MISMATCH-REPAIR GENES, Colorectal Neoplasms, Hereditary Nonpolyposis/complications, business, Neoplasms/diagnosis
Abstract

Lynch syndrome (LS) is characterised by the\ud development of colorectal cancer, endometrial cancer\ud and various other cancers, and is caused by a mutation\ud in one of the mismatch repair genes: MLH1, MSH2,\ud MSH6 or PMS2. In 2007, a group of European experts\ud (the Mallorca group) published guidelines for the clinical\ud management of LS. Since then substantial new\ud information has become available necessitating an\ud update of the guidelines. In 2011 and 2012 workshops\ud were organised in Palma de Mallorca. A total of 35\ud specialists from 13 countries participated in the\ud meetings. The first step was to formulate important\ud clinical questions. Then a systematic literature search\ud was performed using the Pubmed database and manual\ud searches of relevant articles. During the workshops the\ud outcome of the literature search was discussed in detail.\ud The guidelines described in this paper may be helpful for\ud the appropriate management of families with LS.\ud Prospective controlled studies should be undertaken to\ud improve further the care of these families.

Published
2013

17. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

Author

Vasen, H.F., Blanco, I., Aktan-Collan, K., Gopie, J.P., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I.M., Genuardi, M., Heinimann, K., Hes, F.J., Hodgson, S.V., Karagiannis, J.A., Lalloo, F., Lindblom, A., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Sijmons, R.H., Tejpar, S., Thomas, H.J., Rahner, N., Wijnen, J.T., Jarvinen, H.J., Moslein, G., et al., Vasen, H.F., Blanco, I., Aktan-Collan, K., Gopie, J.P., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I.M., Genuardi, M., Heinimann, K., Hes, F.J., Hodgson, S.V., Karagiannis, J.A., Lalloo, F., Lindblom, A., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Sijmons, R.H., Tejpar, S., Thomas, H.J., Rahner, N., Wijnen, J.T., Jarvinen, H.J., Moslein, G., and et al.

Abstract

Item does not contain fulltext, Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

Published
2013

18. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe.

Author

Vasen, H.F., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Rahner, N., Hes, F.J., Hodgson, S., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J., Wijnen, J., Lubinski, J., Jarvinen, H., Claes, E., Heinimann, K., Karagiannis, J.A., Lindblom, A., Dove-Edwin, I., Muller, H., Vasen, H.F., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Rahner, N., Hes, F.J., Hodgson, S., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J., Wijnen, J., Lubinski, J., Jarvinen, H., Claes, E., Heinimann, K., Karagiannis, J.A., Lindblom, A., Dove-Edwin, I., and Muller, H.

Abstract

1 juni 2010, Item does not contain fulltext, Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify

Published
2010

19. Guidelines for the clinical management of familial adenomatous polyposis (FAP).

Author

Vasen, H.F., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Jarvinen, H., Mecklin, J.P., Moller, P., Myrhoi, T., Nagengast, F.M., Parc, Y., Phillips, R., Clark, S.K., Leon, M.P. de, Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J., Wijnen, J., Vasen, H.F., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Jarvinen, H., Mecklin, J.P., Moller, P., Myrhoi, T., Nagengast, F.M., Parc, Y., Phillips, R., Clark, S.K., Leon, M.P. de, Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J., and Wijnen, J.

Abstract

Item does not contain fulltext, BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Published
2008

20. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer).

Author

Vasen, H.F., Moslein, G., Alonso, A., Bernstein, I., Bertario, L., Blanco, I., Burn, J., Capella, G., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Mecklin, J.P., Moller, P., Nagengast, F.M., Parc, Y., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Wijnen, J., Vasen, H.F., Moslein, G., Alonso, A., Bernstein, I., Bertario, L., Blanco, I., Burn, J., Capella, G., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Mecklin, J.P., Moller, P., Nagengast, F.M., Parc, Y., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., and Wijnen, J.

Abstract

Item does not contain fulltext, Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

Published
2007

21. Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations

Author

Alders, M., primary, Mendola, A., additional, Adès, L., additional, Al Gazali, L., additional, Bellini, C., additional, Dallapiccola, B., additional, Edery, P., additional, Frank, U., additional, Hornshuh, F., additional, Huisman, S.A., additional, Jagadeesh, S., additional, Kayserili, H., additional, Keng, W.T., additional, Lev, D., additional, Prada, C.E., additional, Sampson, J.R., additional, Schmidtke, J., additional, Shashi, V., additional, van Bever, Y., additional, Van der Aa, N., additional, Verhagen, J.M., additional, Verheij, J.B., additional, Vikkula, M., additional, and Hennekam, R.C., additional

Published
2012
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26. Genetic heterogeneity in tuberous sclerosis

Author

Janssen, L.A.J., primary, Sandkuyl, L.A., additional, Merkens, E.C., additional, Maat-Kievit, J.A., additional, Sampson, J.R., additional, Fleury, P., additional, Hennekam, R.C.M., additional, Grosveld, G.C., additional, Lindhout, D., additional, and Halley, D.J.J., additional

Published
1990
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30. Requirements for interactive simulation systems.

Author

Sohnle, R.C., Tartar, J., and Sampson, J.R.

Abstract

The evolution of computer hardware and operating systems has made feasible simulation research which benefits from the many advantages of computing in an interactive environment. A general discussion of modelling considerations and the features of discrete simulation systems is followed by a set of basic requirements for interactive simulation languages and monitors. Systems designed for simulation of particular classes of models are briefly contrasted with more general-purpose systems with respect to flexibility, efficiency, and interactive operation. The interactive capability of the language and the communicative function of the monitor emphasize the importance of coordinated design of these elements. To illustrate the principles presented, ceZZ-space modelling and a recently developed interactive ceZZ- space simulation system are discussed. [ABSTRACT FROM PUBLISHER]

Published
1973
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40. A case of an inversion (18)(q11.2q21.1) associated with juvenile polyposis.

Author

Hill, Clare, Lee-Jones, L., Anderson, C.J., Williams, G.T., Best, J.M., Woodford-Richens, K.L., and Sampson, J.R.

Subjects
SYNDROMES, POLYPS, GENETIC mutation, KARYOTYPES
Abstract

Juvenile polyposis syndrome (JPS) is an autosomal dominant cancer predisposing syndrome. It is genetically heterogenous, and is distinct from Cowden and Bayanyan-Zonana syndromes. Germline mutations in BMPR1A and SMAD4/DPC4 have been identified in patients with JPS; both are components of the TGF beta signalling pathway. Juvenile polyps from carriers of SMAD4 mutations may have a greater malignancy potential than those who do not. A 25 year old male presented with rectal bleeding. Initially twelve polyps were found, three of which were removed and were reported to be adenomatous. Subsequent investigations over several years revealed multiple juvenile polyps and review of the original polypectomy specimens led to their re-classification as juvenile polyps. He also developed numerous subcutaneous angiolipomas and severe asthma. His karyotype was found to be 46XY inv(18)(q11.2q21.1). FISH analysis using PAC probe 224-j-22 which encompasses the 11 exon SMAD4 gene, located at 18q21.1, was disrupted by this inversion. We believe this is the first repod of a visible cytogenetic rearrangement causing JPS. Further work is underway to determine whether inactivation of SMAD4 has played a role in development of his angiolipomas. [ABSTRACT FROM AUTHOR]

Published
2003

41. GERMLINE MUTATIONS IN THE BASE EXCISION REPAIR GENE MYH—A NEW POLYPOSIS DISORDER.

Author

Davies, R., Al-Tassan, N., Jones, S., Chmiel, N.H., Maynard, J., Fleming, N., Livingston, A.L., Williams, G.T., Hodges, A.K., Dolwani, S., David, S.S., Cheadle, J.P., and Sampson, J.R.

Subjects
COLON diseases, POLYPS, ESCHERICHIA coli
Abstract

Background: Multiple colorectal adenoma families have been identified that do not conform to classical FAP or HNPCC. We studied the somatic mutation profile of adenomas from affected siblings in one such family to establish the nature of their inherited defect. Method: Family 'N' consisted of seven siblings, 1 with colon cancer at the age of 46, which was associated with adenomas. Screening his siblings identified two with approximately 50 adenomatous colorectal polyps at the ages of 59 and 55, respectively. 11 tumours from these 3 affected siblings were screened for somatic APC gene mutations. Results: 18 somatic inactivating APC gene mutations were identified in these 11 tumours. Remarkably, 15 of these were G:C→T:A transversions. This type of mutation was significantly over-represented when compared to somatic mutations so far described in sporadic and FAP associated adenomas/adenocarcinomas. Similar mutations had previously been reported in DNA repair deficient yeast and bacteria. In E coli a series of enzymes function synergistically to protect cells from the deleterious effects of guanine oxidation. Analysis of the human homologue of mutY (MYH) showed that the affected siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These occur at sub-polymorphic frequency in the general population. Assays of glycosylase activity of the mutant proteins showed their activity was reduced significantly. This provided a link between inherited variants of MYH and the pattern of somatic APC mutation found in family N and implicated defective base excision repair in adenoma formation. Since the original report of family N, we have identified over 20 further families with multiple colorecta adenomas and biallelic germline MYH mutations, confirming the role of MYH in some families with colorectal polyposis. Conclusion: Germline mutations of the base excision repair gene MYH are a cause of multiple colorectal adenomas and... [ABSTRACT FROM AUTHOR]

Published
2003

42. TRUNCATING AND MISSENSE GERM LINE MUTATIONS IN MYH ARE A FREQUENT CAUSE OF A SPECIFIC MULTIPLE COLORECTAL ADENOMA PHENOTYPE.

Author

Sieber, O.M., Lipon, L., Jones, S., Heinimann, K., Barclay, E., Hodgson, S.V., Cheadle, J.P., Orntoft, T.F., Aaltonen, L.A., Sampson, J.R., Tomlinson, I.P.M., and Thomas, H.J.W.

Subjects
COLON cancer, HETEROZYGOSITY
Abstract

Background: Compound heterozygosity for missense variants of the base excision repair (BER) gene MYH has been linked to inheritance of multiple colorectal adenomas or carcinoma in a single UK family. Colorectal adenomas From affected individuals displayed an excess of somatic G:C→T:A transversions in the adenomatous polyposis coli (APC) gene, consistent with a BER defect. Methods: 157 unrelated UK patients with multiple (3 to 115) colorectal adenomas were screened for germ line mutations in MYH and subsets were screened for the related BER genes, MTH1 and OGG1. Adenomas from patients harbouring pathogenic MYH germ line mutations were tested for somatic APC mutations and loss of heterozygosity at MYH. Clinicopathological and molecular data were compared between patients with and without MYH mutations. Results: Fourteen (9%) patients harboured germ line MYH variants, with 8 (5%) having biallelic, pathogenic mutations. Both nonsense and protein truncating MYH mutations were found. Missense variants Y165C and G382D were the most frequent alterations observed. Patients with biallelic MYH mutations had more polyps than carriers of single mutations or MYH wild-type patients (medians, 55 v 3 v 7, respectively; p < 0.01). Four out of 28 (29%) patients with 15 to 115 adenomas had biallelic MYH mutations. All somatic APC mutations identified in such patients were the expected somatic G:C-→T:A transversions. No clearly pathogenic MTH1 or OGG1 germ line mutations were identified. Conclusions: The data provide strong evidence to show that individuals with two allelic MYH mutations are predisposed to a multiple adenoma phenotype. Progression to colorectal carcinoma occurs in some cases. [ABSTRACT FROM AUTHOR]

Published
2003

43. 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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